A Phase I/II, Open Label Study to Assess the Safety and Tolerability of VM202 in Subjects With Amyotrophic Lateral Sclerosis
Phase: PHASE1
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Helixmith Co., Ltd.

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 1 of 101 
 
 
 
A PHASE I/II, OPEN LABEL STUDY TO ASSESS THE SAFETY AND 
TOLERABILITY OF VM202 IN SUBJECTS WITH AMYOTROPHIC 
LATERAL SCLEROSIS 
 
 
 
Protocol VMALS-001 / B 
 
 
September 15, 2013 
 
Sponsor 
ViroMed Co., Ltd. 
 
 
 
 
 
Worldwide Headquarters: 
 
 
 
 
 
DISCLOSURE STATEMENT 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 2 of 101 
 
INVESTIGATOR’S AGREEMENT 
 
 
I, the undersigned, am responsible for the conduct of the study at the site below and agree to the 
following:   
 
 I understand that this protocol is a confidential document.  I agree that the information within 
it will not be disclosed to anyone without prior written authority from the sponsor, VM 
BioPharma, Inc. except to the extent necessary to conduct this study and obtain approval 
from an ethical review committee or other approving body.   
 I understand and will conduct the study according to the protocol, any approved protocol 
amendments, ICH GCP and all applicable regulatory authority requirements and national 
laws.   
 I will not deviate from the protocol without prior written permission from the Sponsor and 
prior review and written approval from the Institutional Review Board, except where 
necessary to prevent any immediate danger to the subject.   
 I have read and understand fully the Investigator Brochure.   
 I have sufficient time to properly conduct and complete the study within the agreed study 
period, and I have available an adequate number of qualified staff and adequate facilities for 
the foreseen duration of the study to conduct the study properly and safely.   
 I will ensure that any staff members at my site(s) who are involved in the study conduct are 
adequately trained regarding this trial‘s operations, the protocol and their responsibilities. In 
the case of delegating any of my study responsibilities I will provide the sponsor with a 
delegation of Investigators responsibilities log.   
 I understand that the study may be terminated or enrollment may be suspended at any time by 
VM BioPharma, Inc. with or without cause, or by me or my institution if it becomes 
necessary to protect the best interest of the study subjects.   
 
 
 
 
Principal Investigator‘s Name (print) 
 
 
 
Title 
 
 
 
Address 
 
 
 
Signature / Date 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 3 of 101 
STUDY SYNOPSIS 
 
PROTOCOL TITLE 
A Phase I/II, Open Label, Study to Assess the Safety and Tolerability 
of VM202 in Subjects with Amyotrophic Lateral Sclerosis 
STUDY PHASE 
I/II 
INVESTIGATIONAL 
AGENT 
VM202 
DOSE 
64 mg of VM202 
POPULATION 
Patients aged ≥ 21 years, but  75 years diagnosed with clinically 
definite, clinically probable, or clinically probable-laboratory supported 
Amyotrophic Lateral Sclerosis (ALS). 
STUDY DESIGN 
A phase I/II, open label, single center study designed to assess the 
safety and tolerability of intramuscular injections of VM202 in 
patients with ALS.  Study enrollment will be staged.  Enrollment will 
be halted after the sixth subject qualifies for treatment.  A Data Safety 
Monitoring Board (DSMB) will conduct a safety evaluation after the 
first patient treated completes the Day 60 follow-up evaluation and the 
five other sequentially enrolled subjects complete at least the Day 30 
follow-up.  Enrollment will be suspended until a formal 
recommendation to proceed (or not proceed) is made by the DSMB.   
NUMBER OF SUBJECTS 
18 
INCLUSION CRITERIA 
1. Age ≥ 21 years, but  75 years 
2. Subjects diagnosed with:  
 clinically definite ALS,  
 clinically probable ALS, or  
 clinically probable-laboratory supported ALS  
as specified in the revised El Escorial / Airlie House diagnostic 
criteria 
3. Onset of ALS < 2 years at Screening 
4. Forced Vital Capacity (FVC) ≥ 60% of predicted 
5. Revised Amyotrophic Lateral Sclerosis Functional Rating Scale 
(ALSFRS-R) ≥ 30 
6. Not taking riluzole, or on a stable dose for at least thirty days prior 
to Screening (defined as no noted toxicities) 
7. Able and willing to give informed consent 
8. If female of childbearing potential, negative urine pregnancy test 
at Screening and using acceptable method of birth control during 
the study. 
 
EXCLUSION CRITERIA 
1. Neurological symptom(s) due to vitamin B12 deficiency 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 4 of 101 
2. Requires tracheotomy ventilation or noninvasive ventilation  
> 16 hours / day 
3. Comorbidities such as Parkinson‘s disease, schizophrenia, renal 
failure, or any other severe complication that, in the Investigator‘s 
opinion, will compromise the safety of the patient or confound 
interpretation of the data collected in this study  
4. Other neuromuscular disease 
5. Inflammatory disorder of the blood vessels (inflammatory 
angiopathy, such as Buerger‘s disease) 
6. Active infection 
7. Chronic inflammatory disease (e.g., Crohn‘s disease, rheumatoid 
arthritis) 
8. Positive HIV or HTLV at Screening 
9. Active Hepatitis B or C as determined by Hepatitis B core 
antibody (HBcAb), antibody to Hepatitis B surface antigen (IgG 
and IgM; HBsAb), Hepatitis B surface antigen (HBsAg) and 
Hepatitis C antibodies (Anti-HCV) at Screening 
10. Subjects with known immunosuppression or currently receiving 
immunosuppressive drugs, chemotherapy or radiation therapy 
11. Stroke or myocardial infarction within last 3 months 
12. Patients with a recent history (< 5 years) of malignant neoplasm 
except basal cell carcinoma or squamous cell carcinoma of the 
skin (if excised and no evidence of recurrence); 
13. Subjects requiring > 81 mg daily of acetylsalicylic acid; subjects 
may be enrolled if willing/able to switch to ≤ 81 mg daily of 
acetylsalicylic acid or to another medication 
14. Subjects requiring regular COX-2 inhibitor drug(s) or non-specific 
COX-1/COX-2 inhibiting drugs, or high dose steroids (excepting 
inhaled steroids); subjects may be enrolled if willing/able to 
undergo medication wash-out prior to the first dosing and to 
refrain from taking these drugs for the duration of the study 
15. Have used an investigational drug within 30 days of Screening 
16. Pregnant or currently lactating 
17. Major psychiatric disorder in past 6 months 
18. Known drug or alcohol dependence or any other factors which will 
interfere with the study conduct or interpretation of the results or 
who in the opinion of the Investigator are not suitable to 
participate. 
 
 
SCREENING 
Screening will include assessment of study eligibility, a medical 
history, vital signs, physical exam, concomitant medications, 12 lead 
EKG, viral screening, FVC, ALSFRS-R, serum chemistry and 
hematology, and urine pregnancy test (for women of childbearing 
potential only).   
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 5 of 101 
PRE-INJECTION 
EVALUATIONS 
Prior to injections on Day 0, subjects will be assessed using the 
ALSFRS-R, the Medical Research Council (MRC) scale for muscle 
strength testing, dynamometry, FVC, and muscle circumference.  
These tests can be conducted one day before the scheduled injection 
visit.  Immediately before injection on Day 0, the following will be 
conducted: recording of concomitant medications, vital signs, and 
blood draw for serum chemistry and hematology, serum HGF and 
copies of VM202 in whole blood.  
INJECTIONS 
VM202 is delivered in 0.5 mL intramuscular injections of a solution 
of 0.5 mg VM202 / mL.  It will be administered over the course of 
four visits: Day 0, Day 7, Day 14, and Day 21.  As in all previous 
VM202 studies, final dose of VM202 for each target muscle group is 
divided and administered 2 weeks apart.  However, in order to reduce 
the injection burden on the ALS patient, injection of the upper limbs 
will be done on separate visits from injection of the lower limbs.  The 
first eligible subject will begin with the lower limb injection series 
and will be injected in accordance with the schedule outlined in Table 
1.  The next sequentially eligible patient will begin with injection of 
the upper limbs (see Table 2).  Subsequent eligible patients will be 
treated in an alternating fashion, such that 9 patients will have 
initiated their VM202 injections in the lower limbs and 9 patients will 
have initiated their VM202 injections in the upper limbs. Please note: 
Regardless of injection order, all subjects will receive the same final 
dose of VM202 and the same number of injections per muscle 
group.  
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 6 of 101 
 
 
Table 1. 
Group 1 Injection Schedule 
TARGET AREA 
DOSE VM202 (mg) / TARGET MUSCLE, 
(NUMBER OF INJECTIONS / MUSCLE GROUP / SIDE (R/L)) 
TOTAL DOSE 
(TOTAL 
NUMBER OF 
INJECTIONS 
(R + L)) 
DAY 0 
DAY 7 
DAY 14 
DAY 21 
Hand 
 
 
 
 
 
Abductor pollicis brevis 
(APB) 
 
1, (2/2) 
 
1, (2/2) 
2, (8) 
first dorsal interosseous 
(FDI) 
 
1, (2/2) 
 
1, (2/2) 
2, (8) 
Upper Arms 
 
 
 
 
 
Biceps 
 
4, (8/8) 
 
4, (8/8) 
8, (32) 
Deltoid  
 
4, (8/8) 
 
4, (8/8) 
8, (32) 
Lower Arms 
 
 
 
 
 
Extensor carpi radialis 
 
1, (2/2) 
 
1, (2/2) 
2, (8) 
Flexor carpi ulnaris 
 
1, (2/2) 
 
1, (2/2) 
2, (8) 
Flexor carpi radialis 
 
1, (2/2) 
 
1, (2/2) 
2, (8) 
Legs 
 
 
 
 
 
Quadriceps 
10, (20/20) 
 
10, (20/20) 
 
20, (80) 
Gastrocnemius 
6, (12/12) 
 
6, (12/12) 
 
12, (48) 
Tibialis anterior 
3, (6/6) 
 
3, (6/6) 
 
6, (24) 
Final Dose (# of injections 
(L + R)) 
19 (76) 
13 (52) 
19 (76) 
13 (52) 
64 (256) 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 7 of 101 
Table 2. 
Group 2 Injection Schedule 
TARGET AREA 
DOSE VM202 (mg) / TARGET MUSCLE, 
(NUMBER OF INJECTIONS / MUSCLE GROUP / SIDE (R/L)) 
TOTAL DOSE 
(TOTAL 
NUMBER OF 
INJECTIONS 
(R + L)) 
DAY 0 
DAY 7 
DAY 14 
DAY 21 
Hand 
 
 
 
 
 
abductor pollicis brevis 
(APB) 
1, (2/2) 
 
1, (2/2) 
 
2, (8) 
first dorsal interosseous 
(FDI) 
1, (2/2) 
 
1, (2/2) 
 
2, (8) 
Upper Arms 
 
 
 
 
 
Biceps 
4, (8/8) 
 
4, (8/8) 
 
8, (32) 
Deltoid 
4, (8/8) 
 
4, (8/8) 
 
8, (32) 
Lower Arms 
 
 
 
 
 
Extensor carpi radialis 
1, (2/2) 
 
1, (2/2) 
 
2, (8) 
Flexor carpi ulnaris 
1, (2/2) 
 
1, (2/2) 
 
2, (8) 
Flexor carpi radialis 
1, (2/2) 
 
1, (2/2) 
 
2, (8) 
Legs 
 
 
 
 
 
Quadriceps 
 
10, 
(20/20) 
 
10, (20/20) 
20, (80) 
Gastrocnemius 
 
6, (12/12) 
 
6, (12/12) 
12, (48) 
Tibialis anterior 
 
3, (6/6) 
 
3, (6/6) 
6, (24) 
Final Dose (# of injections 
(L + R)) 
13 (52) 
19 (76) 
13 (52) 
19 (76) 
64 (256) 
 
 
OTHER STUDY 
PROCEDURES / 
EVALUATIONS 
HGF serum levels will be determined immediately pre-treatment on 
Day 0, immediately pre-treatment on Day 7, immediately pre-
treatment on Day 14, immediately pre-treatment on Day 21, on Day 
30, Day 60 and Day 90.   
The number of copies of VM202 in whole blood will be determined at 
Day 0 (pre-injection, and 2 hours [± 1 hour] post last injection), at Day 
7 (pre-injection, and 2 hours [± 1 hour] post last injection), at Day 14 
(pre-injection, and 2 hours [± 1 hour] post last injection), at Day 21 
(pre-injection, and 2 hours [± 1 hour] post last injection), on Day 30, 
Day 60 and Day 90. 
ALSFRS-R, FVC and muscle strength (as determined by using the 
MRC scale) will be assessed at Day 30, Day 60, Day 90, at 6 months 
and 9 months.  Muscle circumference and dynamometry will be 
conducted on Day 60, Day 90, at 6 months, and 9 months.   
A Data Safety Monitoring Board (DSMB) will monitor patient safety 
throughout the study.   

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 8 of 101 
SCHEDULE OF 
EXAMINATIONS 
Screening (Day -30 to Day 0) 
Day 0 
Day 7 ± 1 days 
Day 14 ± 1 days 
Day 21 ± 1 days 
Day 30 ± 3 days 
Day 60 ± 3 days 
Day 90 ± 7 days 
Month 6 ± 1 month 
Month 9 ± 1 month 
Subjects will be followed up at 12, 18, 24, and 36 months (1 ± month) 
by phone to assess survival. 
STUDY ENDPOINTS 
The primary study endpoint is to evaluate safety and tolerability of 
intramuscular injections of VM202 at different injection sites in 
subjects with ALS.  Secondary endpoints include the assessment of the 
neuroprotective potential of VM202. 
SAFETY 
Adverse events (including serious adverse events, and adverse events 
leading to treatment discontinuation) throughout the 9 months follow-
up will be described according to severity and to their relationship 
with the study drug and injection procedure. Descriptive statistics will 
be used to characterize safety parameters. 
 
PHARMACOKINETICS & 
PHARMACODYNAMICS 
HGF serum levels will be determined immediately pre-treatment on 
Day 0, immediately pre-treatment on Day 7, immediately pre-
treatment on Day 14, immediately pre-treatment on Day 21, on Day 
30, Day 60 and Day 90.  The number of copies of VM202 in whole 
blood will be determined at Day 0 (pre-injection, and 2 hours [± 1 
hour] post injection), at Day 7 (pre-injection, and 2 hours [± 1 hour] 
post injection), at Day 14 (pre-injection, and 2 hours [± 1 hour] post 
injection), at Day 21 (pre-injection, and 2 hours [± 1 hour] post 
injection), on Day 30, Day 60 and Day 90. 
EFFICACY 
This study is not powered to detect differences in efficacy measures.  
However, descriptive statistics (N, mean, median, SD, minimum and 
maximum values, where applicable) of clinically meaningful 
endpoints will be tabulated.  Endpoints will include, but are not 
limited to the following:  
 ALSFRS-R scale 
 Muscle circumference 
 Forced vital capacity 
 Dynamometry (finger pinch, grip strength and extension of lower 
leg) 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 9 of 101 
 Muscle strength as evaluated by the MRC scale – scoring only of 
the subset of muscles specifically injected in this study. 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 10 of 101 
 
TABLE OF CONTENTS 
 
 
INVESTIGATOR‘S AGREEMENT ......................................................................................................... 2 
STUDY SYNOPSIS ............................................................................................................................. 3 
TABLE OF CONTENTS ..................................................................................................................... 10 
ABBREVIATIONS ............................................................................................................................ 14 
PERSONNEL AND FACILITIES .......................................................................................................... 15 
1. 
AMYOTROPHIC LATERAL SCLEROSIS .....................................................................................16 
1.1. 
Pathophysiology .....................................................................................................16 
1.2. 
Current Treatment Options ....................................................................................18 
1.3. 
Unmet Clinical Need..............................................................................................18 
1.4. 
HGF for the Treatment of Amyotrophic Lateral Sclerosis ....................................18 
1.5. 
VM202 ...................................................................................................................20 
1.6. 
Preclinical Data ......................................................................................................21 
1.7. 
Clinical Data ..........................................................................................................21 
1.7.1. 
Phase I study in Critical Limb Ischemia ..................................................21 
1.7.2. 
Phase II study in Critical Limb Ischemia .................................................22 
1.7.3. 
Phase I/II Study in patients with Painful DPN .........................................23 
1.7.4. 
Phase II Study in patients with Painful DPN ...........................................24 
1.8. 
Study and Dose Rationale ......................................................................................25 
2. 
GOOD CLINICAL PRACTICES (GCP) STATEMENT ...................................................................25 
3. 
INVESTIGATIONAL PLAN ........................................................................................................25 
3.1. 
Study Objectives ....................................................................................................25 
3.2. 
Study Design ..........................................................................................................26 
3.3. 
Subject Population .................................................................................................28 
3.3.1. 
Inclusion Criteria ......................................................................................29 
3.3.2. 
Exclusion Criteria .....................................................................................29 
3.4. 
Study Procedures ...................................................................................................30 
3.4.1. 
Informed Consent .....................................................................................30 
3.4.2. 
Subject Identification ...............................................................................30 
3.4.3. 
Screening (Day -30 to Day 0) ...................................................................31 
3.4.4. 
Prohibited Concomitant Medications .......................................................31 
3.4.4.1. 
Medication that may interfere with VM202 bioactivity ..........31 
3.4.4.2. 
Screen Failures .........................................................................31 
3.4.5. 
Treatment Authorization ..........................................................................31 
3.4.6. 
Day 0 – 1st Injection Visit .........................................................................32 
3.4.6.1. 
Pre-Injection (≤ 24 hrs of injections) .......................................32 
3.4.6.2. 
Pre-Injection (≤ 4 hrs of injections) .........................................32 
3.4.6.3. 
1st Dose of VM202 ...................................................................32 
3.4.6.4. 
Post-Injection (1-3 hrs Post Last Injection) .............................32 
3.4.7. 
Day 7 ± 1 Day – 2nd Injection Visit ..........................................................33 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 11 of 101 
3.4.7.1. 
Pre-Injection (≤ 4 hrs of injections) .........................................33 
3.4.7.2. 
2nd Dose of VM202 ..................................................................33 
3.4.7.3. 
Post-Injection (1-3 hrs Post Last Injection) .............................33 
3.4.8. 
Day 14 ± 1 Day – 3rd Injection Visit ........................................................34 
3.4.8.1. 
Pre-Injection (≤ 4 hrs of injections) .........................................34 
3.4.8.2. 
3rd Dose of VM202 ..................................................................34 
3.4.8.3. 
Post-Injection (1-3 hrs Post Last Injection) .............................34 
3.4.9. 
Day 21 ± 1 Day – 4th Injection Visit ........................................................34 
3.4.9.1. 
Pre-Injection (≤ 4 hrs of injections) .........................................34 
3.4.9.2. 
4th Dose of VM202 ..................................................................35 
3.4.9.3. 
Post-Injection (1-3 hrs Post Last Injection) .............................35 
3.4.10. Day 30 ± 3 Days .......................................................................................35 
3.4.11. Day 60 ± 3 Days .......................................................................................36 
3.4.12. Day 90 ± 7 Days .......................................................................................36 
3.4.13. 6 months ± 1 month ..................................................................................36 
3.4.14. 9 months ± 1 month ..................................................................................36 
3.4.15. Months 12, 18, 24, 36 ± 1 month .............................................................37 
3.5. 
Study Completion ..................................................................................................37 
3.5.1. 
Completed Subjects ..................................................................................37 
3.5.2. 
Discontinued Subjects ..............................................................................37 
3.5.3. 
Premature Study Termination ..................................................................38 
3.6. 
Investigational Drug Product and Accountability..................................................38 
3.6.1. 
Investigational Drug Product ....................................................................38 
3.6.2. 
Product Accountability .............................................................................39 
3.6.3. 
Dose and Administration ..........................................................................39 
3.7. 
Prior and Concomitant Medication ........................................................................39 
4. 
EXAMINATIONS AND EVALUATIONS ......................................................................................40 
4.1. 
Evaluations Conducted at Baseline Only ...............................................................40 
4.1.1. 
Medical History ........................................................................................40 
4.1.2. 
Physical Exam ..........................................................................................40 
4.1.3. 
Viral Screening .........................................................................................40 
4.1.4. 
12-Lead EKG ...........................................................................................40 
4.1.5. 
Pregnancy Test (women of childbearing potential only) .........................40 
4.2. 
Evaluations Conducted Throughout the Study ......................................................41 
4.2.1. 
Concomitant Medications .........................................................................41 
4.2.2. 
Vital Signs ................................................................................................41 
4.2.3. 
Serum Chemistry and Hematology ..........................................................41 
4.2.4. 
Serum HGF ...............................................................................................41 
4.2.5. 
Copies of VM202 in Whole Blood ...........................................................42 
4.2.6. 
Forced Vital Capacity ...............................................................................42 
4.2.7. 
revised Amyotrophic Lateral Sclerosis Functional Rating Scale 
(ALSFRS-R) .............................................................................................42 
4.2.8. 
Medical Research Council (MRC) Scale for Muscle Strength Testing ...43 
4.2.9. 
Muscle Circumference .............................................................................43 
4.2.10. Dynamometry ...........................................................................................43 
4.2.11. Injection Site Reaction Assessment .........................................................44 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 12 of 101 
5. 
EVALUATION OF ADVERSE EVENTS .......................................................................................44 
5.1. 
Definitions..............................................................................................................44 
5.2. 
Assessment of AEs ................................................................................................45 
5.2.1. 
AE Causality .............................................................................................46 
5.2.2. 
AE Intensity ..............................................................................................46 
5.3. 
Reporting/Recording of AEs..................................................................................46 
5.4. 
Reporting / Recording of SAEs .............................................................................47 
5.4.1. 
Investigator‘s Responsibility ....................................................................47 
5.4.2. 
Sponsor‘s Responsibility ..........................................................................47 
6. 
STATISTICAL METHODS .........................................................................................................48 
6.1. 
Patient Categorization ............................................................................................48 
6.2. 
Study Endpoints .....................................................................................................48 
6.2.1. 
Safety ........................................................................................................49 
6.2.2. 
Pharmacokinetics & Pharmacodynamics .................................................49 
6.2.3. 
Efficacy ....................................................................................................49 
7. 
ACCESS TO STUDY DOCUMENTS AND STUDY MONITORING...................................................49 
8. 
QUALITY CONTROL AND ASSURANCE....................................................................................50 
9. 
INSTITUTIONAL REVIEW BOARD (IRB) ..................................................................................50 
10. 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) .....................................................................51 
11. 
INFORMED CONSENT PROCESS ...............................................................................................51 
12. 
CONFIDENTIALITY .................................................................................................................52 
13. 
PROTOCOL AMENDMENTS .....................................................................................................52 
14. 
DATA MANAGEMENT .............................................................................................................52 
15. 
RECORD KEEPING AND RETENTION .......................................................................................53 
16. 
INVESTIGATOR FINAL REPORT ...............................................................................................54 
17. 
STUDY REPORT AND PUBLICATION ........................................................................................54 
18. 
REFERENCES ..........................................................................................................................55 
 
 
FIGURES &TABLES 
 
Figure 1. 
Molecular mechanisms of motor neuron injury in ALS ................................. 17 
Figure 2. 
Molecular mechanisms of the neuroprotective effects of HGF ...................... 19 
Figure 3. 
VM202 construct ............................................................................................ 20 
Figure 4. 
Sample injection sites for upper limb injection visits ..................................... 86 
Figure 5. 
Sample injection sites for lower limb injection visits ..................................... 87 
 
Table 1. 
Group 1 Injection Schedule .............................................................................. 6 
Table 2. 
Group 2 Injection Schedule .............................................................................. 7 
Table 3. 
Group 1 Injection Schedule ............................................................................ 27 
Table 4. 
Group 2 Injection Schedule ............................................................................ 27 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 13 of 101 
Table 5. 
Single dose preparation and delivery for Day 0, Day 7, Day 14, and Day 21 
Visits ............................................................................................................... 83 
Table 6. 
Group 1 Injection Schedule ............................................................................ 84 
Table 7. 
Group 2 Injection Schedule ............................................................................ 85 
 
 
TABLE OF APPENDICES 
 
Appendix 1. 
Schedule of Evaluations and Visits & Laboratory Tests by Visit .................. 60 
Appendix 2. 
Sample Informed Consent............................................................................... 63 
Appendix 3. 
Medications Excluded from Use During the Study ........................................ 80 
Appendix 4. 
Test Article Administration ............................................................................ 82 
Appendix 5. 
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)
......................................................................................................................... 88 
Appendix 6. 
Medical Research Council (MRC) Scale for Muscle Strength Testing .......... 90 
Appendix 7. 
Measuring Muscle Circumference .................................................................. 96 
Appendix 8. 
Dynamometry ................................................................................................. 99 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 14 of 101 
ABBREVIATIONS 
 
AE / SAE 
Adverse Event / Serious Adverse Event 
ALS 
Amyotrophic Lateral Sclerosis 
ALT 
Alanine Transaminase (SGPT) 
ALSFRS-R 
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale 
Anti-HCV 
Hepatitis C antibodies 
AST 
Aspartate Transaminase (SGOT) 
cDNA 
Complementary Deoxyribonucleic Acid 
CFR 
Code of Federal Regulation 
CLI 
Critical Limb Ischemia 
cm 
Centimeter(s) 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
Cu/Zn 
Copper/Zinc 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EAAT2 
Excitatory amino acid transporter 2 
EKG 
Electrocardiogram 
ER 
Endoplasmic Reticulum 
FDA 
Food and Drug Administration 
GDNF 
Glial cell line-derived neurotrophic factor 
HBV 
Hepatitis B Virus 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Antibody to Hepatitis B surface antigen (IgG and IgM) 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C Virus 
HGF 
Hepatocyte Growth Factor 
HIV 
Human Immunodeficiency Virus 
HTLV 
Anti-Human T-Cell Lymphotropic Virus 
IND 
Investigational New Drug 
LLOQ 
Lower limit of quantitation 
MCP-1 
Monocyte chemoattractant protein 1 
NGF 
Nerve growth factor 
NMDA 
N-Methyl-D-aspartate 
NO 
Nitric Oxide 
PGE2 
Prostaglandin E2 
RNA 
Ribonucleic Acid 
ROS 
Reactive oxygen species 
SBP 
Systolic Blood Pressure 
SGPT 
Serum Glutamic Pyruvic Transaminase (same as ALT) 
TAF 
Treatment Authorization Form 
TNF 
Tumor necrosis factor 
SOP  
Standard Operating Procedure 
VEGF 
Vascular endothelial growth factor 
WBC 
White Blood Cell Count 
WFI 
Water for Injection 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 15 of 101 
 
PERSONNEL AND FACILITIES 
 
 
STUDY SPONSOR 
ViroMed Co., Ltd dba VM BioPharma 
 
 
 
MEDICAL MONITOR 
 
  
  
 
 
 
 
 
 
 
INVESTIGATORS 
John A. Kessler, M.D. 
Chairman, Davee Department of Neurology, Davee Professor of 
Stem Cell Biology, Director, Feinberg Clinical Neuroscience 
Institute, Director, Northwestern University Stem Cell Institute 
303 East Chicago Avenue 
Chicago, Illinois 60611-3008 
 
 
CRO 
 
 
 
 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 16 of 101 
1. 
AMYOTROPHIC LATERAL SCLEROSIS 
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset neurodegenerative disorder 
characterized by the loss of upper and lower motor neurons.  The disease is diverse in its 
presentation, cause, and progression, but, in general, ALS presents clinically as asymmetric 
muscle weakness, wasting, spasticity, weight loss, and paralysis.  Pathologically, ALS is 
characterized by progressive degeneration and loss of motor neurons in the spinal cord, 
brainstem, and cerebral cortex.  Death usually occurs within 2–5 years of symptoms onset, 
most commonly due to respiratory failure.  While the majority of ALS cases are sporadic 
(primary or idiopathic), about 5 – 10% of patients have a positive family history (familial 
ALS),1,2 with a mutation in the Cu/Zn superoxide dismutase 1 (SOD1) gene accounting for 
10% of familial ALS.3 
 
The incidence of ALS is 1-2 per 100,000 people.  It is estimated that as many as 30,000 
Americans may have the disease at any given time, but less than 6,000 are diagnosed 
annually.  There is no effective treatment for ALS.  The only drug currently approved by 
FDA for the treatment of this disease is a glutamate release inhibitor (Rilutek, generic: 
riluzole), which also interferes with N-methyl-D-aspartate (NMDA) receptor mediated 
events.  Its effect is both minimal and controversial.4 
 
 
1.1. 
PATHOPHYSIOLOGY 
Multiple mechanisms for the selective vulnerability, degeneration and early dying-
back axonopathy of motor neurons have been proposed and investigated.  They 
include: protein misfolding, mitochondrial dysfunction, oxidative damage, defective 
axonal transport, excitotoxicity, insufficient growth factor signaling, and 
inflammation.5-10  Toxicity results from a combination of damage incurred directly 
within motor neurons and through damage incurred by nonneuronal neighbors, 
including astrocytes and microglia, whose actions amplify the initial damage and 
drive disease progression and spread.  Microglia activate an inflammatory cascade 
via secretion of monocyte chemoattractant protein 1 (MCP-1) and other cytokines.  
Astrocytes contribute to neuron injury by releasing inflammatory mediators such as 
nitric oxide (NO) and PGE2, reduced lactate release, activation of pro-NGF-p75 
(nerve growth factor) receptor signaling and reduced activity of the glutamate 
reuptake transporter excitatory amino acid transporter 2 (EAAT2).  Motor neurons 
might also undergo transcriptional dysregulation and abnormal RNA processing 
which, together with overproduction of reactive oxygen species (ROS), contribute to 
aberrant protein folding.  Aberrant proteins can form aggregates, leading to 
proteasome impairment and endoplasmic reticulum (ER) stress.  The resulting 
mitochondrial impairment and dysregulation of calcium handling trigger autophagy 
and the apoptotic cascade. 11,12  The process is ‗contagious‘ and self-perpetuating, 
affecting the dynamics of cell death in neighboring cells due to release of 
interleukin-1, TNF-, and free radicals.13  Figure 1 depicts the molecular processes 
involved in motor neuron injury in ALS. 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 17 of 101 
Figure 1. Molecular mechanisms of motor neuron injury in ALS 
from: Ferraiuolo, L., J. Kirby, et al. (2011)12  
 
The caspase family.  Regardless of the underlying metabolic pathway to 
degeneration, the end result in ALS is motor neuron death.  The major executioners 
in the apoptotic process are proteases known as caspases (cysteine-dependent, 
aspartate-specific proteases).  Caspases directly and indirectly orchestrate the 
morphologic changes of the cell during apoptosis.  They exist as latent precursors, 
which, when activated, initiate the death program by destroying key components of 
the cellular infrastructure and activating factors that mediate damage to the cells.   
 
The first evidence of the role of caspases in a neurodegenerative disease came from 
experiments in which the ―ALS mouse‖ (SODG93A) was cross-bred with a mouse 
expressing a mutant caspase 1 gene that inhibited caspase 1 in neurons.  Mice 
expressing the mutant SOD1 transgene and the mutant caspase 1 transgene survived 
9% longer, and disease progression was slowed by more than 50 percent.14 Caspase 
inhibition in the same model was found to be neuroprotective and extended survival 
by 22%.15   
 
The clinical relevance of these studies is supported by findings in ALS patients.  
Early activation of caspase-1 in ALS contributes significantly to toxicity.16  However, 
neuronal death only occurs following upregulation and concomitant expression of 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 18 of 101 
caspase-3.17,18  A therapy that could block the upregulation of caspases could 
potentially improve survival and quality of life of ALS patients. 
 
 
1.2. 
CURRENT TREATMENT OPTIONS 
Rilutek, (originally manufactured by Sanofi Aventis and approved as an orphan drug 
on December 12, 1995 (NDA 020599)), is now off-patent and available in the 
generic form of riluzole.  Rilutek was approved on the basis of two controlled trials 
in which the time to tracheostomy or death was longer for patients randomized to 
Rilutek than for those randomized to placebo.  These studies admitted patients with 
either familial or sporadic ALS, disease duration of less than 5 years, and a baseline 
forced vital capacity greater than or equal to 60%.  In one study, performed in 
France and Belgium, 155 ALS patients were followed for at least 13 months 
(maximum duration 18 months) after being randomized to either 100 mg/day (given 
50 mg BID) of Rilutek or placebo.  The second study was conducted in both Europe 
and North America.  959 ALS patients were followed for at least 1 year (North 
American centers) and up to 18 months (European centers) after being randomized 
to either 50, 100, 200 mg/day of Rilutek or placebo.  The studies concluded that 
Rilutek extends early survival and / or time to tracheostomy, but there was no 
statistically significant difference in mortality at the end of the studies. 
 
 
1.3. 
UNMET CLINICAL NEED 
Riluzole does not prevent or correct the underlying causes of ALS.  It has not been 
shown to improve muscle strength or neurological function.  Clearly, a therapy that 
could impede or reverse neurodegeneration is needed for patients with ALS. 
 
 
1.4. 
HGF FOR THE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS 
Hepatocyte growth factor (HGF) is a multi-functional mesenchyme-derived cytokine.  
It is a recognized potent angiogenic growth factor and anti-apoptosis agent, 
stimulating the growth of endothelial cells and the migration of vascular smooth 
muscle cells.19-22  HGF stimulates DNA, RNA and protein synthesis by endothelial 
cells in a dose-dependent manner, upregulates vascular endothelial growth factor 
(VEGF) expression, and exhibits greater mitogenic activity than that of VEGF alone 
in human aortic endothelial cells in vitro.21,23-25   
 
Although largely thought of as an angiogenic agent, HGF has been recently 
identified as a neurotrophic factor.26-32  HGF and its cognate receptor (the c-Met 
receptor) are expressed in the peripheral nervous system as well as in various regions 
of the brain and spinal cord.  W. Sun, et al. (2002) found that local sustained HGF 
production in neural tissue in SODG93A mice (transgenic ALS model) alleviated the 
symptoms of ALS by direct neurotrophic activities on motor neurons and indirect 
activities on glial cells.33  It suppresses microgliosis and astrocytosis, which 
contribute to motor neuron degeneration by producing cytotoxic cytokines and 
eventual glial scar formation.33-36    

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 19 of 101 
 
Early in the disease, surviving nerve fibers establish connections and reinnervate 
motor units (muscle groups) that have lost their connection to axons that have died.  
As a result, larger motor units are formed.  HGF may be able to slow disease 
progress by facilitating reinnervation.  It has been demonstrated that HGF can 
promote neurogenesis, angiogenesis, and synaptogenesis and that it can inhibit 
fibrotic changes in ischemic regions better than glial cell line-derived neurotrophic 
factor (GDNF).37   
 
HGF may also have protective effects against excitotoxic injuries, because it has 
been shown to attenuate axonal degeneration by reducing over-excitation 
(excitotoxicity) through modulation of the expression of the scaffolding protein of 
the NMDA receptor at the synapse.38   
 
Finally, HGF may stave off cell death and halt the cascade of neighboring cell 
damage by inhibiting caspase signaling.38,39  In ALS patients, chronic, sublethal 
activation of caspase appears to mediate cell dysfunction, which precedes cell 
death.15,16  Cell dysfunction of substantial magnitude, occurring before cell death, 
might result in symptomatic disease.  Given that caspases may be active in 
individual neurons for a long period (potentially weeks to months), inhibition of 
caspase in these circumstances could reduce cell dysfunction and delay cell death.40  
Figure 2 depicts the action of HGF on motor neurons.  HGF binds to c-Met on cell 
surface and induces autophosphorylation of the intracellular tyrosine residues of c-
Met.  Subsequently, HGF inhibits caspase-1 activation, induces XIAP and inhibits its 
downstream caspases, caspase-3, -7 and -9, thereby effectively dampening caspase-
dependent cascades. Therefore, the neurotrophic action of HGF on motor neurons is, 
at least in part, promoted by preventing caspase-mediated cell death signals. 
 
 
Figure 2. Molecular mechanisms of the neuroprotective effects of HGF 
from: Kadoyama, K., H. Funakoshi, et al. (2007)36 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 20 of 101 
 
The challenge associated with delivering a targeted sustained dose of exogenous 
HGF is in overcoming the instability of HGF in blood circulation and its rapid 
clearance by the liver; HGF has an in vivo half-life of less than 15 minutes.41,42  
 
One approach to increasing HGF available to neurons is to develop a gene transfer 
strategy that would allow for persistent expression of HGF protein in vivo.  Although 
plasmid DNA is one of the least efficient gene transfer systems currently in use, the 
fact that it is associated with limited persistence and no propensity for genomic 
integration, (particularly in skeletal muscle tissue) makes it an attractive option for 
local targeted delivery. 
 
 
1.5. 
VM202 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Safety of VM202.  The use of plasmids for targeted delivery of angiogenic factors 
into muscle tissue is a particularly attractive and a relatively safe therapeutic 
approach, because plasmids have been shown to effectively transfect postmitotic 
cells such as skeletal and heart muscle and to successfully express angiogenic genes 
with very little dissemination and persistence at distant sites.  Following 
intramuscular injection, the plasmid that persists is extrachromosomal and 
integration into host DNA, if it occurs, is negligible.43-45  This local effect of 
conventionally injected naked plasmid DNA is well known.46,47   

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 21 of 101 
 
Potential Efficacy of VM202.  VM202 has demonstrated potential for stimulating 
angiogenesis in animal models.  Its ability to transfect skeletal muscle and produce 
HGF locally at the site of injection may help support nerve health, regeneration and 
to forestall motor neuron die-off.  
 
 
1.6. 
PRECLINICAL DATA 
The non-clinical safety of VM202 has been evaluated for general toxicity following 
single intramuscular and intravenous doses in rats.  In addition, the general toxicity 
of VM202 following multiple intermittent (weekly or monthly) intramuscular doses 
has been evaluated in rabbits and rats, respectively.  The potential for genomic 
integration at the injection site as well as the potential for distribution to and 
persistence of VM202 in reproductive tissues was evaluated in rats. The ability of 
VM202 to induce humoral immune responses was evaluated following intramuscular 
administration with or without adjuvant in mice.  All species utilized for these 
studies (mouse, rat, and rabbit) were shown in in vivo experiments to be able to 
express the plasmid following intramuscular injection.  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
Therefore, the nonclinical efficacy and safety studies support the clinical 
investigation of VM202 in subjects with amyotrophic lateral sclerosis.  
 
 
1.7. 
CLINICAL DATA 
VM202 was/is being evaluated in four clinical trials.  
 
1.7.1. 
PHASE I STUDY IN CRITICAL LIMB ISCHEMIA 
 
 
  

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 22 of 101 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
Median ABI and TBI significantly increased from 0.35 to 0.52 (P=0.005) and 0.15 
to 0.24 (P=0.01) at 12 months follow-up.  TCPO2 showed an improvement trend 
(increase).  A significant reduction in pain was reported by nine of eleven subjects, 
with median VAS decreasing from 58 to 16 (P=0.03) at 6 months follow-up. VAS 
score reduction tracked well with the hemodynamic data.   
 
In general, there was more improvement over baseline in Cohort II (4 mg VM202) 
than in any other cohort.  Cohort I (2 mg of VM202) also experienced a significant 
reduction in pain and modest improvement in hemodynamic measurement.  
Interestingly, 2 subjects in each of these cohorts had diabetes, possibly suggesting 
some benefit of VM202 in this subpopulation.  Doses of aspirin above 81 mg daily 
may have an inhibitory effect on the therapeutic activity of VM202.  Results from 
this study have been published in Gene Therapy in 2011.48 
 
1.7.2. 
PHASE II STUDY IN CRITICAL LIMB ISCHEMIA 
 
 
 
 
 
 
   
 
 
 
  
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 23 of 101 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
1.7.3. 
PHASE I/II STUDY IN PATIENTS WITH PAINFUL DPN 
 
 
 
 
  
 
  
 
 
   
 
 
 
 
   
 
 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 24 of 101 
 
   
 
 
 
 
   
  
 
 
 
 
 
 
1.7.4. 
PHASE II STUDY IN PATIENTS WITH PAINFUL DPN 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Preliminary Conclusions.  These early data support the feasibility and safety of 
intramuscular injections of VM202 in subjects with critical limb ischemia and DPN.  
Results suggest that this therapeutic approach may improve functional outcomes and 
provide symptomatic relief.  VM202 is rapidly eliminated from circulation, and 
appears to remain active only at the injection site.  Considering the potential benefit 
of targeted delivery of HGF to motor neurons in patients with ALS, study of VM202 
in this population is warranted. 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 25 of 101 
 
 
1.8. 
STUDY AND DOSE RATIONALE  
The natural history of ALS is characterized by unremitting deterioration of 
neuromotor function.  Deterioration rates and patterns vary, with death occurring as 
rapidly as 1–2 years, but more commonly, within 3-5 years of initial diagnosis.  For 
the majority of patients, symptoms begin with limb involvement.  Symptoms may 
first manifest in the upper or lower limbs first, but regardless of the order in which 
muscle wasting occurs, the disease is progressive, self-perpetuating, and ultimately 
results in significant atrophy and weakness in all limbs.  We therefore propose 
treating both upper and lower limbs.   
 
The proposed final (cumulative) dose to be administered to each subject is 64 mg 
VM202.  A dosing schedule similar to the one used in the phase I and the phase II 
DPN studies will be used in this study.  Namely, intramuscular injections for each 
target muscle group will be divided into two injection visits, (equal halves), two 
weeks apart.  As in all four prior studies, VM202 will be delivered in a solution of 
0.5 mg VM202 / mL.  The proposed dose is well within that supported by the body 
of pharmacology and toxicology safety studies of VM202.  Safety studies in rabbit, 
rat and mouse models demonstrate that doses of up to approximately 12.8 times the 
cumulative clinical dose proposed in this study are safe and resulted in no toxicities.  
The dose to each muscle group (VM202 is only active once transfected into skeletal 
muscle cells) falls within the doses given in the four other clinical studies.  The 
excellent safety profile of VM202 seen thus far in the phase I and phase II CLI 
studies, the phase I/II study in patients with DPN, and from the ongoing phase II 
DPN study supports this dosing scheme. 
 
 
 
 
2. 
GOOD CLINICAL PRACTICES (GCP) STATEMENT 
This trial will be conducted in compliance with all applicable federal regulations pertaining 
to investigational drugs and devices including but not limited to: 21 CFR Part 50, Part 54, 
Part 56, Part 312, and GCP standards.  This trial will be conducted in compliance with the 
protocol as approved by the Institutional Review Board (IRB) and the Institutional 
Biosafety Committee (IBC) at the study site.  Any deviations from the protocol that may 
affect the safety and welfare of study participants will be immediately reported to the 
Sponsor and to the IRB and IBC per the institution‘s guidelines. 
 
 
 
3. 
INVESTIGATIONAL PLAN 
 
3.1. 
STUDY OBJECTIVES 
The objective of this Phase I/II study is to evaluate the safety and tolerability of IM 
administration of VM202 at different injection sites in subjects with ALS. 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 26 of 101 
 
 
3.2. 
STUDY DESIGN 
This is a phase I/II, open label, single center study designed to assess the safety and 
tolerability of intramuscular injections of VM202 in patients with ALS.  Subjects 
with ALS will be screened for study eligibility after giving informed consent.   
 
Screening. Using the revised El Escorial / Airlie House diagnostic criteria and 
medical history, subjects will be confirmed as having ALS < 2 years.  If applicable, 
the subject will be washed out of prohibited medication (see section 3.4.4).  During 
medication wash-out, screening procedures consisting of assessment of study 
eligibility, a medical history, vital signs, physical exam, concomitant medications, 
ALSFRS-R, viral screening, 12 lead EKG, FVC, serum chemistry and hematology, 
and (urine) pregnancy test (for women of childbearing potential only) will be 
performed. 
 
All screening assessments should occur within the 30 days prior to Day 0 (day of 
first injections). 
 
Injection.  Prior to injections on Day 0, subjects will be assessed using the ALSFRS-
R, the Medical Research Council (MRC) scale for muscle strength testing, 
dynamometry, FVC, and muscle circumference.  These tests can be conducted one 
day before the scheduled injection visit.  Immediately before injection on Day 0, the 
following will be conducted: recording of concomitant medications, vital signs, and 
blood draw for serum chemistry and hematology, serum HGF and copies of VM202 
in whole blood. 
 
VM202 will be delivered in 0.5 mL intramuscular injections of a solution of 0.5 mg 
VM202 / mL.  It will be administered over the course of four visits: Day 0, Day 7, 
Day 14, and Day 21.  As in all previous VM202 studies, final dose of VM202 for 
each target muscle group is divided and administered 2 weeks apart.  However, in 
order to reduce the injection burden on the ALS patient, injection of the upper limbs 
will be done on separate visits from injection of the lower limbs.  The first eligible 
subject will begin with the lower limb injection series and will be injected in 
accordance with the schedule outlined in Table 3.  The next sequentially eligible 
patient will begin with injection of the upper limbs (see Table 4).  Subsequent 
eligible patients will be treated in an alternating fashion, such that 9 patients will 
have initiated their VM202 injections in the lower limbs and 9 patients will have 
initiated their VM202 injections in the upper limbs. Please note: Regardless of 
injection order, all subjects will receive the same final dose of VM202 and the 
same number of injections per muscle group.  
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 28 of 101 
 
 
 
   
 
 
 
-
 
 
 
Serum chemistry and hematology will be determined on Day 0, Day 30, Day 90 and 
9 months. 
 
FVC, ALSFRS-R, and muscle strength (MRC scale) will be assessed at Day 0, Day 
30, Day 60, Day 90, at 6 months and 9 months.  Muscle circumference and 
dynamometry will be ascertained on Day 0, Day 60, Day 90, at 6 months, and 9 
months.   
 
Concomitant medications and vital signs will be recorded throughout the 9 month 
follow-up period.  Adverse events will be assessed starting on Day 0 throughout the 
9 month follow-up period, and injection site reactions will be assessed starting on 
Day 0 through Day 60.  Study enrollment will be staged.  Enrollment will be halted 
after the sixth subject qualifies for treatment.  A Data Safety Monitoring Board 
(DSMB) will conduct a safety evaluation after the first patient treated completes the 
Day 60 follow-up evaluation and the five other sequentially enrolled subjects 
complete at least the Day 30 follow-up.  Enrollment will be suspended until a formal 
recommendation to proceed (or not proceed) is made by the DSMB.   
 
The study will be suspended pending DSMB review if any of the following SAEs 
are attributed to VM202 injections during any time during the study: 
 
 
acute anaphylaxis (including erythema, hives, wheezing, stridor or respiratory 
distress);  
 
temperature >102ºF with negative blood cultures within 24 hours of study drug 
administration; or 
 
evidence of active tissue necrosis at the injection site within two weeks of study 
drug administration. 
 
A summary of the schedule of evaluations and study visits can be found in Appendix 
1. 
 
 
3.3. 
SUBJECT POPULATION 
Eighteen (18) evaluable subjects with ALS meeting the following study entry criteria 
will be enrolled.  

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 29 of 101 
 
3.3.1. 
INCLUSION CRITERIA 
Subjects must satisfy all of the following criteria to be included in the study: 
 
1. 
Age ≥ 21 years, but  75 years 
2. 
Subjects diagnosed with:  
 clinically definite ALS,  
 clinically probable ALS, or  
 clinically probable-laboratory supported ALS;  
as specified in the revised El Escorial / Airlie House diagnostic criteria 
3. 
Onset of ALS < 2 years at Screening; 
4. 
Forced Vital Capacity (FVC) ≥ 60% of predicted; 
5. 
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) ≥ 
30; 
6. 
Not taking riluzole, or on a stable dose for at least thirty days prior to Screening 
(defined as no noted toxicities); 
7. 
Able and willing to give informed consent; 
8. 
If female of childbearing potential, negative urine pregnancy test at Screening 
and using acceptable method of birth control during the study. 
 
3.3.2. 
EXCLUSION CRITERIA 
Subjects will not be eligible for the study if any of the following criteria are present: 
 
1. 
Neurological symptom(s) due to vitamin B12 deficiency; 
2. 
Requires tracheotomy ventilation or noninvasive ventilation > 16 hours / day; 
3. 
Comorbidities such as Parkinson‘s disease, schizophrenia, renal failure, or any 
other severe complication that, in the Investigator‘s opinion, will compromise 
the safety of the patient or confound interpretation of the data collected in this 
study;  
4. 
Other neuromuscular disease; 
5. 
Inflammatory disorder of the blood vessels (inflammatory angiopathy, such as 
Buerger‘s disease); 
6. 
Active infection; 
7. 
Chronic inflammatory disease (e.g., Crohn‘s disease, rheumatoid arthritis); 
8. 
Positive HIV or HTLV at Screening; 
9. 
Active Hepatitis B or C as determined by Hepatitis B core antibody (HBcAb), 
antibody to Hepatitis B surface antigen (IgG and IgM; HBsAb), Hepatitis B 
surface antigen (HBsAg) and Hepatitis C antibodies (Anti-HCV) at Screening; 
10. Subjects with known immunosuppression or currently receiving 
immunosuppressive drugs, chemotherapy or radiation therapy; 
11. Stroke or myocardial infarction within last 3 months; 
12. Patients with a recent history (< 5 years) of malignant neoplasm except basal 
cell carcinoma or squamous cell carcinoma of the skin (if excised and no 
evidence of recurrence); 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 30 of 101 
13. Subjects requiring > 81 mg daily of acetylsalicylic acid; subjects may be 
enrolled if willing/able to switch to ≤ 81 mg daily of acetylsalicylic acid or to 
another medication; 
14. Subjects requiring regular COX-2 inhibitor drug(s) or non-specific COX-
1/COX-2 inhibiting drugs, or high dose steroids (excepting inhaled steroids); 
subjects may be enrolled if willing/able to undergo medication wash-out prior to 
the first dosing and to refrain from taking these drugs for the duration of the 
study; 
15. Have used an investigational drug within 30 days of Screening; 
16. Pregnant or currently lactating; 
17. Major psychiatric disorder in past 6 months; 
18. Known drug or alcohol dependence or any other factors which will interfere 
with the study conduct or interpretation of the results or who in the opinion of 
the Investigator are not suitable to participate. 
 
 
3.4. 
STUDY PROCEDURES 
Prior to recruitment of any subjects into the study, written approval of the protocol 
and informed consent must be obtained from the IRB and IBC (if applicable). 
 
3.4.1. 
INFORMED CONSENT 
The Investigator will explain the study purpose, procedures, and subject‘s 
responsibilities to the potential participant.  The subject's willingness and ability to 
meet the follow-up requirements will be determined and written informed consent 
will be obtained (Appendix 2).  The subject will sign and date the informed consent 
form.  The Investigator will also sign and date the consent form.  The original 
informed consent form will be retained with the subject records; a copy will be 
provided to the subject.   
 
Following is a detailed list of study visits from screening to final follow-up and the 
required procedures/tests.  Methodologies for specific tests/ procedures are described 
in Section 0. 
 
3.4.2. 
SUBJECT IDENTIFICATION 
To maintain confidentiality, the subject‘s name should not be recorded on any study 
document other than the informed consent form.  All subjects that give informed 
consent (sign the informed consent form) will be assigned a unique identifier in the 
following format: X-YY-ZZZ.  X is the site number, YY is the sequential subject ID 
number, and ZZZ are the subject initials (initials of first name/middle name /last 
name) or Z-Z (initials of first and last name separated by hyphen, if no middle name).  
For example, the first subject named John Simon Doe at site 1 will be assigned 1-01-
JSD; or if John doesn‘t have a middle name, it would be 1-01-J-D.    
   
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 31 of 101 
3.4.3. 
SCREENING (DAY -30 TO DAY 0) 
Prior to full screening, subjects will give informed consent.  If applicable, the subject 
will be washed out of prohibited medication (see section 3.4.4).  Subject eligibility 
will be assessed as follows: 
 
 Evaluation of Eligibility Criteria  
 Medical History 
 Physical Exam  
 Viral screening – HIV, Anti-Human T-Cell Lymphotropic Virus (HTLV), Active 
Hepatitis B or C as determined by Hepatitis B core antibody (HBcAb), antibody 
to Hepatitis B antigen (IgG and IgM; HBsAb), Hepatitis B surface antigen 
(HBsAg) and Hepatitis C antibodies (Anti-HCV) 
 EKG 
 Urine pregnancy test (for women of childbearing potential only) 
 Concomitant Medications 
 Vital Signs, including height 
 Serum chemistry and hematology 
 FVC 
 ALSFRS-R 
3.4.4. 
PROHIBITED CONCOMITANT MEDICATIONS 
 
3.4.4.1. 
MEDICATION THAT MAY INTERFERE WITH VM202 BIOACTIVITY 
COX-1 and COX-2 inhibiting drugs may interfere with the bioactivity of VM202, 
and are therefore prohibited from use during the study.  Other than the maximal 81 
mg daily dose of aspirin (acetylsalicylic acid), subjects must agree to not take any of 
these drugs until completion of the 9 month follow-up visit.  The patient needs to be 
advised that common over the counter medications that are prohibited include: Bayer 
(> 81mg), Excedrin, Aleve, Advil (motrin, ibuprofen).  A more complete list of the 
excluded medications, including the washout period, can be found in Appendix 3. 
 
3.4.4.2. 
SCREEN FAILURES 
Subjects not meeting all study entry criteria will be designated as a screen failures.  
End of study procedures will not be performed for these subjects, but their reason for 
discontinuation will be recorded on Screening Log.  Screen failures will be replaced. 
 
3.4.5. 
TREATMENT AUTHORIZATION 
After providing written informed consent, potential study participants will undergo 
Screening assessments.  The site will complete a Treatment Authorization Form 
(TAF) for subjects determined to be eligible for study participation.  The TAF 
includes the subject identification number, demographic information (gender, date of 
birth), date of informed consent and indication that the subject meets all inclusion and 
exclusion criteria.  The completed TAF will be faxed to the Sponsor or its designee.  
The Sponsor or its designee will confirm whether the subject can be treated and 
assign the Injection Schedule.  Upon receipt, the Investigator or designee will 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 32 of 101 
schedule the subject to undergo the study treatment.  Note: adherence to this process 
is mandatory to track enrollment and to confirm initial treatment. 
 
3.4.6. 
DAY 0 – 1
ST INJECTION VISIT 
 
3.4.6.1. 
PRE-INJECTION (≤ 24 HRS OF INJECTIONS) 
 FVC 
 ALSFRS-R 
 Muscle strength (MRC Scale)  
 Muscle circumference 
 Dynamometry 
 
3.4.6.2. 
PRE-INJECTION (≤ 4 HRS OF INJECTIONS) 
 Concomitant Medications 
 Vital Signs 
 Serum Chemistry and Hematology 
 Serum HGF  
 Copies of VM202 in whole blood 
 
3.4.6.3. 
1
ST DOSE OF VM202 
Patients receiving initial injection in the lower limbs will receive 38 injections (0.5 
mL / each injection) in each leg as follows: 
 
 Quadriceps - 20 injections/leg  
 Calves – 12 injections/leg 
 Tibialis anterior – 6 injections/leg 
 
Patients receiving initial injection in the upper limbs will receive 26 injections (0.5 
mL / each injection) in each arm as follows: 
 
Hand: 
 abductor pollicis brevis (APB) – 2 injections/hand 
 first dorsal interosseous (FDI) – 2 injections/hand 
Lower Arms: 
 Extensor carpi radialis – 2 injection/arm 
 Flexor carpi ulnaris – 2 injection/arm 
 Flexor carpi radialis – 2 injection/arm 
Upper Arms: 
 Biceps – 8 injections/arm 
 Deltoid – 8 injections/arm 
 
3.4.6.4. 
POST-INJECTION (1-3 HRS POST LAST INJECTION) 
 Vital Signs 
 Copies of VM202 in whole blood (2 hours ± 1 hour post last injection) 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 33 of 101 
 Injection site assessment 
 Adverse event assessment 
 
 
3.4.7. 
DAY 7 ± 1 DAY – 2
ND INJECTION VISIT 
 
3.4.7.1. 
PRE-INJECTION (≤ 4 HRS OF INJECTIONS) 
 Concomitant Medications 
 Vital Signs 
 Serum HGF  
 Copies of VM202 in whole blood 
 Injection site assessment 
 Adverse event assessment 
 
3.4.7.2. 
2
ND DOSE OF VM202 
Patients that received injections in the upper limbs last injection visit (1st injection), 
will receive 38 injections (0.5 mL / each injection) in each leg as follows: 
 
 Quadriceps - 20 injections/leg  
 Calves – 12 injections/leg 
 Tibialis anterior – 6 injections/leg 
 
Patients that received injections in the lower limbs last injection visit (1st injection), 
will receive 26 injections (0.5 mL / each injection) in each arm as follows: 
 
Hand: 
 abductor pollicis brevis (APB) – 2 injections/hand 
 first dorsal interosseous (FDI) – 2 injections/hand 
Lower Arms: 
 Extensor carpi radialis – 2 injection/arm 
 Flexor carpi ulnaris – 2 injection/arm 
 Flexor carpi radialis – 2 injection/arm 
Upper Arms: 
 Biceps – 8 injections/arm 
 Deltoid – 8 injections/arm 
 
3.4.7.3. 
POST-INJECTION (1-3 HRS POST LAST INJECTION) 
 Vital Signs 
 Copies of VM202 in whole blood (2 hours ± 1 hour post last injection) 
 Injection site assessment 
 Adverse event assessment 
 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 34 of 101 
3.4.8. 
DAY 14 ± 1 DAY – 3
RD INJECTION VISIT 
 
3.4.8.1. 
PRE-INJECTION (≤ 4 HRS OF INJECTIONS) 
 Concomitant Medications 
 Vital Signs 
 Serum HGF  
 Copies of VM202 in whole blood  
 Injection site assessment 
 Adverse event assessment 
 
3.4.8.2. 
3
RD DOSE OF VM202 
Patients that received injections in the upper limbs last injection visit (2nd injection), 
will receive 38 injections (0.5 mL / each injection) in each leg as follows: 
 
 Quadriceps - 20 injections/leg  
 Calves – 12 injections/leg 
 Tibialis anterior – 6 injections/leg 
 
Patients that received injections in the lower limbs last injection visit (2nd injection), 
will receive 26 injections (0.5 mL / each injection) in each arm as follows: 
 
Hand: 
 abductor pollicis brevis (APB) – 2 injections/hand 
 first dorsal interosseous (FDI) – 2 injections/hand 
Lower Arms: 
 Extensor carpi radialis – 2 injection/arm 
 Flexor carpi ulnaris – 2 injection/arm 
 Flexor carpi radialis – 2 injection/arm 
Upper Arms: 
 Biceps – 8 injections/arm 
 Deltoid – 8 injections/arm 
 
3.4.8.3. 
POST-INJECTION (1-3 HRS POST LAST INJECTION) 
 Vital Signs 
 Copies of VM202 in whole blood (2 hours ± 1 hour post last injection) 
 Injection site assessment 
 Adverse event assessment 
 
 
3.4.9. 
DAY 21 ± 1 DAY – 4
TH INJECTION VISIT 
 
3.4.9.1. 
PRE-INJECTION (≤ 4 HRS OF INJECTIONS) 
 Concomitant Medications 
 Vital Signs 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 35 of 101 
 Serum HGF  
 Copies of VM202 in whole blood 
 Injection site assessment 
 Adverse event assessment 
 
3.4.9.2. 
4
TH DOSE OF VM202 
Patients that received injections in the upper limbs last injection visit (3rd injection), 
will receive 38 injections (0.5 mL / each injection) in each leg as follows: 
 
 Quadriceps - 20 injections/leg  
 Calves – 12 injections/leg 
 Tibialis anterior – 6 injections/leg 
 
Patients that received injections in the lower limbs last injection visit (3rd injection), 
will receive 26 injections (0.5 mL / each injection) in each arm as follows: 
 
Hand: 
 abductor pollicis brevis (APB) – 2 injections/hand 
 first dorsal interosseous (FDI) – 2 injections/hand 
Lower Arms: 
 Extensor carpi radialis – 2 injection/arm 
 Flexor carpi ulnaris – 2 injection/arm 
 Flexor carpi radialis – 2 injection/arm 
Upper Arms: 
 Biceps – 8 injections/arm 
 Deltoid – 8 injections/arm 
 
3.4.9.3. 
POST-INJECTION (1-3 HRS POST LAST INJECTION) 
 Vital Signs 
 Copies of VM202 in whole blood (2 hours ± 1 hour post last injection) 
 Injection site assessment 
 Adverse event assessment 
 
3.4.10. 
DAY 30 ± 3 DAYS 
 Concomitant Medications 
 Vital Signs 
 Serum chemistry and hematology 
 FVC 
 ALSFRS-R 
 Muscle strength (MRC scale) 
 Serum HGF 
 Copies of VM202 in whole blood  
 Injection site assessment 
 Adverse event assessment 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 36 of 101 
 
3.4.11. 
DAY 60 ± 3 DAYS 
 Concomitant Medications 
 Vital Signs 
 FVC 
 ALSFRS-R 
 Muscle strength (MRC Scale)  
 Muscle circumference 
 Dynamometry 
 Serum HGF 
 Copies of VM202 in whole blood  
 Injection site assessment 
 Adverse event assessment 
 
 
3.4.12. 
DAY 90 ± 7 DAYS 
 Concomitant Medications 
 Vital Signs 
 Serum chemistry and hematology 
 FVC 
 ALSFRS-R 
 Muscle strength (MRC Scale) 
 Muscle circumference 
 Dynamometry 
 Serum HGF 
 Copies of VM202 in whole blood  
 Adverse event assessment 
 
 
3.4.13. 
6 MONTHS ± 1 MONTH 
 Concomitant Medications 
 Vital Signs 
 FVC 
 ALSFRS-R 
 Muscle strength (MRC Scale) 
 Muscle circumference 
 Dynamometry 
 Adverse event assessment 
 
 
3.4.14. 
9 MONTHS ± 1 MONTH 
 Physical exam 
 EKG 
 Concomitant Medications 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 37 of 101 
 Vital Signs 
 Serum chemistry and hematology 
 FVC 
 ALSFRS-R 
 Muscle strength (MRC Scale) 
 Muscle circumference 
 Dynamometry 
 Adverse event assessment 
 
 
3.4.15. 
MONTHS 12, 18, 24, 36 ± 1 MONTH 
 Phone call to assess survival 
 
 
3.5. 
STUDY COMPLETION 
 
3.5.1. 
COMPLETED SUBJECTS 
Each subject in the study will undergo formal clinical assessments throughout the 9 
Month Study follow-up visits.  Patients will receive follow-up phone calls at 12, 18, 
24, and 36 months to assess survival only. 
 
3.5.2. 
DISCONTINUED SUBJECTS 
Any subject may voluntarily discontinue the study at any time without prejudice.  
The Investigator may discontinue a subject from the study at any time if (s)he 
considers that remaining in the study compromises the subject‘s health or the subject 
is not sufficiently cooperative. In either event, reason(s) for discontinuation should 
be recorded on the CRF. 
 
Possible reasons for study discontinuation include the following: 
 
• Adverse events (AEs) necessitating discontinuation from the study (pre-treatment) 
• The subject is lost to follow-up 
• Subject decision 
• Investigator decision 
• Other reason 
 
The reasons for any subject discontinuation will be specified and recorded on the 
study completion form of the CRF.  Additional subjects may be enrolled if subjects 
discontinue prior to the 90 day visit. 
 
Subjects discontinued for AE(s) will be followed-up after subject‘s discontinuation 
until the event is resolved or considered medically stable by the Investigator.   
 
Subjects that withdraw prior to study completion will undergo the following 
assessments if possible: 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 38 of 101 
 
1. Concomitant Medications 
2. Vital signs 
3. Physical exam 
4. EKG 
5. Serum Chemistry and Hematology 
6. Serum HGF if discontinued prior to Day 90 
7. Copies of VM202 in whole blood if discontinued prior to Day 90  
8. Injection site reaction assessment if discontinued prior to Day 60 
9. Adverse Events 
 
In case of a subject lost-to-follow-up, the Investigator must do his/her best to contact 
the subject (by phone or letter) at least twice.  If no response is obtained from the 
subject, the Investigator is encouraged to contact one of the subject‘s relatives or 
his/her general practitioner.  Documentation of these contacts must be recorded in 
the subject medical chart.  It can be, for instance, the acknowledgement of receipt of 
a letter sent to the subject.   
 
3.5.3. 
PREMATURE STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study for any safety, ethical or 
administrative reason at any time. 
 
 
 
3.6. 
INVESTIGATIONAL DRUG PRODUCT AND ACCOUNTABILITY 
 
3.6.1. 
INVESTIGATIONAL DRUG PRODUCT 
VM202 is a DNA plasmid which contains a novel genomic cDNA hybrid human 
hepatocyte growth factor (HGF) coding sequence (HGF-X7) expressing two 
isoforms of HGF, HGF728 and HGF723.  The key feature of HGF-X7 is that it was 
designed by inserting a series of intron sequences into certain sites of HGF cDNA so 
that both isoforms of HGF protein are expressed simultaneously and efficiently as in 
the human genome.  Because there is no change in the coding region of the HGF 
gene, HGF proteins generated from VM202 are identical to the wild-type human 
HGF proteins.   
 
The plasmid has 7,377 base pairs, a HCMV enhancer / promoter, a growth hormone 
polyadenylation terminator sequence, ColEl originator, and the Kanamycin 
resistance gene, on a pCK backbone.   
 
VM202 is supplied in a sterile glass vial containing 2.5 mg of lyophilized study 
product.  VM202 should be stored in a refrigerator at temperatures between 2o C and 
8o C in an appropriately locked room accessible only to the pharmacist, or a duly 
designated person.  Since VM202 does not contain preservatives, opened vials of 
VM202 and VM202 reconstituted with water for injection (WFI) must be used 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 39 of 101 
within 6 hours when stored at room temperature. VM202 should never be frozen.  A 
complete description of test article administration can be found in Appendix 4. 
 
3.6.2. 
PRODUCT ACCOUNTABILITY 
In accordance with federal regulations (21CFR 312.62), all Investigators are required 
to keep accurate records showing final disposition of all investigational drugs.   
 
Investigational drugs are to be used only in accordance with this protocol and under 
supervision of the Study Pharmacist or a duly designated person.  The Study 
Pharmacist or his/her designee will maintain an accurate record of the receipt of the 
test drug as shipped by the Sponsor / Designee, including the date received.  In 
addition, an accurate drug disposition record will be kept, specifying the amount 
dispensed to each subject and the date of dispensation.  This inventory record must 
be available for inspection at any time.  Copies of this record will be provided to the 
Sponsor by the Study Pharmacist at the conclusion of the study. 
 
After the study is completed, the Study Pharmacist must account for all drug used, 
unused and partially used.  Unused study medication from the study site will be 
returned to the Sponsor / Designee as directed in writing by the Sponsor for gross 
reconciliation. 
 
3.6.3. 
DOSE AND ADMINISTRATION 
VM202 is supplied in a sterile glass vial containing 2.5 mg of lyophilized study 
product.  Before administration, it will be reconstituted with 5 mL of water for 
injection (WFI) by the study pharmacist for a final VM202 concentration of 0.5 mg / 
mL.  Each reconstituted vial is only to be used for one subject.  A complete 
description of test article administration can be found in Appendix 4. 
 
 
 
3.7. 
PRIOR AND CONCOMITANT MEDICATION 
All concomitant medications (taken within 30 days of the first injection) will be 
recorded on the CRF at each study visit.  For each medication taken, the following 
information will be collected: 
 
 Medication trade name; 
 Indication for which the medication was given; 
 Dose/strength, route, and frequency of administration; 
 Date started and date stopped (or continuation at study exit). 
 
 
 
 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 40 of 101 
4. 
EXAMINATIONS AND EVALUATIONS 
 
4.1. 
EVALUATIONS CONDUCTED AT BASELINE ONLY 
 
4.1.1. 
MEDICAL HISTORY 
A medical history will be obtained at Screening/Baseline.  All positive findings will 
be carefully documented on the CRF.  Any new finding discovered during screening 
and prior to the first study drug administration (Day 0) will be considered to be part 
of the medical history and will not be recorded as an adverse event. 
 
The Investigator will confirm the diagnosis of ALS using the revised El Escorial / 
Airlie House diagnostic criteria. 
 
4.1.2. 
PHYSICAL EXAM 
A physical exam will be performed at Screening and at 9 months.  The exam will 
include the following: head, eyes, ears, nose, and throat (HEENT), heart, lungs, 
abdomen, extremities, lymph nodes, and musculoskeletal, neurological, 
gastrointestinal, and dermatological systems.  Any clinically significant 
abnormalities should be recorded in the subject‘s CRF. 
 
4.1.3. 
VIRAL SCREENING 
The local laboratory will be responsible for Screening viral testing and assays to 
include: HIV-1, HIV-2, HTLV, and active HBV and HCV as determined by 
Hepatitis B core antibody (HBcAb), antibody to Hepatitis B antigen (IgG and IgM; 
HBsAb), Hepatitis B surface antigen (HBsAg) and Hepatitis C antibodies (Anti-
HCV). 
 
4.1.4. 
12-LEAD EKG 
A 12 lead electrocardiogram (EKG) will be conducted at Screening and at 9 months.  
The EKG recording will be printed out, and a copy will be placed with subject 
records.  Any (clinically significant) abnormalities will be documented.  
 
4.1.5. 
PREGNANCY TEST (WOMEN OF CHILDBEARING POTENTIAL ONLY) 
For women of childbearing potential, a urine beta human chorionic gonadotropin (β-
HCG) test will be performed at Screening.  Results of the test must be negative and 
effective contraception documented.  Acceptable methods of contraception include: 
 
• Barrier type devices (e.g., female condom, diaphragm and contraceptive sponge) 
used only in combination with a spermicide; 
• Intrauterine device; 
• Oral contraceptive agents; 
• Depo-provera (medroxyprogesterone acetate); 
• Levonorgestrel implants; 
 
Abstention, the rhythm method and / or contraception by a partner are not considered 
acceptable methods of contraception. 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 41 of 101 
 
 
4.2. 
EVALUATIONS CONDUCTED THROUGHOUT THE STUDY 
 
4.2.1. 
CONCOMITANT MEDICATIONS 
Concomitant medications will be recorded at Screening and at each visit using the 
trade name or generic name as described in Section 3.7. 
 
4.2.2. 
VITAL SIGNS 
Vital signs consisting of blood pressure (while subject is sitting), temperature, body 
weight, heart rate, and respiratory rate will be measured and recorded at Screening 
and at every visit through the 9 month follow-up.  Body weight need only be 
measured once during injection visits (Day 0, Day 7, Day 14, Day 21). All other 
vital sign measurements will be made both pre and post injection. 
 
4.2.3. 
SERUM CHEMISTRY AND HEMATOLOGY  
Evaluation of serum chemistry and hematology will be conducted at Screening, Day 
0, Day 30, Day 90 and 9 months.  Evaluations will be conducted at a local laboratory 
at each site. 
 
Serum chemistry evaluations will include: calcium, glucose, sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline 
phosphatase, albumin, and total protein. 
 
Hematology evaluations will include: complete blood count (CBC): red blood cells 
(RBC); hemoglobin (Hgb), hematocrit (HCT), mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration 
(MCHC), platelets and white blood cells (WBC) with differential.  Abnormal 
readings do not necessarily constitute an adverse event; the results need to be 
reviewed in the context of the subject‘s health. 
 
Laboratory testing by visit is provided in Appendix 1. 
 
4.2.4. 
SERUM HGF 
Serum HGF will be determined by ELISA at the following follow-up visits: 
immediately pre-treatment on Day 0, immediately pre-treatment on Day 7, 
immediately pre-treatment on Day 14, immediately pre-treatment on Day 21, on Day 
30, Day 60, and Day 90.  A minimum 6 cc blood draw will be taken at each time 
point.  Allow blood to clot for 30 – 60 minutes at room temperature then centrifuge 
for 10 minutes at 1000 x g.  Divide the isolated serum into six (6) equal aliquots of 
~0.3 mL each. (0.5mL plastic storage tubes provided).  Samples should be labeled 
with subject ID, draw date, study number and visit interval (i.e., Day 0, 7, 14, 21, 30, 
60 or 90).  Samples will be maintained in a cooler containing dry ice and then placed 
in a ≤ -65°C freezer until shipped for analysis.  At the request of the Sponsor or its 
designee, serum HGF samples will be batched with VM202 samples, and shipped in 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 42 of 101 
a special container with temperature tracking recorder to Charles River Laboratories 
for analysis. 
 
Charles River Laboratories 
Preclinical Services Nevada 
6995 Longley Lane 
Reno, NV  89511 
Phone: (775) 682-2079 
 
4.2.5. 
COPIES OF VM202 IN WHOLE BLOOD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
4.2.6. 
FORCED VITAL CAPACITY 
Forced Vital Capacity (FVC) is a pulmonary function test that quantifies the volume 
of air that can forcibly be blown out after full inspiration.  It correlates with survival 
in ALS.50  FVC will be determined during Screening, on Day 0 before the treatment 
(injection), on Day 30, Day 60, Day 90, at 6 months and 9 months.  FVC 
measurement will be performed by trained personnel as recommended for ALS 
clinical trials using standard techniques in the sitting position and expressed as a 
percentage of the expected value.51   
 
4.2.7. 
REVISED AMYOTROPHIC LATERAL SCLEROSIS FUNCTIONAL RATING 
SCALE (ALSFRS-R) 
The revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is 
a validated rating scale for measuring the global function of patients with ALS.52  It 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 43 of 101 
provides a health professional-generated estimate of the patient‘s degree of 
functional impairment, which can be evaluated serially to objectively assess any 
response to treatment or progression of disease.  The ALSFRS-R includes twelve 
questions that ask the physician to rate his/her impression of the patient‘s level of 
functional impairment in performing one of twelve common tasks, e.g. climbing 
stairs.  Each task is rated on a five-point scale from 0 = can't do, to 4 = normal ability. 
Individual item scores are summed to produce a reported score of between 0=worst 
and 48=best.   The ALSFRS-R will be conducted at Screening, on Day 0 before the 
treatment (injection), on Day 30, Day 60, Day 90, at 6 months and 9 months.  Details 
can be found in Appendix 5.   
 
4.2.8. 
MEDICAL RESEARCH COUNCIL (MRC) SCALE FOR MUSCLE STRENGTH 
TESTING 
The Medical Research Council (MRC) Scale is a validated instrument used in 
assessing muscle strength.  It uses the numeral grades 0 – 5 to characterize muscle 
strength as follows: 
 
0 - No contraction 
1 - Flicker or trace contraction 
2 - Active movement, with gravity eliminated 
3 - Active movement against gravity 
4 - Active movement against gravity and resistance 
5 - Normal power  
 
The MRC scale will be used to assess muscle strength in the muscle groups injected 
with VM202.  This assessment will be conducted on Day 0 before the treatment 
(injection), on Day 30, Day 60, Day 90, at 6 months and 9 months.  The muscle 
groups to be evaluated and the methods of evaluation can be found in Appendix 6. 
 
4.2.9. 
MUSCLE CIRCUMFERENCE 
The muscle circumference of the following groups of muscles will be assessed on 
Day 0 before the treatment (injection), and on Day 60, Day 90, at 6 months and 9 
months.  Measurements will be taken bilaterally: 
 
 Mid-arm: at the midpoint of a vertical line that joins the acromion process to the 
olecranon process 
 Mid forearm: at the proximal one third point of a vertical line that joins the 
medial epicondyle to the styloid process of the ulna 
 Mid-thigh: midpoint of a vertical line that joins the anterior superior iliac spine 
to the superior edge of the patella 
 Mid-leg: at the proximal one third point of a vertical line that joins the fibular 
head to the lateral malleolus 
 
The procedures for measuring muscle circumference can be found in Appendix 7. 
 
4.2.10. 
DYNAMOMETRY 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 44 of 101 
Finger pinch force, grip strength, and lower leg extension will be measured using 
non-AC powered dynamometers manufactured by Hoggan Health Industries, Inc.  
Data will be collected on the Data Collection Software Package that works with all 
the Hoggan FET dynamometers.  These measurements will be performed on Day 0 
before the treatment (injection), Day 60, Day 90, 6 months, and 9 months. 
 
4.2.11. 
INJECTION SITE REACTION ASSESSMENT 
Local injection sites reactions will be assessed on Day 0 post injection, Day 7 pre 
and post injection, Day 14 pre and post injection, Day 21 pre and post injection, Day 
30, and Day 60.  Any adverse reaction should be reported as an AE. 
 
 
 
5. 
EVALUATION OF ADVERSE EVENTS 
 
5.1. 
DEFINITIONS 
An Adverse Event (AE) is the development of an untoward medical occurrence or 
the deterioration of a pre-existing medical condition following or during exposure to 
an investigational product, whether or not considered causally related to the product.   
 
An untoward medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver) or clinically significant abnormal results of an 
investigation (e.g., laboratory findings, electrocardiogram). 
 
Conditions or diseases that are chronic but stable should not be recorded on AE 
pages of the CRF.  In addition, changes in a chronic condition or disease that are 
consistent with natural disease progression are NOT considered AEs and also should 
not be recorded on AE pages of the CRF.  These medical conditions should be 
adequately documented on the appropriate page of the CRF (medical history and/or 
physical examination).  
 
An adverse reaction means any adverse event caused by a drug.  Adverse reactions 
are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  For the purposes of 
IND safety reporting, ‗reasonable possibility‘ means there is evidence to suggest a 
causal relationship between the drug and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug. 
 
A serious adverse event (SAE) is any untoward medical occurrence which: 
 Results in death; 
 Is life-threatening; 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 45 of 101 
 Requires inpatient hospitalization (admission to hospital with a stay > 24 hours) 
or prolongation of hospitalization (note, elective procedures requiring 
hospitalization are not considered a SAE); 
 Results in permanent impairment of a body function or permanent damage to a 
body structure; or 
 Requires medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure. 
 
Additionally, important medical events that may not result in death, be life-
threatening or require hospitalization may be considered SAEs when they jeopardize 
the subject or require medical or surgical intervention to prevent one of the serious 
outcomes listed above.  Examples of such medical events include: allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse.  Medical and scientific judgment 
must be exercised when classifying events as serious. 
 
Life-threatening means that the subject is, in the view of the Investigator, at 
immediate risk of death from the AE as it occurred.  It does not include an AE which, 
had it occurred in a more serious form, might have caused death.   
 
Persistent or significant disability/incapacity means that the event resulted in 
permanent or significant and substantial disruption of the subjects‘ ability to carry 
out normal life functions.   
 
An unexpected AE is an AE, the nature or severity of which is not consistent with 
the applicable product information (e.g., Investigator Brochure for an unapproved 
product).  Expected means that the event has been previously observed with the test 
article and is identified and/or described in the applicable product information.  It 
does not mean that the event is expected with the underlying disease(s) or 
concomitant medications.  It is expected that certain disease states will have 
reoccurring adverse events some of which may be considered expected over time. 
 
 
5.2. 
ASSESSMENT OF AES 
All AEs experienced by study subjects, regardless of severity, which occur between 
the first study drug administration and the 9 month follow-up visit of the study must 
be recorded on the AE form provided with the CRF.  This will include the following 
information: 
 
 Description of the AE 
 Date of onset 
 Duration 
 Frequency 
 Severity 
 Seriousness (yes/no) 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 46 of 101 
 Treatment 
 Outcome 
 Relationship to study medication, injection procedure  and/or  underlying disease  
 
All AEs and SAEs must be followed until resolution, or the condition stabilizes.  The 
Investigator is responsible to ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as possible the nature 
and/or causality of the AE or SAE.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals.  The Sponsor or its designee may request that the Investigator perform 
or arrange for the conduct of supplemental measurements and/or evaluations. 
 
5.2.1. 
AE CAUSALITY 
The study Investigator will determine whether an AE is related or unrelated to study 
medication, the procedure (intramuscular injection) and / or the underlying disease 
using the following criteria: 
 
Not related: An adverse event that is not related to the use of the test article or 
administration procedure.   
 
Possibly related: An adverse event that might be due to the use of the test article or 
administration procedure. An alternative explanation, e.g., concomitant study 
product(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, a causal relationship cannot be excluded.   
 
Probably related: An adverse event that might be due to the use of the test article or 
administration procedure. The relationship in time is suggestive. An alternative 
explanation is less likely, e.g., concomitant drug(s), concomitant disease(s). 
 
Definitely related: An AE that is due to the use of the test article or administration 
procedure. The event cannot be reasonably explained by an alternative explanation – 
e.g., concomitant drug(s), concomitant disease(s).  
 
5.2.2. 
AE INTENSITY 
The intensity of the AE/SAE will be defined by the following criteria: 
 
Mild: 
The AE is noticeable to the subject but does not interfere with 
routine activity. 
Moderate: 
The AE is discomforting and interferes with routine activity. 
Severe: 
The AE significantly limits the subject‘s ability to perform 
routine activities despite symptomatic therapy. 
 
 
5.3. 
REPORTING/RECORDING OF AES 
Throughout the course of the study, all efforts will be made by the Investigator to 
remain alert to possible AEs.  The first concern will be the safety of the subject, and 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 47 of 101 
for providing appropriate medical intervention.  The period of observation for 
collection of AEs starts during the first intramuscular injection procedure (Day 0) 
until the 9 month follow-up visit.  Any AE should be recorded on the appropriate 
CRF page(s). 
 
 
5.4. 
REPORTING / RECORDING OF SAES 
 
5.4.1. 
INVESTIGATOR’S RESPONSIBILITY 
SAEs will be recorded following the first study drug administration through the 9 
month follow-up visit.  Any SAE that occurs during this investigation, whether or 
not related to the study medication, must be reported immediately (within 72 hours) 
to the Sponsor and MedTech Consultants, Inc., the designated CRO.   
 
Each SAE must be followed with appropriate medical management until resolved or 
assessed as chronic or stable regardless of whether or not, in the opinion of the 
Investigator, the event is thought to be related to the study medication.   
 
The Investigator will be required to provide complete information concerning each 
SAE to the CRO and Sponsor within 5 calendar days of the event.  This information 
must be recorded in the subject‘s medical record and then transcribed onto the SAE 
FAX Form.  The completed SAE Form (including the Investigator‘s opinion of the 
relationship of the SAE to the study medication), copies of related results/reports, 
consultant report(s), and other relevant information will be faxed and/or mailed to 
the CRO. 
 
In the event of an SAE leading to hospitalization, every effort will be made by the 
investigational site to obtain medical records, including a hospital discharge 
summary.  In the event of a fatal AE, documentation of any available postmortem 
findings, including autopsy, will be provided to the Sponsor or their designee.  In 
any event, the Investigator will provide a narrative summary of circumstances, 
events related to the death, and cause of death, if known.  Any follow-up information 
obtained must be recorded on an SAE follow-up report form. 
 
The Investigator must comply with the applicable local regulatory requirements 
related to the reporting of SAEs to regulatory authorities and the Institutional 
Review Board (IRB), and Institutional Biosafety Committee (IBC) if applicable.  
Upon receipt from the Sponsor of an initial or follow-up IND Safety Report or other 
safety information, the Investigator must promptly notify his or her IRB, and IBC (if 
applicable). 
 
5.4.2. 
SPONSOR’S RESPONSIBILITY 
All AEs and SAEs will be reported on an annual basis to FDA in accordance with 
the IND regulation (21 CFR Part 312).  Per the 2010 FDA Guidance Document for 
Industry and Investigators ―Safety Reporting Requirements for INDs and BA/BE 
Studies,‖ events categorized as ‗possibly‘ or ‗probably‘ related will be treated as 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 48 of 101 
‗suspected adverse reactions.‘  Events categorized as ‗definitely‘ related will be 
treated as an ‗adverse reaction.‘ 
 
All serious, unexpected adverse reactions and suspected adverse reactions will be 
reported to FDA and to all participating Investigators as an IND Safety Report 
within 15 calendar days of the event after the sponsor determines that the suspected 
adverse reaction qualifies for reporting (21 CFR §312.32).  Any unexpected fatal or 
life-threatening AEs will be reported to the Agency within 7 calendar days after the 
sponsor‘s initial receipt of the information. 
 
The Sponsor will notify all participating Investigators of any new safety information 
that alters the current risk-benefit assessment of the study medication or that would 
be sufficient to consider changes in VM202 administration or in the overall conduct 
of the trial. 
 
 
 
 
6. 
STATISTICAL METHODS 
The objective of this Phase I/II study is to evaluate the safety of IM administration of 
VM202 in subjects with amyotrophic lateral sclerosis.  Sample size estimations were not 
based on formal statistical hypotheses testing due to the exploratory nature of this Phase 
I/II study.  Hypothesis testing will not be performed on any endpoint. 
 
6.1. 
PATIENT CATEGORIZATION 
Screen Failure - Any patient who was consented and entered into the screening 
process appropriately, but subsequently did not meet the entry criteria in order to be 
treated.  Patients who fail screening will not be followed for safety or efficacy 
assessment, and no other study procedures will be performed. 
 
Evaluable Patient - Any patient who received the study drug. 
 
Lost to follow-up - A patient deemed to be lost to follow-up is any patient who 
received treatment, but who does not complete scheduled study visits to 9 months.  
This includes those patients who withdraw consent and refuse further study 
participation and all attempts to contact the patient are deemed unsuccessful. 
 
 
6.2. 
STUDY ENDPOINTS 
The primary study endpoint is to evaluate safety and tolerability of intramuscular 
injections of VM202 at different injection sites in subjects with ALS.  Secondary 
endpoints include the assessment of the potential of VM202 to reduce 
neurodegeneration and muscle wasting as determined by the ALSFRS-R, muscle 
strength (MRC scale), muscle circumference measurements and dynamometry.  FVC 
will also be tracked and trended. 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 49 of 101 
6.2.1. 
SAFETY 
Any patient who receives VM202 will be included in the safety analysis population.  
Adverse events, serious adverse events, and adverse events leading to treatment 
discontinuation will be summarized using descriptive statistics.  Categorical 
variables will be summarized by the number and percentage of patients in each 
category. Continuous variables will be summarized using n, mean, SD, median, 
minimum, and maximum values.  No statistical testing will be performed. 
 
6.2.2. 
PHARMACOKINETICS & PHARMACODYNAMICS 
HGF serum levels will be determined immediately pre-treatment on Day 0, 
immediately pre-treatment on Day 7, immediately pre-treatment on Day 14, 
immediately pre-treatment on Day 21, on Day 30, Day 60, and Day 90.  The number 
of copies of VM202 in whole blood will be determined at Day 0 (pre-injection, and 2 
hours [± 1 hour] post last injection), at Day 7 (pre-injection, and 2 hours [± 1 hour] 
post last injection), at Day 14 (pre-injection, and 2 hours [± 1 hour] post last 
injection), at Day 21 (pre-injection, and 2 hours [± 1 hour] post last injection), on 
Day 30, Day 60, and Day 90. 
 
6.2.3. 
EFFICACY 
This is a phase I /II study, not powered to detect differences in efficacy measures.  
However, descriptive statistics of clinically meaningful endpoints will be tabulated.  
The potential of VM202 to reduce neurodegeneration and muscle wasting will be 
characterized using the ALSFRS-R, muscle strength (MRC scale), muscle 
circumference measurements and dynamometry.  FVC will also be tracked and 
trended.  Survival will also be recorded. 
 
 
 
 
7. 
ACCESS TO STUDY DOCUMENTS AND STUDY MONITORING 
The Sponsor has designated MedTech Consultants to monitor the progress of this study.  
The clinical monitor, as a representative of the Sponsor, has the obligation to follow this 
study closely.  In addition to conducting a site visit prior to initiation of enrollment, the 
clinical monitor will visit the study facilities regularly, and utilize telephone and written 
communications on an ongoing basis to maintain current knowledge of the study.   
 
During periodic visits to the study site, the monitor will review the source documents used 
in the preparation of the CRFs to verify the accuracy and completeness of the information 
contained in those reports in preparation for retrieval.  All source documents must contain 
all information required by the CRF.  All data generated during this study and the source 
documents from which they originated are subject to inspection by the Sponsor or its 
representatives, the FDA and other regulatory agencies. 
 
Upon completion of the study, the clinical monitor will conduct a final visit (close-out) to 
the site.  The objectives of this visit are to ascertain that all regulatory records and reports 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 50 of 101 
are complete, verify that study drug and other supplies have been accounted for and ensure 
that the Investigator is aware of his/her responsibilities post-study. 
 
 
 
8. 
QUALITY CONTROL AND ASSURANCE 
The Sponsor employees and/or their contracted representatives utilize Standard Operating 
Procedures (SOP) designed to ensure that research procedures and documentation are 
consistently conducted/prepared to the highest quality standards.  These SOPs also require 
compliance with Health Authority regulations and Good Clinical Practice guidance. 
 
A Quality Assurance audit may be conducted by the Sponsor or its designee at any time 
during or after completion of a study.  The Investigator will be given adequate notice if 
he/she is selected for an audit.  The audit will include, but is not limited to, a review of all 
informed consent forms, a review of CRFs, associated source documents and medical 
records, a review of regulatory documentation, an assessment of study conduct and 
protocol compliance, and a review of the investigational drug accountability.  At the 
conclusion of an audit, the auditor will conduct a brief meeting with the Investigator to 
review the findings of the audit. 
 
 
 
9. 
INSTITUTIONAL REVIEW BOARD (IRB) 
Prior to the initiation of the study, the protocol, the informed consent form and 
Investigator‘s brochure will be submitted to the IRB for approval.  By signing the 
"Statement of Investigator" form (form FDA 1572), the Investigator is assuring that an IRB 
which complies with the requirements set forth in 21 CFR Part 56 will be responsible for 
the initial and continuing review of the proposed clinical study.  A copy of the IRB 
approval letter for the protocol, the informed consent, and the protocol signature page must 
be submitted to the Sponsor or its designee, prior to release of investigational supplies to 
the study site.  The approval letter must refer to the specific protocol and the informed 
consent form.  The study site must maintain an accurate and complete record of all reports, 
documents and other submissions made to the IRB concerning this protocol.  A list of the 
IRB members, their titles or occupations, and their institutional affiliation, or an IRB 
assurance number must be provided to the Sponsor or its designee prior to release of study 
supplies. 
 
FDA/relevant health authority regulations require that all advertisements for subject 
recruitment be approved by an IRB prior to implementation.  The complete text and format 
must be submitted to the Sponsor or its designee for approval prior to IRB submission. 
 
The Investigator is responsible for notifying the IRB of any SAEs as required by the IRB.  
A copy of the notification must be forwarded to the Sponsor or its designee.   
 
Status reports must be submitted to the IRB at least once a year (or more frequently as 
required by the IRB) and the IRB must be notified of completion or termination of the 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 51 of 101 
study.  A final report must be provided to the IRB and the Sponsor within 3 months of 
study completion or termination.  This report should include: any deviations from the 
protocol, the number of participants evaluated, the number of participants who withdrew or 
were withdrawn and the reasons for withdrawal, any significant adverse events and the 
Investigator's summation of the study. 
 
 
 
10. INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) 
The site at which this trial is being conducted will ensure that an Institutional Biosafety 
Committee (IBC) is in place.  The IBC will ensure that the site conforms to the 
requirements set forth in the Section IV-B-2 of the National Institutes of Health (NIH) 
Guidelines for Research Involving Recombinant DNA Molecules, promulgated by the 
National Institutes of Health/Office of Biotechnology Activities (NIH/OBA).  
 
The Investigator will be responsible for petitioning the IBC and obtaining approval prior to 
enrolling any subject in the study.  The Investigator will also be required to obtain and 
follow all biohazard safety guidelines promulgated by the IBC, and to report all findings as 
required to the IBC and to NIH/OBA.   
 
If a potential clinical site does not receive any NIH funding (either directly or indirectly) 
and does not have an institutional IBC, they can participate in the study if they issue a 
certification statement to that effect.  The certification statement will be submitted to the 
OBA. 
 
 
 
11. INFORMED CONSENT PROCESS 
It is the responsibility of the Investigator to inform each subject, prior to performing any 
study-related assessments, of the purpose of this clinical trial, including possible risks and 
benefits and document the informed consent process in the subject‘s chart.  A sample 
informed consent form containing the required elements of informed consent is provided in 
Appendix 2.  Any changes made to this sample must be approved by the Sponsor or its 
designee, prior to submission to the IRB.  After approval by the Sponsor or its designee, the 
informed consent must be submitted to and approved by the IRB.  Prior to entry into the 
study or initiation of any study-related procedures, the subject must read, sign and date the 
informed consent form.  The person executing the consent must also sign and date the final 
consent form page.  The original informed consent form is to be retained by the study site 
and a copy is to be given to the subject.   
 
The informed consent must be written in a language in which the subject is fluent.  If a 
foreign language translation is required, a statement of certification of the translation must 
be issued.  Regulations require that foreign language informed consent forms be submitted 
to the IRB for approval.  The Investigator must forward a copy of the consent form, the 
certified foreign language translation and an IRB approval letter to the Sponsor or its 
designee. 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 52 of 101 
 
 
 
12. CONFIDENTIALITY 
In accordance with GCP and with the national data protection laws, all information 
concerning the subjects in the study must be treated as strictly confidential by all persons 
involved in the study. 
 
The Investigator acknowledges that any and all information acquired from the Sponsor or 
its designee or developed or acquired in connection with the study are strictly confidential.  
The Investigator will not disclose any confidential information to any third party nor use 
confidential information for any purpose without first obtaining the consent of Sponsor in 
writing.  Such consent shall be deemed to have been given for disclosure to any person for 
whom the Investigator is responsible at his/her center, but only so far as required for the 
purposes of the study, and, in the case of disclosures to staff, only if such staff are bound by 
obligations of confidentiality no less strict than those set out herein. 
 
 
 
13. PROTOCOL AMENDMENTS 
The Sponsor will document modifications to the protocol in the form of a written 
amendment.  Protocol modifications that impact subject safety or the validity of the study 
must be approved by the IRB before implementation.  In the case of a medical emergency, 
to remove immediate apparent hazard to subjects, a change may be made preferably after 
discussion with the Sponsor or its designee.  In these instances, the IRB and FDA will be 
notified as soon as possible.  
 
 
 
14. DATA MANAGEMENT 
All data relating to study procedures will be entered into CRFs provided by the Sponsor or 
its designee.  All requested information must be entered on the CRF.  If an item is not 
available or not applicable this fact should be indicated.   
 
Obvious errors (self-evident corrections) will be corrected and documented by the Sponsor 
or its designee.  Other errors or omissions will result in queries which will be sent to the 
investigational site on Data Clarification Forms (DCF)/Query Forms for resolution.  A 
copy of the signed DCF is to be kept by the site with the CRFs.  Once the original is 
received by the Sponsor or its designee, the resolutions will be reviewed and entered into 
the database.   
 
Data will be entered into a computer database developed specifically for this trial.  Access 
to the database will be restricted to personnel responsible for data entry and to data 
management and statistics personnel who are directly involved in the management or 
analysis of this trial.  During the course of the trial, data queries will be generated for data 
items that are potentially erroneous and require appropriate clarification or correction.  

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 53 of 101 
Prior to database lock, statistical verification of the data will be undertaken in order to 
further assure data quality. 
 
 
 
15. RECORD KEEPING AND RETENTION 
Data generated for the study should be stored in a limited-access file area and be accessible 
only to representatives of the study site, the Sponsor and its representatives and 
FDA/relevant health authorities/regulatory agencies.  All reports and communications 
relating to study subjects will identify subjects only by initials and subject identification 
number.  Complete subject identification will be kept by the Investigator.  This information 
will be treated with strict adherence to professional standards of confidentiality. 
 
An Investigator must in reasonable time, upon request from any properly authorized officer 
or employee of FDA/relevant health authority or regulatory agency, permit such officer or 
employee to have access to requested records and reports, and copy and verify any records 
or reports made by the Investigator.  Upon notification of a visit by the FDA/relevant 
health authority or regulatory agency, the Investigator will contact the Sponsor or its 
designee immediately.  The Investigator will also grant Sponsor representatives the same 
privileges offered to FDA/relevant health authority or regulatory agents/officers/employees. 
 
The Investigator must provide the Sponsor or its designee with the following documents 
prior to study initiation and retain a copy in the study file: 
 
 
A completed and signed Form FDA 1572.  If during the course of the study any 
changes occur that are not reflected on the 1572, a new 1572 form must be completed 
and sent to Sponsor/CRO. 
 
Current signed curriculum vitae (within 2 years) and current medical licenses for the 
Principal Investigator and all co-Investigators listed on the 1572. 
 
A copy of the original approval for conducting the study by the IRB.  Renewals, with 
continuance of the study, must be submitted at yearly intervals or as required by IRB 
policy. 
 
A copy of the IRB approved informed consent form. 
 
IRB member list and DHHS General Assurance Number (if IRB has an Assurance 
number). 
 
Signed Financial Disclosure Form for all personnel listed on the 1572.   
 
The signature page of this protocol signed and dated by the Principal Investigator. 
 
In addition to the documents listed above, the study site will also retain the following items: 
 
 Certifications and laboratory reference ranges for all local laboratories used for this 
study. 
 All original informed consent forms with required signatures 
 All IRB correspondence (i.e., informed consent [including any approved revisions], 
protocol, AE, advertisements, newsletters) 
 Copy of the Study Monitoring Log Sheet 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 54 of 101 
 Clinical and non-clinical supply shipment forms 
 Copies of all correspondence pertaining to the study (except budget issues) between the 
Sponsor or the CRO and the site 
 Copies of all SAEs reports submitted to the Sponsor its designee 
 Copies of all IND Safety Reports submitted to the site by the Sponsor its designee 
 Copies of approved package labeling 
 Study personnel signature log 
 
All study-related records must be maintained for at least 2 years after a marketing 
application (NDA/BLA) is approved for the drug; or if an application is not approved for 
the drug, until at least 2 years after shipment and delivery of the drug for investigational 
use is discontinued and FDA/health authorities or regulatory agencies have been notified.  
The Sponsor will notify the principal Investigator when records are no longer needed.  The 
Investigator will not discard any records without notifying the Sponsor.  If the principal 
Investigator moves from the current investigational site, the Sponsor should be notified of 
the name of the person who will assume responsibility for maintenance of the records at the 
investigational site or the new address at which the records will be stored.  The Investigator 
will notify the Sponsor as soon as possible in the event of accidental loss or destruction of 
any study documentation. 
 
 
 
16. INVESTIGATOR FINAL REPORT 
The Investigator shall provide the IRB and the Sponsor with an accurate final report within 
3 months after completion, termination or discontinuation of the study.  The final report 
may not precede retrieval of CRFs which have not been monitored. 
 
 
 
17. STUDY REPORT AND PUBLICATION 
The data resulting from this study will be the proprietary information of the Sponsor and 
may be made public after all data have been analyzed and the study results are available.  
None of the data resulting from this study will be allowed to be presented or published in 
any form, by the Investigator or any other person, without the prior written approval of the 
Sponsor.  At the end of the study, a clinical study report will be written by the Sponsor or 
its designee.   
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 55 of 101 
18. REFERENCES 
 
1. 
Nelson LM. Epidemiology of ALS. Clin Neurosci 1995;3:327-31. 
2. 
Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and management of 
amyotrophic lateral sclerosis. Nat Rev Neurol 2011;7:639-49. 
3. 
Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene 
are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59-62. 
4. 
Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis 
(ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2012;3:CD001447. 
5. 
Jaronen M, Vehvilainen P, Malm T, et al. Protein disulfide isomerase in ALS mouse glia 
links protein misfolding with NADPH oxidase-catalyzed superoxide production. Hum 
Mol Genet 2012. 
6. 
Cozzolino M, Ferri A, Valle C, Carri MT. Mitochondria and ALS: Implications from 
novel genes and pathways. Mol Cell Neurosci 2012. 
7. 
Barber SC, Shaw PJ. Oxidative stress in ALS: key role in motor neuron injury and 
therapeutic target. Free Radic Biol Med 2010;48:629-41. 
8. 
Papadimitriou D, Le Verche V, Jacquier A, Ikiz B, Przedborski S, Re DB. Inflammation 
in ALS and SMA: sorting out the good from the evil. Neurobiol Dis 2010;37:493-502. 
9. 
McCombe PA, Henderson RD. The Role of immune and inflammatory mechanisms in 
ALS. Curr Mol Med 2011;11:246-54. 
10. 
Wallis N, Zagami CJ, Beart PM, O'Shea RD. Combined excitotoxic-oxidative stress and 
the concept of non-cell autonomous pathology of ALS: insights into motoneuron 
axonopathy and astrogliosis. Neurochem Int 2012;61:523-30. 
11. 
Boillee S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their 
nonneuronal neighbors. Neuron 2006;52:39-59. 
12. 
Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ. Molecular pathways of motor 
neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol 2011;7:616-30. 
13. 
Friedlander RM. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 
2003;348:1365-75. 
14. 
Friedlander RM, Brown RH, Gagliardini V, Wang J, Yuan J. Inhibition of ICE slows 
ALS in mice. Nature 1997;388:31. 
15. 
Li M, Ona VO, Guegan C, et al. Functional role of caspase-1 and caspase-3 in an ALS 
transgenic mouse model. Science 2000;288:335-9. 
16. 
Pasinelli P, Houseweart MK, Brown RH, Jr., Cleveland DW. Caspase-1 and -3 are 
sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated 
familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2000;97:13901-6. 
17. 
Yuan J, Yankner BA. Apoptosis in the nervous system. Nature 2000;407:802-9. 
18. 
Martin LJ. Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible 
contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol 
1999;58:459-71. 
19. 
Bussolino F, Di Renzo MF, Ziche M, et al. Hepatocyte growth factor is a potent 
angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 
1992;119:629-41. 
20. 
Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J 
Biochem 1996;119:591-600. 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 56 of 101 
21. 
Jayasankar V, Woo YJ, Pirolli TJ, et al. Induction of angiogenesis and inhibition of 
apoptosis by hepatocyte growth factor effectively treats postischemic heart failure. J Card 
Surg 2005;20:93-101. 
22. 
Nakagami H, Kaneda Y, Ogihara T, Morishita R. Hepatocyte growth factor as potential 
cardiovascular therapy. Expert Rev Cardiovasc Ther 2005;3:513-9. 
23. 
Gille J, Khalik M, Konig V, Kaufmann R. Hepatocyte growth factor/scatter factor 
(HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured 
keratinocytes. J Invest Dermatol 1998;111:1160-5. 
24. 
Morishita R, Aoki M, Yo Y, Ogihara T. Hepatocyte growth factor as cardiovascular 
hormone: role of HGF in the pathogenesis of cardiovascular disease. Endocr J 
2002;49:273-84. 
25. 
Jayasankar V, Woo YJ, Bish LT, et al. Gene transfer of hepatocyte growth factor 
attenuates postinfarction heart failure. Circulation 2003;108 Suppl 1:II230-6. 
26. 
Hashimoto N, Yamanaka H, Fukuoka T, et al. Expression of HGF and cMet in the 
peripheral nervous system of adult rats following sciatic nerve injury. Neuroreport 
2001;12:1403-7. 
27. 
Giacobini P, Messina A, Wray S, et al. Hepatocyte growth factor acts as a motogen and 
guidance signal for gonadotropin hormone-releasing hormone-1 neuronal migration. J 
Neurosci 2007;27:431-45. 
28. 
Kato N, Nemoto K, Nakanishi K, et al. Nonviral gene transfer of human hepatocyte 
growth factor improves streptozotocin-induced diabetic neuropathy in rats. Diabetes 
2005;54:846-54. 
29. 
Koike H, Morishita R, Iguchi S, et al. Enhanced angiogenesis and improvement of 
neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin 
synthase gene. FASEB J 2003;17:779-81. 
30. 
Tsuchihara T, Ogata S, Nemoto K, et al. Nonviral Retrograde Gene Transfer of Human 
Hepatocyte Growth Factor Improves Neuropathic Pain-related Phenomena in Rats. Mol 
Ther 2008. 
31. 
Tonges L, Ostendorf T, Lamballe F, et al. Hepatocyte growth factor protects retinal 
ganglion cells by increasing neuronal survival and axonal regeneration in vitro and in 
vivo. J Neurochem 2011;117:892-903. 
32. 
Kitamura K, Iwanami A, Nakamura M, et al. Hepatocyte growth factor promotes 
endogenous repair and functional recovery after spinal cord injury. J Neurosci Res 
2007;85:2332-42. 
33. 
Sun W, Funakoshi H, Nakamura T. Overexpression of HGF retards disease progression 
and prolongs life span in a transgenic mouse model of ALS. J Neurosci 2002;22:6537-48. 
34. 
Akita H, Takagi N, Ishihara N, et al. Hepatocyte growth factor improves synaptic 
localization of the NMDA receptor and intracellular signaling after excitotoxic injury in 
cultured hippocampal neurons. Exp Neurol 2008;210:83-94. 
35. 
Tyndall SJ, Walikonis RS. Signaling by hepatocyte growth factor in neurons is induced 
by pharmacological stimulation of synaptic activity. Synapse 2007;61:199-204. 
36. 
Kadoyama K, Funakoshi H, Ohya W, Nakamura T. Hepatocyte growth factor (HGF) 
attenuates gliosis and motoneuronal degeneration in the brainstem motor nuclei of a 
transgenic mouse model of ALS. Neurosci Res 2007;59:446-56. 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 57 of 101 
37. 
Shang J, Deguchi K, Ohta Y, et al. Strong neurogenesis, angiogenesis, synaptogenesis, 
and antifibrosis of hepatocyte growth factor in rats brain after transient middle cerebral 
artery occlusion. J Neurosci Res 2011;89:86-95. 
38. 
Ishihara N, Takagi N, Niimura M, et al. Inhibition of apoptosis-inducing factor 
translocation is involved in protective effects of hepatocyte growth factor against 
excitotoxic cell death in cultured hippocampal neurons. J Neurochem 2005;95:1277-86. 
39. 
Ishigaki A, Aoki M, Nagai M, et al. Intrathecal delivery of hepatocyte growth factor from 
amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic 
lateral sclerosis model. J Neuropathol Exp Neurol 2007;66:1037-44. 
40. 
Genestine M, Caricati E, Fico A, et al. Enhanced neuronal Met signalling levels in ALS 
mice delay disease onset. Cell Death Dis 2011;2:e130. 
41. 
Kawaida K, Matsumoto K, Shimazu H, Nakamura T. Hepatocyte growth factor prevents 
acute renal failure and accelerates renal regeneration in mice. Proc Natl Acad Sci U S A 
1994;91:4357-61. 
42. 
Liu ML, Mars WM, Zarnegar R, Michalopoulos GK. Uptake and distribution of 
hepatocyte growth factor in normal and regenerating adult rat liver. Am J Pathol 
1994;144:129-40. 
43. 
Wolff JA, Dowty ME, Jiao S, et al. Expression of naked plasmids by cultured myotubes 
and entry of plasmids into T tubules and caveolae of mammalian skeletal muscle. J Cell 
Sci 1992;103 ( Pt 4):1249-59. 
44. 
Wolff JA, Budker V. The mechanism of naked DNA uptake and expression. Adv Genet 
2005;54:3-20. 
45. 
Malecki M, Kolsut P, Proczka R. Angiogenic and antiangiogenic gene therapy. Gene 
Ther 2005;12 Suppl 1:S159-69. 
46. 
Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events. In: 
CBER, ed. Rockville; 2006. 
47. 
Considerations for Plasmid DNA Vaccines for Infectious Disease Indications. In: CBER, 
ed. Rockville; 2007. 
48. 
Henry TD, Hirsch AT, Goldman J, et al. Safety of a non-viral plasmid-encoding dual 
isoforms of heypatocyte growth factor in critical limb ischemia patients: a phase I study. 
Gene Ther 2011. 
49. 
Ajroud-Driss S, Christiansen M, Allen JA, Kessler JA. Phase 1/2 Open-label Dose-
escalation Study of Plasmid DNA Expressing Two Isoforms of Hepatocyte Growth 
Factor in Patients With Painful Diabetic Peripheral Neuropathy. Mol Ther 2013;21:1279-
86. 
50. 
Czaplinski A, Yen AA, Appel SH. Forced vital capacity (FVC) as an indicator of survival 
and disease progression in an ALS clinic population. J Neurol Neurosurg Psychiatry 
2006;77:390-2. 
51. 
Brinkmann JR, Andres P, Mendoza M, Sanjak M. Guidelines for the use and 
performance of quantitative outcome measures in ALS clinical trials. J Neurol Sci 
1997;147:97-111. 
52. 
Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional 
rating scale that incorporates assessments of respiratory function. BDNF ALS Study 
Group (Phase III). J Neurol Sci 1999;169:13-21. 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 58 of 101 
 
 
 
 
APPENDICES 
 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 59 of 101 
 
 
TABLE OF APPENDICES 
 
 
Appendix 1. 
Schedule of Evaluations and Visits & Laboratory Tests by Visit .................. 60 
Appendix 2. 
Sample Informed Consent............................................................................... 63 
Appendix 3. 
Medications Excluded from Use During the Study ........................................ 80 
Appendix 4. 
Test Article Administration ............................................................................ 82 
Appendix 5. 
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)
......................................................................................................................... 88 
Appendix 6. 
Medical Research Council (MRC) Scale for Muscle Strength Testing .......... 90 
Appendix 7. 
Measuring Muscle Circumference .................................................................. 96 
Appendix 8. 
Dynamometry ................................................................................................. 99 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 60 of 101 
 
 
 
 
Appendix 1. 
Schedule of Evaluations and Visits & Laboratory Tests by Visit 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
Page 61 of 101 
SCHEDULE OF EVALUATIONS AND VISITS 
 
Procedure 
Screening / 
Baseline 
(-30 – 0 D) 
1st Injection 
Day 0 
2nd Injection 
Day 7 ± 1 D 
3rd Injection 
Day 14 ± 1 D 
4th Injection 
Day 21 ± 1 D 
Day 30 
± 3 D 
Day 60 
± 3 D 
Day 90 
± 7 D 
6 M 
± 1 M 
9 M 
± 1 M 
12, 18, 
24 and 
36 M 
Withdrawal 
before 9M 
Visit 
Pre-
dose 
Post-
dose 
Pre-
dose 
Post-
dose 
Pre-
dose 
Post-
dose 
Pre-
dose 
Post-
dose 
Baseline Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral screening  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety and Efficacy 
Parameters 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry and 
Hematology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FVC 
 
† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALSFRS-R 
 
† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Muscle strength (MRC 
Scale) 
 
† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Muscle circumference 
 
† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dynamometry 
 
† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum HGF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Copies of VM202 in 
whole blood 
 
 
* 
 
* 
 
* 
 
* 
 
 
 
 
 
 
1 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection site reaction 
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone call follow-up to 
assess survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
† 
Can be conducted the day before injections 
* 
2 hours after injection (± 1 hour) 
1. If withdrawal occurred before Day 90 Visit 
2. If withdrawal occurred before Day 60 Visit 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
Page 62 of 101 
SCHEDULE OF LABORATORY EVALUATIONS 
 
Parameters 
Screen 
Day 0 
Day 7, 14, 21 
Day 30 
Day 60 
Day 90 
6 Months 
9 Months 
Early 
Withdrawal 
Serum HGF 
 
 pre-
injection 
 pre-
injection 
 
 
 
 
 
 (< Day 90) 
VM202 
 
 pre & post 
injection 
 pre & post 
injection 
 
 
 
 
 
 (< Day 90) 
HTLV, HIV-1, HIV-2 
 
 
 
 
 
 
 
 
 
Hepatitis B and C† 
 
 
 
 
 
 
 
 
 
Hematology 
Hematocrit 
 
 
 
 
 
 
 
 
 
Hemoglobin 
 
 
 
 
 
 
 
 
 
RBC 
 
 
 
 
 
 
 
 
 
WBC with differential 
 
 
 
 
 
 
 
 
 
Platelets 
 
 
 
 
 
 
 
 
 
MCV 
 
 
 
 
 
 
 
 
 
MCH 
 
 
 
 
 
 
 
 
 
MCHC 
 
 
 
 
 
 
 
 
 
Chemistry 
Albumin 
 
 
 
 
 
 
 
 
 
Alkaline Phosphatase 
 
 
 
 
 
 
 
 
 
ALT 
 
 
 
 
 
 
 
 
 
AST 
 
 
 
 
 
 
 
 
 
Bicarbonate 
 
 
 
 
 
 
 
 
 
BUN 
 
 
 
 
 
 
 
 
 
Calcium 
 
 
 
 
 
 
 
 
 
Chloride 
 
 
 
 
 
 
 
 
 
Creatinine 
 
 
 
 
 
 
 
 
 
Glucose 
 
 
 
 
 
 
 
 
 
Potassium 
 
 
 
 
 
 
 
 
 
Sodium 
 
 
 
 
 
 
 
 
 
Total Protein 
 
 
 
 
 
 
 
 
 
Total Bilirubin 
 
 
 
 
 
 
 
 
 
† Hepatitis B core antibody (HBcAb), antibody to Hepatitis B surface antigen (IgG and IgM; HBsAb), Hepatitis B surface antigen (HBsAg) and Hepatitis C antibodies 
(Anti-HCV) 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 63 of 101 
 
 
 
 
Appendix 2. 
Sample Informed Consent 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 64 of 101 
 
TITLE: 
A Phase I/II, Open Label Study to Assess the Safety and Tolerability of 
VM202 in Subjects with Amyotrophic Lateral Sclerosis 
(Protocol VMALS-001) 
 
SPONSOR:  VM BioPharma 
 
 
  
 
 
 
  
 
 
 
 
PRINCIPAL INVESTIGATOR: 
John A. Kessler, M.D. 
Ken and Ruth Davee Professor of Stem Cell Biology  
Professor in Ken and Ruth Davee Department of 
Neurology and Molecular Pharmacology and 
Biological Chemistry  
 
INSTITUTION: 
 
Northwestern University Stem Cell Institute 
303 East Chicago Avenue 
Chicago, Illinois 60611-3008 
 
SUBJECT INITIALS: 
[INSERT SUBJECT‘S INITIALS] 
 
SUBJECT NUMBER: 
[INSERT SUBJECT‘S UNIQUE STUDY 
NUMBER] 
 
You are being asked to participate in a research study sponsored by VM BioPharma.  Before you 
decide whether to participate, it is important for you to know why the research is being done, and 
what it will involve.  Please take your time to read the following information carefully, and feel 
free to discuss your decision with your family, friends, and your primary care doctor.  Please ask 
your study doctor to explain if there is anything that is not clear or if you would like more 
information.  If you agree to take part in this study, you need to sign this consent form.  Your 
signature on this form means that you have been told about and understand the purpose of the 
study, procedures to be followed, and any benefits or risks.  Your signature on this form also 
means that you want to take part in this study if you meet the criteria, based on the results of 
your medical tests, which must be done before you are asked to continue your participation in the 
study.  After you agree, you will be provided with a copy of this signed form for your records.   

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 65 of 101 
 
Do I have to take part? 
Taking part in this study is entirely voluntary, and you may refuse to participate or withdraw 
from the study at any time without influencing your regular medical treatment and without 
giving a reason.  A decision to withdraw at any time, or a decision not to take part, will not affect 
the standard of care you receive.  Regardless of your decision, you will still be treated for your 
medical condition.   
 
 
Why is this research study being done? 
You are being considered for participation in this research study because you have been 
diagnosed with amyotrophic lateral sclerosis (ALS).  The specific events that result in ALS are 
not well understood, but all ALS patients experience damage to the nerve cells in the brain and 
spinal cord that are responsible for controlling voluntary movement (motor neurons).  For 
unknown reasons, in ALS, these motor neurons stop working.  The muscles the motor neuron 
control no longer function, and they gradually become paralyzed.   
 
Supporting motor neuron health and function may slow down the degenerative processes in ALS.  
Researchers have discovered that a protein called hepatocyte growth factor (HGF) that your body 
naturally produces in small amounts can protect nerves.  Unfortunately, your body only makes a 
small amount of this protein and not always in the areas where you need it.  Researchers have 
found a way to increase the amount of HGF in your limbs.  They have isolated the genes 
responsible for directing the production of HGF, and have designed a product that can be 
injected into your muscles. 
 
In this research study, the HGF gene will be injected into the muscles of your arms, hands, and 
legs to evaluate if it affects your ALS symptoms and disease progression.  The product being 
used in this study is called VM202.  VM202 is an experimental drug that is not yet approved by 
regulatory authorities (the US Food and Drug Administration [FDA]).  VM202 is a plasmid (a 
small piece of DNA), which includes the genes for HGF.  VM202 has been used in two small 
studies in the United States in patients with painful diabetic neuropathy (another neural 
degenerative disease); in two small studies in patients with critical limb ischemia, and in a study 
in Korea in patients with coronary artery disease.  VM202 has also been tested in people 
undergoing coronary bypass surgery.  It is hoped that VM202 injected into your muscles will 
slow down the progression of your ALS symptoms.   
 
 
Who is in charge of this study? 
The Principal Investigator is John A. Kessler, M.D.  This study is sponsored and funded by VM 
BioPharma Co., Ltd.  VM BioPharma Co., Ltd. will use a specialized research company, called a 
contract research organization, in addition to specialized laboratories to manage and execute 
some parts of the detailed requirements of the study.   
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 66 of 101 
How many people will take part in this research study? 
A total of 18 patients will take part in this study at Northwestern University.   
 
 
What happens if I agree to be in this research study? 
After you sign this consent form indicating you want to participate in this study, you will need to 
undergo some tests to see if you qualify for the study.  If you do not meet all of the study entry 
criteria, you will not be able to participate in the study and your doctor will discuss with you 
other options that you may have for treatment of your medical condition.  The study doctor will 
tell you whether you are able to participate in this study after the initial test results are received 
and reviewed.   
 
This study is an open label clinical study.  All patients will receive the same final dose of 
VM202 (64 mg).  VM202 is delivered by administering small injections into the muscles.  
Individual injections contain 0.5 ml of fluid with 0.25 mg VM202.  This is about one tenth of a 
teaspoon of fluid per injection.   
 
You will receive VM202 injections four times (every 7 days) after you qualify for the study.  
Each week, you will alternate between receiving injections in the arms and hands or injections in 
the legs.  In this way, your arms will be treated twice with VM202 and your legs will be treated 
twice with VM202.   
 
The first eligible patient will begin the injection series with injections in the legs.  The next 
eligible patient will receive initial injections in the arms and subsequently eligible patients will 
alternate between initiating treatment in the arms or legs.  Depending when you qualify, the 
injections will start in your arms and hands OR in your legs. 
 
When receiving injections in the arms, you will get 26 injections of VM202 distributed over each 
arm (upper arm, forearm, and hand) for a total of 52 injections (right arm/hand and left 
arm/hand).  When receiving injections in the legs, you will get 38 injections of VM202 
distributed over each leg (thigh and calf) for a total of 76 injections (right leg and left leg).   
 
All patients will receive the same final dose of VM202 (64 mg) and the same number of 
injections in the arms and legs. 
 
What tests, procedures, and diagnostic studies will be done during this study?  
There are 10 visits which span 9 months total time from visit #2 to visit #9.  Depending on the 
visit, different tests will be done.  Visit #1 may actually take more than one visit to accomplish 
depending on how many tests can be scheduled on that first day, but is usually completed within 
a week before the first injection procedure (Visit #2).  Below is a detailed description of each of 
the required visits and the laboratory tests, procedures, and evaluations that will be done during 
the visits.   
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 67 of 101 
Description of the tests, procedures, and diagnostic studies to be done  
 
Medical history – Discussion with your doctor of your medical history, including ALS family 
history, current symptoms and any changes that have happened.   
 
Physical exam – Your doctor will give you a physical exam and will check your reflexes, 
strength, balance, and coordination.  This exam will also include taking your sitting blood 
pressure, temperature, heart rate, height and weight (vital signs).   
 
Medication Review – Discussion with your doctor of what medications and dietary supplements 
you have taken or are currently taking.  Please note, some medications may not be taken during 
the study since they may interfere with the potential effect of the study medication or ability to 
assess the response to the study medication.  The doctor will talk to you about these medications; 
if you are currently taken any of these medications, you will be asked to stop taking these 
medications for the duration of the study.      
 
Assessment of ALS – Assessment by your doctor of your ALS symptoms. 
 
Injection site reaction assessment – Assessment by your doctor of any pain or other reaction at 
the locations where VM202 was injected. 
 
Assessment of side effects – Assessment by your doctor of any unpleasant medical experiences, 
side effects, or discomforts that may have happened to you.   
 
Questionnaire – You and your doctor will fill out a short questionnaire about your ALS 
symptoms during the screening process and right before the first injections.  This questionnaire, 
(ALS Functional Rating Scale [ALSFRS-R]), asks about your ability to function in certain daily 
activities.  You will be asked to complete this questionnaire again at some visits. 
 
Forced Vital Capacity (FVC) – To test how well your lungs are working, we will measure the 
greatest amount of air you can exhale (breath out) following a deep breath. For this test, we will 
ask you to hold a mouthpiece in your mouth, breathe in deeply, and breathe out slowly for as 
long as you can.  
 
Muscle Strength – The strength in your arms and legs will be evaluated by physical exam using 
a scoring method (Medical Research Council [MRC] scale).  The scale ranges from ‗0‘ (No 
contraction) to ‗5‘ (Normal power).  Muscle strength and range of motion will also be measured 
using a small device called a hand-held dynamometer.  The evaluator will hold the device in his 
or her hand and will push against your arms and legs while you try to hold against this pushing.  
This testing will take approximately 30 minutes. This should not hurt, but may be slightly 
uncomfortable due to pressure and may make your muscles tired.  You will also be asked to 
squeeze a hand-held dynamometer to measure the strength of your fingers. 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 68 of 101 
Muscle Circumference – The size of your arm and leg muscles will be measured using a 
standard, flexible, non-elastic, plastic measuring tape. 
 
Pregnancy test – If you are a female of child bearing age, you will undergo a urine pregnancy 
test to confirm that you are not pregnant.  You cannot participate if you are pregnant or plan to 
become pregnant during the course of the trial.   
 
12 Lead EKG – An electrocardiogram (EKG) is a measurement of your heart‘s electrical 
activity that is traced and sent to a machine, which can be read by your doctor.  This procedure is 
not painful and involves lying as still as possible for a few minutes with sticky pads (electrodes) 
on your chest, arms and legs which are connected through wires to the EKG machine.  This test 
typically takes approximately 15 to 20 minutes. 
 
Blood tests – Routine blood tests will be done at certain visits.  Laboratory tests will also include 
testing for VM202 and HGF levels in the blood at certain visits.  The screening evaluation 
laboratory tests will include viral tests for various diseases including HIV (the AIDS virus), 
HTLV (human T-cell lymphotropic virus), hepatitis B (HBV), and hepatitis C (HCV).  
 
Following is a list of each visit and the specific tests that will be done. 
 
Visit # 1: Screening/Baseline Evaluations 
Screening is a process of evaluating your initial health status and assessing the status of your 
ALS.  Screening is usually completed within one month before the first study injections if you 
qualify for this study.  If you agree to take part in this research study, you will first sign this 
consent form, and then undergo screening.  Screening will involve the following procedures:  
medical history, physical exam, vital signs, medication review, determination of how well your 
lungs are working, determination of your ALS status (completion of questionnaire), blood tests 
including a viral screen; urine pregnancy test (if you are a female of childbearing age), and the 
12 lead EKG. 
 
Please note:  If any of your viral test results are positive you may need to have a second test to 
make sure the results are the same.  The doctor or his/her nurse will tell you how to find medical 
help and counseling as needed, and you will not be able to take part in this study.  The study 
Sponsor will not pay for the cost of the repeat tests, or any other follow-up medical care, or 
counseling for a positive or abnormal test result.   
 
It takes approximately one to two weeks to get all of the initial test results.  After your doctor has 
reviewed the results of these tests he/she will determine whether you are eligible for participation 
in the study.  If you are eligible for the study and you do wish to continue, you will be scheduled 
for the first set of injections which will be done at your next visit (Visit #2).   
 
 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 69 of 101 
Visit # 2 – Day 0 of the Study: First Injection Procedure 
 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done:  
medication review, vital signs, measurement of lung function (FVC), the ALSFRS-R 
questionnaire, measurement of muscle circumference, measurement of muscle strength and range 
of motion, and blood tests including HGF and VM202. 
 
Injection Procedure:   
The injection procedure will be done in your doctor‘s office.  The doctor will use a syringe with 
a fine needle to inject 0.5 ml of VM202 at sites evenly distributed over your arm or leg muscles 
(depending on which series of injections you are assigned to start with).  If you are receiving 
injections in the arms, you will receive 26 injections in each arm as follows: 
 
 Hand – 4 injections in each hand: 2 in the palm in the large muscle under the thumb; 2 in the 
muscle between the thumb and forefinger 
 Forearm - 6 injections in each forearm: 4 on the inside of the forearm, 2 on the outer forearm 
 Upper arm – 16 injections in each upper arm: 8 in the biceps, 8 in the deltoids (upper arm / 
shoulder) 
 
If you are receiving injections in the legs, you will receive 38 injections in each leg as follows: 
 
 Thigh – 20 injections evenly distributed over the front of each thigh 
 Calf – 12 injections evenly distributed over the back of each calf, 6 injections on the front of 
each calf 
 
Each injection will take 3 - 5 seconds.  The entire injection procedure is expected to take 30 
minutes. 
 
After Injection Procedure:  
After the injection procedure is performed, the following tests and/or evaluations will be done:  
vital signs, injection site reaction assessment, blood tests for VM202, and assessment of side 
effects. 
 
Before you go home discharge instructions about what you need to do to take care of yourself, 
what medications you should take, and who to call if you have a problem after you leave the 
clinic, will be reviewed with you by the nurse and/or doctor.  Research personnel will be on call 
anytime to answer any questions that you may have and respond to reports you may have of any 
symptoms.   
 
 
 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 70 of 101 
Visit # 3 – Day 7 of the Study: Second Injection Procedure 
 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done:  
medication review, vital signs, blood tests for HGF and VM202, injection site reaction 
assessment, and assessment of side effects. 
 
Injection Procedure:   
The injection procedure will be done in your doctor‘s office.  The doctor will use a syringe with 
a fine needle to inject 0.5 ml of VM202 at sites evenly distributed over your arm or leg muscles 
(the limbs not injected in the previous visit).  If you are receiving injections in the arms, you will 
receive 26 injections in each arm as follows: 
 
 Hand – 4 injections in each hand: 2 in the palm in the large muscle under the thumb; 2 in the 
muscle between the thumb and forefinger 
 Forearm - 6 injections in each forearm: 4 on the inside of the forearm, 2 on the outer forearm 
 Upper arm – 16 injections in each upper arm: 8 in the biceps, 8 in the deltoids (upper arm / 
shoulder) 
 
If you are receiving injections in the legs, you will receive 38 injections in each leg as follows: 
 
 Thigh – 20 injections evenly distributed over the front of each thigh 
 Calf – 12 injections evenly distributed over the back of each calf, 6 injections on the front of 
each calf 
 
Each injection will take 3 - 5 seconds.  The entire injection procedure is expected to take 30 
minutes. 
 
After Injection Procedure:  
After the injection procedure is performed, the following tests and/or evaluations will be done:  
vital signs, injection site reaction assessment, blood tests for VM202, and assessment of side 
effects. 
 
Before you go home discharge instructions about what you need to do to take care of yourself, 
what medications you should take, and who to call if you have a problem after you leave the 
clinic, will be reviewed with you by the nurse and/or doctor.  Research personnel will be on call 
anytime to answer any questions that you may have and respond to reports you may have of any 
symptoms.   
 
 
Visit # 4 – Day 14 of the Study: Third Injection Procedure 
 
Before Injection Procedure:  

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 71 of 101 
The following tests will be performed before you have your injection procedure done:  
medication review, vital signs, blood tests for HGF and VM202, injection site reaction 
assessment, and assessment of side effects. 
 
Injection Procedure:   
The injection procedure will be done in your doctor‘s office.  The doctor will use a syringe with 
a fine needle to inject 0.5 ml of VM202 at sites evenly distributed over your arm or leg muscles 
(the limbs not injected in the previous visit).  If you are receiving injections in the arms, you will 
receive 26 injections in each arm as follows: 
 
 Hand – 4 injections in each hand: 2 in the palm in the large muscle under the thumb; 2 in the 
muscle between the thumb and forefinger 
 Forearm - 6 injections in each forearm: 4 on the inside of the forearm, 2 on the outer forearm 
 Upper arm – 16 injections in each upper arm: 8 in the biceps, 8 in the deltoids (upper arm / 
shoulder) 
 
If you are receiving injections in the legs, you will receive 38 injections in each leg as follows: 
 
 Thigh – 20 injections evenly distributed over the front of each thigh 
 Calf – 12 injections evenly distributed over the back of each calf, 6 injections on the front of 
each calf 
 
Each injection will take 3 - 5 seconds.  The entire injection procedure is expected to take 30 
minutes. 
 
After Injection Procedure:  
After the injection procedure is performed, the following tests and/or evaluations will be done:  
vital signs, injection site reaction assessment, blood tests for VM202, and assessment of side 
effects. 
 
Before you go home discharge instructions about what you need to do to take care of yourself, 
what medications you should take, and who to call if you have a problem after you leave the 
clinic, will be reviewed with you by the nurse and/or doctor.  Research personnel will be on call 
anytime to answer any questions that you may have and respond to reports you may have of any 
symptoms.   
 
 
Visit # 5 – Day 21 of the Study: Fourth and Final Injection Procedure 
 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done:  
medication review, vital signs, blood tests for HGF and VM202, injection site reaction 
assessment, and assessment of side effects. 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 72 of 101 
 
Injection Procedure:   
The injection procedure will be done in your doctor‘s office.  The doctor will use a syringe with 
a fine needle to inject 0.5 ml of VM202 at sites evenly distributed over your arm or leg muscles 
(the limbs not injected in the previous visit).  If you are receiving injections in the arms, you will 
receive 26 injections in each arm as follows: 
 
 Hand – 4 injections in each hand: 2 in the palm in the large muscle under the thumb; 2 in the 
muscle between the thumb and forefinger 
 Forearm - 6 injections in each forearm: 4 on the inside of the forearm, 2 on the outer forearm 
 Upper arm – 16 injections in each upper arm: 8 in the biceps, 8 in the deltoids (upper arm / 
shoulder) 
 
If you are receiving injections in the legs, you will receive 38 injections in each leg as follows: 
 
 Thigh – 20 injections evenly distributed over the front of each thigh 
 Calf – 12 injections evenly distributed over the back of each calf, 6 injections on the front of 
each calf 
 
Each injection will take 3 - 5 seconds.  The entire injection procedure is expected to take 30 
minutes. 
 
After Injection Procedure:  
After the injection procedure is performed, the following tests and/or evaluations will be done:  
vital signs, injection site reaction assessment, blood tests for VM202, and assessment of side 
effects. 
 
Before you go home discharge instructions about what you need to do to take care of yourself, 
what medications you should take, and who to call if you have a problem after you leave the 
clinic, will be reviewed with you by the nurse and/or doctor.  Research personnel will be on call 
anytime to answer any questions that you may have and respond to reports you may have of any 
symptoms.   
 
 
Visit # 6 – 1 Month after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: medication review, vital signs, blood 
tests including HGF and VM202, measurement of lung function (FVC), the ALSFRS-R 
questionnaire, measurement of muscle strength using the MRC scale, injection site reaction 
assessment, and assessment of side effects. 
 
 
 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 73 of 101 
Visit # 7 – 2 Months after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: medication review, vital signs, 
measurement of lung function (FVC), the ALSFRS-R questionnaire, measurement of muscle 
circumference, measurement of muscle strength using the MRC scale, measurement of muscle 
strength and range of motion using a hand-held dynamometer, and blood tests for HGF and 
VM202, injection site reaction assessment, and assessment of side effects. 
 
 
Visit # 8 – 3 Months after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: medication review, vital signs, 
measurement of lung function (FVC), the ALSFRS-R questionnaire, measurement of muscle 
circumference, measurement of muscle strength using the MRC scale, measurement of muscle 
strength and range of motion using a hand-held dynamometer, and blood tests including HGF 
and VM202, and assessment of side effects. 
 
 
Visit # 9 – 6 Months after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: medication review, vital signs, 
measurement of lung function (FVC), the ALSFRS-R questionnaire, measurement of muscle 
circumference, measurement of muscle strength using the MRC scale, measurement of muscle 
strength and range of motion using a hand-held dynamometer, and assessment of side effects. 
 
Visit # 10 – 9 Months after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: physical exam, 12 lead EKG, 
medication review, vital signs, measurement of lung function (FVC), the ALSFRS-R 
questionnaire, measurement of muscle circumference, measurement of muscle strength using the 
MRC scale, measurement of muscle strength and range of motion using a hand-held 
dynamometer, blood tests, and assessment of side effects. 
 
 
Home Visits 
If your ALS symptoms worsen after you receive all of your injections and you are unable to 
come to the clinic for study visits, please let the study staff know.  We will do your remaining 
study visits as ―home visits.‖ 
 
After you have completed your 9-month follow-up visit, you do not have to return for any more 
visits.  You will receive a call from the study coordinator 12, 18, 24 and 36 months after initial 
treatment to check on your health. 
 
 
How long will I be in this research study? 
Your last follow up visit will be approximately 9 months, but we will continue to follow your 
progress for up to 3 years.  After the third year phone call, you will have completed this study. 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 74 of 101 
 
What do I have to do as a participant in this study? 
Participation in this study requires you to make sure that you are available to attend all your 
scheduled visits through 9 months.  During your participation in the study you will be asked to 
report any unpleasant medical experiences that you may have.   
 
You must not use any additional prescription medication before the 9 month study visit without 
first checking with your study doctor.  If you use any non-prescription medication you should 
inform your doctor of the details (medication, dose, etc.) at each study visit.   
 
You also must not participate in any other clinical trial before the 9 month study visit.   
 
What about my rights to decline participation or withdraw from the study? 
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw 
from the study at any time.  If you withdraw from the study, no new data about you will be 
collected for study purposes.   
 
Your decision not to participate or to withdraw from the study will not involve any penalty or 
loss of benefits to which you are entitled, and will not affect your access to health care.  If you do 
decide to stop your participation in the study, you should talk to your doctor immediately so 
he/she can advise you of any additional tests that may be needed for your safety.  Your doctor 
may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if he/she determines that it is no longer in your best interest to continue.  The Sponsor 
or regulatory agencies may stop this study at any time without your consent.  If this occurs, you 
will be notified and your study doctor will discuss with you other options you may have.   
 
What are the risks of this research study? 
There are known risks and discomforts involved in some of the tests and evaluations.  There are 
also unknown risks.  Below is a description of these risks.  Your doctor will discuss the risks and 
procedures with you before you start in the study.   
 
Risks from Injection Procedures 
VM202 will be injected into your muscles using a fine needle.  There may be some pain at the 
injection site at the time of injection.  There may be swelling, bruising or inflammation near the 
injection site.    There may be a risk of an allergic reaction, fever or tissue damage from the 
injection.  Because HGF has the potential to create new blood vessels, there may be risk of 
promoting tumor growth (cancer) or of increasing the number of blood vessels in the back of 
your eye and damaging your retina.   
 
Risks to women who can get pregnant or are breastfeeding 
Being a part of this study while pregnant may expose the unborn child to significant risks.  
Therefore, pregnant women cannot take part in this study.  If you are a woman who can get 
pregnant, a urine pregnancy test will be done and it must show that you are not pregnant before 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 75 of 101 
you can participate in this study.  You must also agree not to become pregnant during this study.  
You may not take part in this study if you are breastfeeding.  If sexually active and with 
childbearing potential, you must agree to use an acceptable method of birth control for the whole 
study.   
 
The following birth control measures are acceptable:  
 Barrier type devices (examples are condom, diaphragm, and contraceptive sponge) used only 
in combination with a spermicide; 
 Intrauterine device (IUD); 
 Birth control pills 
 Depo-provera (medroxyprogesterone acetate); 
 Levonorgestrel implants; 
 
Abstention, the rhythm method, and/or contraception by the partner are not acceptable methods 
of contraception.   
 
If you do become pregnant during this study or think that you might be pregnant, you must 
inform your study doctor immediately.  If this happens, the study doctor will discuss with you 
what you should do.  If you get pregnant, you will be asked to stop taking part in the study and 
you will be asked for information about the pregnancy and the baby.   
 
Risks from taking a blood sample 
You will have routine blood samples taken from a vein in your arm by a needle stick.  Risks 
associated with drawing blood from your arm include slight discomfort and/or bruising.  
Infection, bleeding, clotting, or fainting are also possible, although unlikely.  The number of 
times that you will have a blood sample drawn for this study totals about 13 times over 
approximately 10 months.  Each time your blood is drawn roughly 1 to 2 tablespoons of blood 
will be taken.   
 
Risks from EKG  
In rare circumstances, a rash or irritation at the location of the electrocardiogram electrode 
placement can occur due to the adhesive.  If this should occur it will be assessed and treated 
using clinical standards of care with appropriate medication(s) and/or compresses. 
 
Unknown risks 
In addition to the risks already described, there may be other discomforts or risks from this study 
drug and/or procedures that we do not know about.  You will be watched for signs and symptoms 
of any side effects and you should tell your doctor if you do not feel well or experience any 
unusual symptoms.   
 
 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 76 of 101 
Are there benefits to taking part in this research study? 
There may be no direct benefit to you by participating in this study.   
 
Knowledge from this study may help us better understand how to treat people with ALS.     
 
What if new information becomes available? 
If additional data regarding potential safety risks become available during the study, your 
research doctor will tell you about it and discuss with you whether you want to continue in the 
study.  If you decide to withdraw from the study, your research doctor will make arrangements 
for your care to continue.  If you decide to continue in the study you may be asked to sign an 
updated consent form which will explain the new information clearly.   
 
Also, on receiving new information your research doctor might consider it to be in your best 
interests to withdraw you from the study.  He/she will explain the reasons and arrange for your 
care to continue.   
 
Will I need to pay for the tests and procedures? 
Participation in this study will be of no cost to you.  All medical exams, urine and blood tests, 
and study evaluations and procedures that are required for this research study are provided to you 
at no cost to you.  You will also not need to pay for the VM202 injections.  VM BioPharma Co., 
Ltd. pays for this research.  However, if taking part in this study leads to procedures or care not 
included in this study, it may lead to added costs for you or your insurance company.   
 
What happens if I am injured because I took part in this research study? 
In the event of an injury resulting from your participation in this study, you will be provided with 
appropriate medical care.  However the costs incurred may, ultimately, be borne by your medical 
insurance.  Further information concerning this and your rights as a research subject can be 
obtained from Dr. John A. Kessler, M.D. or by phone [INSERT PHONE NUMBER] or by mail 
[INSERT MAILING ADDRESS].   
 
What are my rights if I take part in this research study? 
You have the right to refuse to sign this consent.  Taking part in this research study does not take 
away any other rights or benefits you might have if you did not take part in the study.  Taking 
part in this study does not give you any special privileges.  You will not be penalized in any way 
if you decide not to take part or if you stop after you start the study.  Specifically, you do not 
have to be in this study to receive or continue to receive medical care from your doctor.  If you 
stop the study you would still receive medical care for your condition although you would not be 
able to get the VM202 product.   
 
For any questions pertaining to your rights as a research subject, you may contact [PROVIDE 
CONTACT NAME] of the Institutional Review Board [PROVIDE NAME OF IRB AND 
CONTACT PHONE NUMBER].   
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 77 of 101 
What about confidentiality? 
The personal information obtained about you during the course of this study will remain 
confidential.  When recording the results of the study you will be referred to only by a unique 
subject identifier code number and your initials.  Except when required by law, you will not be 
identified by name, social security number, address, telephone number, or any other direct 
personal identifier in study records.   
 
Your records may be reviewed in order to meet Federal Food and Drug Administration (US FDA) 
regulations, or other national and/or local health regulatory authorities.  Your records may be 
copied by, or for these groups.  If your research record is reviewed by any of these groups, they 
may also need to review your entire medical record.  Copies of the study records that do not 
include your name, but may be traced back to you may also be given to the groups listed below.  
The Sponsor may send a copy of the records to the FDA or other regulatory agencies.   
 
By agreeing to participate in this research study, you consent to give representatives of the 
following entities access to your research-related medical records to ensure the proper conduct of 
the research and verify the accuracy of the collected data.  Clinical monitors, auditors, IRB 
members, and regulatory authorities will be granted access to your original medical records for 
verification of clinical trial procedures and/or data, without violating your confidentiality, to the 
extent permitted by the applicable laws and regulations.   
 
Reviewers for the study may include the Sponsor (VM BioPharma Co., Ltd.), or its 
representatives such as members of the Steering Committee, Executive Committee or Data 
Monitoring Committee, the Contract Research Organization identified as MedTech Consultants, 
Inc., and the IRB or other Research Committee(s) that approve and oversee research in the 
hospitals and clinics.  Additionally, representatives of national regulatory authorities (for 
example the Food and Drug Administration in the USA), representatives of the central laboratory 
facilities appointed by the Sponsor responsible for analyzing the urine and blood tests, and other 
representatives as designated by the Sponsor who will have a role in the handling and analysis of 
the study data or in trial operations.   
 
Complete confidentiality cannot be promised because information needs to be shared as 
described.  However, information will be collected and shared following professional standards 
of confidentiality.   
 
What will happen to the results of this study? 
The results of this research study will be used to support an application to regulatory agencies 
that approve drugs for use on prescription.  In addition, the results may be used in scientific 
publications or presented at medical meetings.  Your identity as a participant will not be revealed.   
 
 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 78 of 101 
Who has reviewed this study? 
The study has been reviewed by the FDA, and an IRB (research ethics committee). 
 
Who can answer my questions? 
You may talk to the study doctor or IRB at any time about any questions or concerns you have 
on this study.  A copy of this form will be placed in your medical record.  A copy of this form 
will also be given to you.   
 
What alternatives are there to participation in this study?   
Riluzole (Rilutek®) is an available medication that has been shown to lengthen survival time in 
ALS patients, and you will be able to continue taking riluzole if you were taking this medication 
at the time of study entry.  Currently, however, there are no approved drugs or treatment 
strategies known to stop or reverse the progression of ALS.   
 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF VM202 IN 
SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS  
(PROTOCOL VMALS-001) 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 79 of 101 
 
 
STATEMENT OF CONSENT 
 
I confirm that I have read and understand this consent form.  I confirm that the purpose of this 
study, procedures to be followed, risks and benefits have been explained to me.  I have been 
allowed to ask questions, and my questions have been answered to my satisfaction.  I have 
decided of my own free will to agree to take part in this study.   
 
I understand that my participation is voluntary and that I am free to withdraw at any time, 
without giving any reason, and without my medical care or legal rights being affected.   
 
I understand that sections of any or all of my medical records may be reviewed by 
representatives of the Sponsor, VM BioPharma, its representatives, or by regulatory authorities.  
I give permission for these individuals to have access to my records.  I understand that I will not 
identified by name in any report concerning the study.  I understand that a description of this 
clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  This 
Web site will not include information that can identify me.  I understand that I will be provided 
clinically appropriate medical care and that I have access to my doctor in case of any injury or 
deterioration in my health or well-being caused directly by my participation in this study.   
 
 
 
 
 
 
 
(Printed Name of Participating Subject) 
 
 
 
 
 
 
 
 
 
 
: 
(Signature of Participating Subject) 
 
Date 
 
Time 
 
 
 
 
 
 
(Printed Name of Physician or his/her 
Representative Obtaining Consent 
 
 
 
 
 
 
 
 
 
 
: 
(Signature of Physician or his/her Representative 
Obtaining Consent) 
 
Date 
 
Time 
 
 
 
 
 
Original copy for researcher/site file; 1 copy for subject.   
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 80 of 101 
 
 
 
 
Appendix 3. 
Medications Excluded from Use During the Study 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 81 of 101 
WASHOUT TABLE FOR COX-2 INHIBITORS & STEROIDS 
Drug 
Example of Common Name(s) 
Minimum Dose 
Allowed During 
Study 
Washout Period 
Cox-2 specific Inhibitors 
celecoxib 
Celebrex 
none 
2 weeks 
Non-steroidal Anti-inflammatory Drugs (NSAIDs: nonspecific inhibitors of both Cox-1 and Cox-
2) 
acetylsalicylic acid 
Aspirin 
Arthritis Foundation Safety Coated 
Aspirin, Bayer Aspirin, Bayer 
Children's Aspirin, Ecotrin 
81 mg daily 
2 weeks for doses 
over 81 mg daily 
diclofenac 
Voltaren 
Arthrotec, cambia, cataflam, flector, 
pennsaid, solaraze, zipsor 
none 
2 weeks 
diflunisal 
Dolobid 
none 
2 weeks 
etodolac 
Lodine 
none 
1 week 
fenoprofen 
Nalfon 
none 
1 week 
flurbiprofen 
Ansaid 
none 
1 week 
ibuprofen 
Motrin, Advil, caldorol, profen 
none 
1 week 
idomethacin 
Indocin 
none 
1 week 
ketoprofen 
Nexcede, Orudis 
none 
None for topical 
formulation, 1 week 
for all others 
ketorolac 
Sprix, acuvail, acular 
none 
1 week 
mefenamic acid 
Ponstel 
none 
1 week 
meloxicam 
Mobic 
none 
1 week 
nabumetone 
Relafen, Relifex and Gambaran 
none 
1 week 
naproxen sodium 
Aleve, Anaprox, Antalgin, Feminax 
Ultra, Flanax, Inza, Midol Extended 
Relief, Miranax, Naposin, Naprelan, 
Naprogesic, Naprosyn, Narocin, 
Proxen, Synflex, Xenobid 
none 
2 weeks 
oxaprozin 
Daypro 
none 
1 week 
piroxicam 
Feldene 
none 
1 week 
sulindac 
Clinoril 
none 
1 week 
tolmetin 
Tolectin 
none 
1 week 
 
Corticosteroids 
(topical, injected, 
oral) 
Prednisone, betamethasone, 
dexamethasone, cortisone, 
triamcinolone 
none† 
1 week 
Please note, some of these medications are provided in combination with other drugs in new formulations (e.g. 
AGGRENOX®  (aspirin/extended-release dipyridamole); Excedrin (acetaminophen; aspirin; caffeine)) 
† inhaled steroids for the treatment of respiratory disorders are allowed 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 82 of 101 
 
 
 
 
 
Appendix 4. 
Test Article Administration 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 83 of 101 
1. 
Test article preparation  
 
VM202 - VM202 is supplied in a sterile glass vial containing 2.5 mg of lyophilized study 
product.  Before administration, it will be reconstituted with 5.0 mL of water for injection 
(WFI) for a final VM202 concentration of 0.5 mg / mL.  Each reconstituted vial is only to be 
used for one subject.   
 
ALS patients will receive injections both in the upper limbs and lower limbs.  In order to 
reduce the injection burden on the ALS patient, injection of the upper limbs will be 
performed on separate visits from injection of the lower limbs.  Depending on whether the 
upper or lower limbs will be injected first VM202 will be prepared as follows:  
 
Table 5. Single dose preparation and delivery for Day 0, Day 7, Day 14, and Day 21 Visits 
Treatment Arm 
Number of Vials 
Reconstituted at 
each visit 
Number of 
injections† 
Total Volume 
to be Injected  
Upper Limb Injections 
13 mg VM202 
, 
 
 
 
 
 
 
 
 
 
 
 
†Injection volume for each individual injection = 0.5 mL 
 
 
2. Test material administration – Patients will receive injections of VM202 on Day 0, Day 7, 
Day 14 and Day 21.  A fine needle (e.g. 27 gauge, 1‖) suitable for IM injections will be used.  
Distribute injection sites evenly over each target muscle group, carefully avoiding fascia.   
 
 Inject the entire amount of the drug per each injection in about 3-5 seconds.  Immediately 
after completion of injection, lightly press the injection site with the finger head in order 
to prevent reflux.  Do not massage the injection site.  
 
 Subsequent administrations – Subsequent administrations should also be distributed 
evenly over each target muscle, and, as much as is possible, at different injection sites (if 
previously identified by an indelible marker).  If marks made to identify previous 
injection sites are visible, every effort should be made to inject at alternate locations. 
 
Sample injection sites for upper limb injections and lower limb injections are depicted in 
Figure 4 and Figure 5, respectively.  The first eligible subject will begin with the lower limb 
injection series as assigned by the Sponsor or its designee and will be injected in accordance 
with the schedule outlined in Table 6.   
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 84 of 101 
 
Table 6. 
Group 1 Injection Schedule 
TARGET AREA 
DOSE VM202 (mg) / TARGET MUSCLE, 
(NUMBER OF INJECTIONS / MUSCLE GROUP / SIDE (R/L)) 
TOTAL DOSE 
(TOTAL NUMBER OF 
INJECTIONS (R +L )) 
DAY 0 
DAY 7 
DAY 14 
DAY 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The next sequentially eligible patient will begin with injection of the upper limbs as assigned 
by the Sponsor or its designee (see Table 7).  Subsequent eligible patients will be treated in 
an alternating fashion as assigned by the Sponsor or its designee, such that 9 patients will 
have initiated their VM202 injections in the lower limbs and 9 patients will have initiated 
their VM202 injections in the upper limbs. Please note: Regardless of injection order, all 
subjects will receive the same final dose of VM202 and the same number of injections per 
muscle group.  
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 85 of 101 
 
Table 7. 
Group 2 Injection Schedule 
TARGET AREA 
DOSE VM202 (mg) / TARGET MUSCLE, 
(NUMBER OF INJECTIONS / MUSCLE GROUP / SIDE (R/L))
TOTAL DOSE 
(TOTAL NUMBER OF 
INJECTIONS (R + L)) 
DAY 0 
DAY 7 
DAY 14 
DAY 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 87 of 101 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 88 of 101 
 
 
 
 
 
 
Appendix 5. 
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 89 of 101 
 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 90 of 101 
 
 
 
 
 
Appendix 6. 
Medical Research Council (MRC) Scale for Muscle Strength Testing 
 
 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 91 of 101 
The following muscle groups will be evaluated using the MRC Scale: 
 
Muscle Group 
MRC Scale Score 
0 
1 
2 
3 
4 
5 
Right upper arm abduction 
 
 
 
 
 
 
Left upper arm abduction 
 
 
 
 
 
 
Right elbow flexion 
 
 
 
 
 
 
Left elbow flexion 
 
 
 
 
 
 
Right wrist extension 
 
 
 
 
 
 
Left wrist extension 
 
 
 
 
 
 
Right wrist flexion 
 
 
 
 
 
 
Left wrist flexion 
 
 
 
 
 
 
Right index finger abduction 
 
 
 
 
 
 
Left index finger abduction 
 
 
 
 
 
 
Right thumb abduction 
 
 
 
 
 
 
Left thumb abduction 
 
 
 
 
 
 
Right knee extension 
 
 
 
 
 
 
Left knee extension 
 
 
 
 
 
 
Right foot dorsal flexion 
 
 
 
 
 
 
Left foot dorsal flexion 
 
 
 
 
 
 
Right foot plantar flexion 
 
 
 
 
 
 
Left foot plantar flexion 
 
 
 
 
 
 
Total score (90) 
 
 
0 - No contraction 
1 - Flicker or trace contraction 
2 - Active movement, with gravity eliminated 
3 - Active movement against gravity 
4 - Active movement against gravity and resistance 
5 - Normal power  
 
 
Evaluation will proceed using the following algorithm: 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 92 of 101 
 
 
General Guidelines 
 
1. For each muscle tested, the examiner stands to the side being tested, and the subject is sitting 
upright and positioned to allow full movement of the joint against gravity.   
2. The examiner demonstrates the desired movement against gravity.  The examiner then 
requests the subject to repeat the motion.  
3. If the subject can move through the desired range of motion against gravity, the examiner 
attempts to apply resistance in the testing position while stating "Hold it, don't let me push it 
down" or "Hold it, don't let me bend it"  
4. If the subject tolerates no resistance, the muscle score is Grade 3. If the subject tolerates 
some resistance, the score is Grade 4, and full resistance, Grade 5.  
5. If the subject cannot move against gravity, the subject is repositioned to allow movement of 
the extremity with gravity eliminated.  If supporting the limb, the examiner provides neither 
assistance nor resistance to the subject's voluntary movement. This gravity-eliminated 
positioning will vary for each muscle tested. If the subject cannot complete at least partial 
range of motion with gravity eliminated, the muscle or tendon is observed and/or palpated for 
contraction. 
6. For a bedridden subject who cannot sit up in a bed placed in the chair position or on the edge 
of the bed, alternate positions for testing the lower extremity are included in this protocol. 
 
 
Upper Arm (shoulder) Abduction 
 Testing position - arm out from the side at shoulder level  
 The examiner demonstrates the motion, then states "Lift your arm out to the side to shoulder 
level." The hand giving resistance is contoured over the subject's arm just above the elbow. 
The other hand stabilizes the shoulder above the shoulder joint. The examiner states "Hold it, 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 93 of 101 
don't let me push it down." To assess grades 3, 4, or 5, please see General Guidelines, section 
4 above. 
 If weaker than Grade 3, the subject lies supine with arms at the side. The examiner supports 
the arm just above the elbow and at the wrist to assure that the shoulder does not externally 
rotate (turn outward).  The subject attempts to move the arm out to the side. The examiner 
states: "Try to move your arm out to the side". Grade 2 is assigned if the subject moves with 
gravity eliminated. 
 If weaker than Grade 2, the examiner states "Try to move your arm out to the side" and 
palpates the middle deltoid muscle for contraction, and scores as Grade 1 or 0 as previously 
defined. 
 
 
Elbow Flexion 
 Test position - forearm supinated and flexed slightly more than 90 degrees.  
 Verbal instructions: "Bend your elbow slightly more than 90 degrees". The hand giving 
resistance is contoured over the flexor surface of the forearm proximal to the wrist. The 
examiner's other hand applies counterforce by cupping the palm over the anterior superior 
aspect of the shoulder. The examiner then states: "Hold it. Don't let me push it down" and 
scores Grades 3, 4, or 5 as previously described. 
 If weaker than Grade 3, the shoulder is abducted to 90 degrees. The examiner supports the 
arm under the elbow and, if necessary, the wrist as well. The forearm is turned with the 
thumb facing the ceiling. With the elbow extended, the subject attempts to flex the elbow. 
The examiner states: "Try to bend your elbow." Grade 2 is assigned if the subject can flex the 
elbow. 
 If weaker than Grade 2, the forearm is supinated and positioned at the side in approximately 
45 degrees of elbow flexion. The examiner states "Try to bend your elbow", palpates the 
biceps tendon and scores as either Grade 1 or 0. 
 
 
Wrist Extension 
 Test position - arm at the side, elbow flexed to 90 degrees 
with the forearm pronated and the wrist fully extended.  
 Verbal instructions: "Bend your wrist up as far as possible." 
The examiner's hand giving resistance is placed over the back 
of the subject's hand just distal to the wrist. The examiner's 
other hand supports the subject's forearm. The examiner then 
states: "Hold it. Don't let me push it down" and scores Grades 
3, 4 or 5. 
 If weaker than Grade 3, the elbow is flexed to 90 degrees and forearm turned with thumb 
facing the ceiling. The forearm and wrist are supported by the examiner. The examiner states: 
"Bend your hand toward me". Grade 2 is assigned if the subject can extend the wrist. 
 If weaker than Grade 2, the examiner states "Bend your wrist toward me" and palpates the 
two extensor tendons, one on each side of the wrist and scores as Grade 1 or 0. The examiner 
is careful not to palpate the tendons in the middle of the wrist. 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 94 of 101 
Wrist Flexion 
 Test position - arm at the side, elbow flexed to 90 degrees 
with the forearm supinated and the wrist fully extended.  
 Verbal instructions: "Bend your wrist up as far as possible." 
The examiner's hand giving resistance is placed on the palm of 
the subject's hand just distal to the wrist. The examiner's other 
hand supports the subject's forearm. The examiner then states: 
"Hold it. Don't let me push it down" and scores Grades 3, 4 or 
5. 
 If weaker than Grade 3, the forearm and wrist are supported by the examiner. The examiner 
states: "Bend your hand toward me". Grade 2 is assigned if the subject can flex the wrist. 
 If weaker than Grade 2, the examiner states "Bend your wrist toward me" and palpates the 
flexor tendons and scores as Grade 1 or 0.  
  
 
Index finger abduction  
 Test position - arm at the side, elbow flexed to 90 degrees, fingers extended, with the wrist in 
the midposition between supination and pronation.  
 Verbal instructions: "Spread your fingers apart." The examiner's finger giving resistance to 
the superior portion of the tip of the index finger.  The examiner then states: "Hold it. Don't 
let me push it down" and scores Grades 3, 4 or 5. 
 If weaker than Grade 3, the forearm and wrist are pronated and the hand is placed on a flat 
surface. The examiner states: "Spread your fingers apart". Grade 2 is assigned if the subject 
can abduct the index finger. 
 If weaker than Grade 2, the examiner states "Spread your fingers apart" and palpates the FDI 
muscle belly and scores as Grade 1 or 0.  
 
 
Thumb abduction 
 Test position - arm at the side, elbow flexed to 90 
degrees, forearm supinated and supported on a flat 
surface, with the wrist and fingers extended. 
 Verbal instructions: "Raise your thumb straight 
up" such that the thumb moves in a plane that is at 
a right angle to the palmar surface. The examiner's 
finger gives resistance to the superior portion of 
the thumb.  The examiner then states: "Hold it. 
Don't let me push it down" and scores Grades 3, 4 
or 5. 
 If weaker than Grade 3, the forearm and wrist are 
placed in midposition between supination and pronation. The examiner then states: "Move 
your thumb inward‖ such that the thumb moves in a plane that is at a right angle to the 
palmar surface. Grade 2 is assigned if the subject can abduct the thumb. 
 If weaker than Grade 2, the examiner states "Move your thumb inward‖ and palpates the 
APB muscle belly and scores as Grade 1 or 0. 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 95 of 101 
 
Knee Extension 
 Test position - sitting upright with the knee fully extended to 0 degrees. Avoid knee 
hyperextension.  
 Verbal instructions; "Straighten your knee". The hand giving resistance is contoured on top 
of the leg just proximal to the ankle. The other hand is placed under the thigh above the knee. 
The examiner then states "Hold it. Don't let me bend it" and scores Grades 3, 4 or 5. 
 If weaker than Grade 3, the subject lays on the non-testing side. The examiner stands behind 
the subject at knee level. The leg not being tested may be flexed for stability. One arm 
cradles the leg being tested around the thigh with the hand supporting the underside of the 
knee. The other hand holds the leg just above the ankle. The examiner states: "Straighten 
your knee." Grade 2 is assigned if the subject can extend the knee (Figure 3).  
 If weaker than Grade 2, the subject is supine and the examiner states: "Push the back of your 
knee down" or "Tighten your knee cap" and palpates the quadriceps tendon, and scores as 
Grade 1 or 0. 
 
 
Foot Dorsiflexion 
 Test position - sitting, with the heel on floor, foot in full dorsiflexion, and shoes and socks 
removed.  
 Verbal instructions: "Bend your foot up as far as possible." The toes are relaxed during the 
test. The hand giving resistance is cupped over the top of the foot proximal to the toes. The 
other hand is contoured around the front of the leg just proximal to the ankle. The examiner 
then states "Hold it, don't let me push it down" and scores Grade 3, 4 or 5.  
 If weaker than Grade 3, but there is partial range 
of motion against gravity, assign Grade 2. 
 If weaker than Grade 2, palpate the tibialis 
anterior tendon, and score as Grade 1or 0. 
 The bedridden subject is tested supine, with the 
leg extended and a pillow placed under the knee. 
 
 
Foot Plantarflexion 
 Test position - sitting, with the heel on floor, 
foot in full dorsiflexion, and shoes and socks 
removed.  
 Verbal instructions: "Lift your heel and point 
your toes down as far as possible." The hand giving resistance is cupped over the top of the 
foot proximal to the ankle. The other hand is contoured around the front of the leg just 
proximal to the ankle. The examiner then states "Hold it, don't let me push it down" and 
scores Grade 3, 4 or 5.  
 If weaker than Grade 3, but there is partial range of motion against gravity, assign Grade 2. 
 If weaker than Grade 2, palpate the tibialis anterior tendon, and score as Grade 1or 0. 
 The bedridden subject is tested supine, with the leg extended and a pillow placed under the 
knee. 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 96 of 101 
 
 
 
 
 
 
Appendix 7. 
Measuring Muscle Circumference 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 97 of 101 
To reduce variability, whenever possible, the same health care professional should conduct all of 
the muscle circumference measurements.  Conduct all measurements bilaterally. 
 
 
Mid-upper Arm Muscle Circumference: 
Locate the midpoint of the upper arm.  
 Seat the subject in a comfortable chair with his/her hip and knee 
joint flexed at 90° and their forearm resting on a supporting 
armrest with the palm facing up.   
 The elbow should be flexed at 90 degrees with palm facing 
upwards 
 Stand behind the subject & locate the lateral tip of the acromion 
and the most distal point on the olecranon process 
 Place a tape measure so that it passes between these 2 landmarks 
and mark the midpoint  
 
Measure the upper arm circumference  
 The subject can stand with arms hanging freely at the sides or stay 
seated and dangle his/her arms at his/her side with the palms 
facing the thighs 
 Place the tape measure perpendicular to the long axis of the arm 
at the marked midpoint and measure the circumference to the 
nearest mm. (e.g. 18.1 cm) 
 
 
 
Forearm Muscle Circumference: 
 Seat the subject in a comfortable chair with 
his/her hip and knee joint flexed at 90° and 
his/her forearm resting on a supporting 
armrest with the palm facing up.   
 The elbow should be flexed at 120 degrees 
with palm facing upwards 
 Mark the proximal one third point of a 
vertical line that joins the medial epicondyle 
to the styloid process of the ulna.   
 
Measure the forearm circumference  
 The subject can stand with arms hanging 
freely at the sides or stay seated and dangle 
his/her arms at his/her side with the palms 
facing the thighs  
 Place the tape measure perpendicular to the 
long axis of the arm at the marked point and 
measure the circumference to the nearest mm.  
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 98 of 101 
 
Mid-thigh Muscle Circumference: 
 Seat the subject in a comfortable 
chair with his/her hip and knee joint 
flexed at 90°. 
 Identify the anterior superior iliac 
spine (slightly above the inguinal 
crease) and the superior edge of the 
patella. No pressure should be 
applied at the inguinal crease, but, 
folds of fat tissue may have to be 
lifted on to measure at the crease. 
 Mark the midpoint of the thigh  
 Place the tape measure perpendicular 
to the long axis of the thigh at the 
marked point and measure the 
circumference to the nearest mm. 
 
 
 
 
 
 
Calf Circumference: 
 Seat the subject in a comfortable chair with his/her 
hip and knee joint flexed at 90°. 
 Identify the fibular head and the lateral malleolus. 
 Mark the lower leg at the one third point of a vertical 
line that joins the fibular head to the lateral malleolus 
 Place the tape measure perpendicular to the long axis 
of the lower leg at the marked point and measure 
the circumference to the nearest mm. 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 99 of 101 
 
 
 
 
 
 
Appendix 8. 
Dynamometry 
 
 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 100 of 101 
 
Finger Pinch Strength 
Maximal finger pinch strength will be tested using a MicroFet 4 digital dynamometer (Hoggan 
Health Industries, West Jordan, Utah). Measurements should be conducted bilaterally. 
 
 Seat the subject in a comfortable chair with his/her shoulder adducted and neutrally rotated, 
and with the elbow positioned at 90°, and the forearm and wrist in a neutral position.  
 Demonstrate how to use the finger pinch and to show that pinching very tightly registers the 
best score. 
 Ask the subject to hold the dynamometer between the lateral aspect of the middle phalanx of 
the index finger and thumb pad. 
 
 
 
 Instruct the subject to squeeze as hard as he/she can for 3 seconds.  
 Repeat 3 times. Record maximal pinch grip force for each trial. 
 The average of 3 consecutive tests will be calculated for each subject. 
 
Grip Strength  
Maximal grip pinch strength will be tested using a MicroFet 4 digital dynamometer (Hoggan 
Health Industries, West Jordan, Utah). Measurements should be conducted bilaterally. 
 
 Seat the subject in a comfortable chair with his/her shoulder adducted 
and neutrally rotated, and with the elbow positioned at 90°, and the 
forearm with the wrist just over the end of the arm of the chair—wrist 
in a neutral position, thumb facing upwards. 
 Demonstrate how to use the handgrip dynamometer to show that 
gripping very tightly registers the best score.  
 Position the subject‘s hand so that the thumb is around one side of the 
handle and the four fingers are around the other side. The instrument 
should feel comfortable in the hand. Alter the position of the handle if 
necessary. 
 The observer should hold the head of the dynamometer as the subject 
grips it. The aim of this is to support the weight of the dynamometer 

 
 
 
Protocol VMALS-001/B 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 101 of 101 
(to negate the effect of gravity on peak strength), but care should be taken not to restrict its 
movement. 
 Instruct the subject to squeeze as hard as he/she can for 3 seconds.  
 Repeat 3 times. Record maximal grip force for each trial. 
 The average of 3 consecutive tests will be calculated for each subject. 
 
 
Lower Leg Extension 
Maximal lower leg extension strength will be tested using a MicroFet 3 digital dynamometer 
(Hoggan Health Industries, West Jordan, Utah). Measurements should be conducted bilaterally.  
 
 Seat the subject in a comfortable chair with his/her hip and knee joint flexed at 90° and feet 
flat on the floor.  
 The examiner places the dynamometer against the anterior leg proximal to the malleoli. 
 Instruct the subject to straighten out his/her knee and hold his/her 
leg in that position for 3 seconds.  
 Repeat 3 times.  
 Record maximal leg extension for each trial 
 The average of 3 consecutive tests will be calculated for each 
subject.