A Phase1, Randomized, Double-Blind, Placebo-Controlled Study of Single, Twice Daily (BID), and Repeated Dosing of Ascending Doses, to Evaluate Safety, Tolerability, and Systemic Exposure of Intranasal Administration Apo-Si-K170A-C76 in Healthy Subjects.
Phase: PHASE1
Conditions: SARS-CoV-2 (COVID-19) Infection
Sponsor: Interna Therapeutics Ltd.

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 1 of 81                                                           Version 4.0 
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CLINICAL STUDY PROTOCOL 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Centre 
Study of Single, Twice Daily (BID) Doses, and Repeated BID Dosing of 
Ascending Doses, to Evaluate the Safety, Tolerability, and Systemic Exposure 
of Intranasal Apo-Si-K170A-C76 in Healthy Adult Subjects 
 
 
 
Short Title 
Safety, Tolerability, and Systemic Exposure of Apo-Si-
K170A-C76 in Healthy Volunteers 
Protocol Number: 
Sir-001 
Investigational Product: 
Apo-Si-K170A-C76 
Phase: 
1 
Sponsor: 
Interna Therapeutics Ltd. (formerSirVir Ltd. /ApoSense 
Ltd.) 
5 Odem St., P.O. Box 7119, 
Petach Tikva 4917002, Israel 
Tel: 972-73-2397600 
Protocol Date: 
6 Nov, 2024 
 
Protocol Version: 
Version 4.0 
 
 
Compliance Statement 
This study will be conducted in compliance with the protocol, Good Clinical Practice and all 
other applicable regulatory requirements, including the archiving of essential documents.  
 
Confidential Information 
This document contains confidential information which should not be copied, referred to, 
released or published without written approval from Interna Therapeutics , Ltd. 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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PROTOCOL APPROVAL – SIGNATURE PAGE 
Protocol Title: 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, 
Single-Centre Study of Single, Twice Daily (BID) Doses and 
Repeated BID Dosing of Ascending Doses, to Evaluate the 
Safety, Tolerability, and Systemic Exposure of Intranasal 
Apo-Si-K170A-C76 in Healthy Adult Subjects 
Protocol Number:                  Sir-001 
Investigational Products: 
Apo-Si-K170A-C76 
 
 
Interna Therapeutics Ltd. (former SirVir Ltd. / Aposense Ltd.) commits to conduct the study as 
described herein in accordance with the current Declaration of Helsinki and the guidelines on Good 
Clinical Practices (cGCPs) and in compliance with the obligations and requirements of the local 
regulations and the Sponsor’s Standard Operating Procedures (SOPs).  The above -titled study 
protocol was subjected to critical review and the information presented is consistent with the 
current knowledge of the risks and benefits of the investigational product. The following 
individuals approve the Sir-001 protocol, Version 1.0, dated December 12th, 2023.  All changes to 
this version of the protocol must have prior written approval and require an amendment or 
administrative letter.  
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 3 of 81                                                           Version 4.0 
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Sponsor Representative: 
Dr. Hagit Grimberg 
5 Odem St., P.O. Box 7119, 
Petach Tikva 4917002, Israel 
Tel: 972-73-2397600 
Email: Hagit@Interna.Bio 
 
 
Signature: 
 
Hagit Grimberg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 
 12-11-2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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Statistical Consultant: 
Gil Harari, PhD. 
CEO, MediStat Ltd. 
3 HaNehoshet St. 
Ramat Hachayal, Tel-Aviv, Israel 
Tel: +972 3 6444465 
Fax: +972 3 6444467 
Email: gil@medistat.co.il 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 6 of 81                                                           Version 4.0 
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TABLE OF CONTENTS 
PROTOCOL APPROVAL – SIGNATURE PAGE ........................................................................2 
INVESTIGATOR PROTOCOL ACKNOWLEDGMENT .............................................................5 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES AND FIGURES................................................................................................9 
LIST OF TERMS AND ABBREVIATIONS ................................................................................10 
PROTOCOL SYNOPSIS ..............................................................................................................12 
1. 
INTRODUCTION AND BACKGROUND ...........................................................................30 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................................36 
3. 
OVERALL STUDY DESIGN ................................................................................................37 
4. 
STUDY POPULATION .........................................................................................................43 
5. 
STUDY PROCEDURES ........................................................................................................49 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 7 of 81                                                           Version 4.0 
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6. 
INVESTIGATIONAL PRODUCT ........................................................................................55 
7. 
SAFETY AND PHARMACOVIGILANCE ..........................................................................59 
8. 
STATISTICAL METHODOLOGY .......................................................................................68 
9. 
ETHICS ..................................................................................................................................71 
10. QUALITY CONTROL AND QUALITY ASSURANCE .....................................................73 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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11. STUDY ADMINISTRATION ...............................................................................................75 
12. REFERENCES .......................................................................................................................80 
13. APPENDICES ........................................................................................................................81 
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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LIST OF TABLES AND FIGURES  
 
Table 1  Schedule of Assessments: Cohorts 1, 2 and 3 (single dose) ............................................24 
Table 2  Schedule of Assessments: Cohorts 4 and 5 (BID dose)...................................................26 
Table 3  Schedule of Assessments: Cohorts 6 and 7 (repeated dose BID) ....................................28 
Table 4  Study Dosing Plan ...........................................................................................................38 
Table 5  Study Products administered: ..........................................................................................55 
 
 
Figure 1: Apo-Si-K170A-C76 First-In-Human Dosing Study – Study Design .......................37 
 

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
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LIST OF TERMS AND ABBREVIATIONS 
AE(s) 
Adverse Event(s) 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
cGCP 
current Good Clinical Practice 
DSMC 
Data Safety Monitoring Committee  
dsiRNA 
double stranded short interfering RNA  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
ET 
Early Termination 
F/U 
Follow-up 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization Identification 
IN 
Intranasal 
IP 
Investigational Product 
IRB 
Institutional Review Board  
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Medical Monitor  
MNMs 
Molecular Nano Motors  
MOH 
Ministry of Health 
NA 
Not Applicable  
NOAEL 
No-Observed-Adverse-Effect Level  
PI 
Principal Investigator 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetics 
PP 
Per Protocol (population) 
PT 
Preferred Term 
RISC 
RNA-induced silencing complex 
RU 
Research Unit 
SAE 
Serious Adverse Event 
siRNA 
Small interfering RNA  

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 11 of 81                                                           Version 4.0 
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SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SSC 
Safety Steering Committee  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TEAEs 
Treatment-Emergent Adverse Events 
TNSS 
Total Nasal Symptom Score  
 
 
 
 
 
 
 
 
 

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
CONFIDENTIAL                                                  Page 12 of 81                                                              Version 4.0 
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PROTOCOL SYNOPSIS 
Title 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Centre 
Study of Single, Twice Daily (BID) Doses and Repeated BID Dosing of 
Ascending Doses, to Evaluate the Safety, Tolerability, and Systemic Exposure 
of Intranasal Apo-Si-K170A-C76 in Healthy Adult Subjects. 
Study number 
Sir-001 
Study Phase 
First in Human (phase 1) 
Investigational 
Site 
Hadassah Clinical Research Center, Israel  
Indication 
Healthy volunteers 
Study Design 
and Periods 
This is a prospective, randomized, double-blind, placebo-controlled study 
designed to assess the safety, tolerability, and systemic exposure of single, BID 
dosed and repeated BID dosing of ascending doses of intranasal Apo-Si-K170A-
C76 in healthy adult subjects. 
Upon signing the informed consent, the subjects will undergo a screening period 
for eligibility evaluation. Subjects will be admitted to the Research Unit (RU) on 
Day 1 and eligibility will be confirmed again. Eligible subjects, as determined by 
the Principal Investigator (PI), will be randomized as close as possible prior to 
1st drug administration on Day 1 to receive either intranasal Apo-Si-K170A-C76 
or matching placebo. Dosing will depend on the cohort the subjects are assigned 
to.    
Intranasal (IN) administration is performed to both nostrils of all participants. 
The nasal spray device contains the Study Drug at 20 mg/mL and delivers 0.1 mL 
volume per actuation. The subjects will receive 1-3 actuations per nostril 
alternately according to dosing group. After each actuation, an inspiration will 
be performed, and around a 5-second delay will be introduced between each new 
actuation. Thus, during each administration cohort, dosages registered as 
dose/nostril are received twice per subject, one dose to each nostril.  
 
The study will be composed of 7 dosing cohorts. Cohort 1 will involve an initial 
administration of a single (low) dose of Apo-Si-K170A-C76 (2mg/100µl/nostril, 
to both nostrils). Cohort 2 will involve administration of a single dose of Apo-
Si-K170A-C76 at a double dose of the first dose (4mg/200µl/nostril, to both 
nostrils). Cohort 3 will involve administration of a single dose of Apo-Si-K170A-
C76 at the target dose (x3 of first dose, 6mg/300µl/nostril, to both nostrils). 
Cohort 4 will involve BID administration of the same dose as cohort 2, separated 
by 6 hours, and cohort 5 will involve BID administration of the same dose as 
cohort 3, separated by 6 hours, with a new bottle. Administration in cohorts 1-5 
will take place on Day 1. Cohort 6 will involve administration of repeated BID 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 13 of 81                                                           Version 4.0 
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doses of Apo-Si-K170A (at the same dose level or lower than that administered 
in Cohort 4) taken from Day 1 to Day 5. Cohort 7 will involve administration of 
repeated BID doses of Apo-Si-K170A-C76 (at the target dose level or lower than 
that administered in Cohort 5) taken also from Day 1 to Day 5. 
The study drug (or placebo) will be administered to both nostrils via intranasal 
spray, while the subject is seated. To note: In cases  where more than 1 
actuation in each nostril is required ( Cohorts  2-7), the actuations will be 
performed  in an alternately manner. It is necessary to prime the pump bottle 
by spraying it into the air four times prior to using each new bottle. In case of 
failure by the fourth prime actuation, up to 2 more actuations are allowed. If by 
the 6th priming actuation, no or minimal liquid is delivered the bottle will be 
discarded and replaced with another bottle.  
 
Subjects will remain in bed for at least 2 hours post administration. An 
examination of the nasal cavity  will be performed by a study physician at 
screening, 24 hours (+1hr) after each dose  and at the  last follow up visit for all  
subjects in all cohorts. 
The initial dose for this study is based on the non-clinical No-Observed-
Adverse-Effect Level (NOAEL).  
All study staff (with the exception of specified unblinded pharmacy staff), study 
subjects, and the Sponsor will remain blinded to study drug/placebo allocation. 
Each subject will participate in one cohort. Subjects will be screened and 
randomized to active Apo-Si-K170A-C76 or matching placebo in a 3:1 ratio: 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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Part 1  
Dose Concentration 
 
Number of Subjects 
Apo-Si-K170A-C76 
Placebo 
Cohort 1 
2mg/nostril, 4mg/both nostrils 
6 
2 
Cohort 2 
4mg/nostril, 8mg/both nostrils 
6  
2  
Cohort 3 
6mg/nostril, 12mg/both nostrils 
6 
2 
Cohort 4 
4mg/nostril, 8 mg/both nostrils BID 
(16mg/day/both nostrils) 
6 
2 
Cohort 5 
6mg/nostril, 12 mg/both nostrils BID 
(24mg/day/both nostrils) 
6 
2 
Cohort 6 
4mg/nostril, 8 mg/both nostrils BID 
(16mg/day/both nostrils) for 5 days 
6 
2 
Cohort 7 
6mg/nostril, 12 mg/both nostrils BID 
(24mg/day/both nostrils) for 5 days 
6 
2 
Total Subjects 
42 
14 
 
 
Randomization will be performed on Day 1 in a staggered manner: initially, two 
sentinel subjects (one active and one placebo) will be randomized and dosed with 
blinded treatment prior to the remaining subjects. One sentinel subject will be 
dosed with active drug (Apo-Si-K170A-C76) and the other with matching 
placebo. The remaining 6 subjects in the dose cohort will be randomized and 
dosed if no safety concerns (without clinically significant AEs) are identified in 
the sentinel subjects; The decision to proceed and dose additional subjects 
following the first 2 sentinel subjects, according to the randomization schedule, 
will be at the discretion of the investigator and following his review of all their 
medical data. Following completion of cohorts 1, 2 and 3, subjects will be dosed 
in cohort 4. The second dose in this cohort will be administered 6 hours after the 
first one. Cohort 5 will follow in the same manner. Subjects in cohorts 6 and 7 
will be dosed with 4mg/nostril BID or 6mg/nostril BID (of the initial dose), 
respectively, for 5 days. If safety concerns are observed at any time after the 
repeated administration, a lower dose will be selected.   
The decision to escalate to the next dose level, to investigate lower, intermediary, 
or higher doses, will be done by the Safety Steering Committee (SSC) which will 
review blinded emerging data of subjects in a given cohort including safety and 
tolerability. A minimum of 7 days post-dose safety data will be reviewed by the 
SSC to determine the next dose level. All dose escalation decisions, except for 
the transitions between cohort 3 to cohort 4 and cohort 5 to cohort 6, will be 
taken by the SSC. If the SSC considers that an unblinded review of data is 
required to make a decision, then the independent Data Safety Monitoring 
Committee (DSMC) will be asked to undertake this review and make their 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 15 of 81                                                           Version 4.0 
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recommendations. The transition between cohort 3 to cohort 4 and between 
cohort 5 to cohort 6 will be reviewed and confirmed by the DSMC. The transition 
from cohort 5 to cohort 6 will involve, in addition to safety data, the review of 
all systemic exposure results obtained from 5. To note that based on the results 
of the systemic exposure of Cohort 5, the levels of systemic exposure for all or 
part of Cohorts 1-4  samples will be  analyzed as well. 
The subjects will be admitted to the clinic on Day 1. For cohorts 1-5, overnight 
confinement between Day 1 to Day 2 is mandatory and will be discharged on 
Day 2 after all assessments have been completed for this day. For cohorts 6-7, 
confinement to the clinic between Day 1 and through Day 6 is required i.e., 
subjects will be discharged from the clinic on Day 6, after all required 
assessments and procedures have been completed for that day. 
All subjects will arrive at the clinic for a follow up visit 7±2 days after last day 
of administration, i.e., in cohorts 1-5, subjects will arrive on Day 8±2 and 
subjects in cohorts 6-7 will arrive on Day 12±2. Subjects in all cohorts will 
receive the treatment after standardized meals. Water will be freely available at 
all other times. Grapefruit juice and Caffeine containing beverages should be 
avoided until after the 24-hour (±1 hour) post dose blood sampling. 
Investigational 
Products 
Active: 
Intranasal Apo-Si-K170A-C76: Solution of 20 mg/ml in 5% glucose, 0.5% 
benzyl alcohol in RNase free water  
Placebo: 
5% glucose, 0.5% benzyl alcohol in RNase free water 
Study 
Objectives 
Primary Objectives 
 
To evaluate the safety and tolerability of single, BID doses and repeated BID, 
ascending doses of Apo-Si-K170A-C76 administered intranasally (IN) in healthy 
adult subjects. 
 
Secondary Objective 
To evaluate the systemic exposure of Apo-Si-K170A-C76 following intranasal 
administration in healthy adult subjects. 
 
Study 
Population and 
Number of 
planned 
Subjects  
56 healthy subjects are planned to be enrolled (42 active and 14 placebo 
subjects) 
 
Family members can participate in the study. 
Methodology 
 
Screening will take place only once for each participant.  
Cohorts 1-5 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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Screening Up to 21 days prior to dosing: 
1. 
Visit 1 /Screening 
 
 
Treatment Period: 
2. 
Visit 2 / Day 1, admission to the RU and treatment administration 
(single dose (cohorts 1-3) or BID (cohorts 4-6)) 
3. 
Visit 3 / Day 2, 24h post dose assessments 
Discharge from the RU will occur on Day 2 
 
Follow Up (EOS) 
 
4. 
Visit 4 / Day 8 (± 2 days), FU / EOS 7±2 days after administration.  
 
Cohorts 6-7 
Screening Up to 21 days prior to dosing: 
1. 
Visit 1 /Screening 
 
 
Treatment Period: 
2. 
Visit 2 / Day 1, admission to the RU and treatment administration 
(BID) 
3. 
Visit 3 / Day 2, treatment administration (BID) 
4. 
Visit 4 / Day 3, treatment administration (BID) 
5. 
Visit 5 / Day 4, treatment administration (BID) 
6. 
Visit 6 / Day 5, treatment administration (BID) 
7. 
Visit 7 / Day 6, 24h post Day 5-1st dose assessments 
Discharge from the RU will occur on Day 6.  
 
Follow Up (EOS) 
 
8. 
Visit 8 / Day 12 (± 2 days), 7±2 days after last administration, 
FU / EOS 
 
For detailed clinical and safety procedures performed at each visit, please refer 
to the Schedule of Assessments (Table 1, Table 2 and Table 3 for cohorts 1-3, 4-
5 and 6-7, respectively. 
 
From ICF signature up until the first treatment - only Serious Adverse Events 
(SAEs) and non-serious protocol-related (procedure-related) adverse events will 
be reported in the subject’s source and eCRF.  

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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Following initiation of study treatment and until EOS (during the study period) - 
all related and non-related adverse events will be recorded in the subject's eCRF. 
Based upon GCP rules, the relevant AE's will be reported by the Principal 
Investigator to the Local Ethics Committee.    
Clinical Study 
Duration 
The total duration for each participating subject is up to 35 days: Up to 21 days 
of screening and 14 days (7±2 days after last dose) including treatment and the 
follow up visit period (depending on the cohort the subject is assigned to) 
Subject 
Inclusion 
Criteria 
1. Male and female participants must be ≥ 18 years old. 
2. Understands the study procedures described in the Informed Consent Form 
(ICF), be willing and able to comply with the protocol, and provides written 
consent. 
3. Not pregnant or lactating and willing to comply with the contraceptive 
requirements from enrolment to 3 months post last dose. Contraceptive 
requirements include the following: 
a. Use a condom with a spermicide to prevent pregnancy in a female 
partner or to prevent exposure of any partner (male and female) to the 
study intervention treatment.  
b. Male sterilization with the appropriate post vasectomy documentation 
of the absence of sperm in the ejaculate (please note that the use of 
condom with spermicide will still be required to prevent partner 
exposure). This applies only to males participating in the study.  
c. In addition, for female partners and female participants of child-
bearing potential, must use another form of contraception such as one 
of the highly effective methods (pills, Intra Uterine Device (IUD)).  
d. True abstinence - sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. 
The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle 
of the subject.  
e. In addition to the contraceptive requirements above, male subjects 
must agree not to donate sperm for 3 months post last dose. 
4. In good health with no history of clinically significant medical conditions (as 
described in Exclusion criteria) that would interfere with subject safety, as 
defined by relevant medical history, physical examination and routine 
laboratory tests, ECG and determined by the Investigator at an admission 
evaluation. 
5. Subjects will have a documented relevant medical history either prior to 
entering the study and/or following relevant  medical history review with the 
study physician at screening. 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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Subject 
Exclusion 
Criteria 
The presence of any of the following will exclude the potential study participant 
from entering the study: 
Clinical History 
1. History or evidence of any clinically significant or currently active 
cardiovascular, 
(including 
thromboembolic 
events), 
respiratory, 
dermatological, gastrointestinal, endocrine, hematological, hepatic, 
immunological, 
rheumatological, 
metabolic, 
urological, 
renal, 
neurological, or psychiatric illness. Specifically: 
a. Subjects with any history of physician diagnosed and/or objective 
test-confirmed asthma, chronic obstructive pulmonary disease, 
pulmonary hypertension, reactive airway disease, or chronic lung 
condition of any etiology or who have experienced: 
o Significant/severe wheeze in the past 
o Respiratory symptoms including wheeze which has ever resulted 
in hospitalization. 
o Known bronchial hyper-reactivity to viruses. 
b. History of thromboembolic, cardiovascular, or cerebrovascular 
disease 
c. History or evidence of diabetes mellitus 
 
d. Any concurrent serious illness including history of malignancy that 
could interfere with the aims of the study or a subject completing the 
study. Basal cell carcinoma within 5 years of treatment or with 
evidence of recurrence is also an exclusion. 
e. Migraine with associated neurological symptoms such as hemiplegia 
or vision loss.  Cluster headache/migraine or prophylactic treatment 
for migraine 
f. History 
or 
evidence 
of 
autoimmune 
disease 
or 
known 
immunodeficiency of any cause. 
g. Other major disease that, in the opinion of the Investigator, could 
interfere with a subject completing the study and necessary 
investigations. 
h. Immunosuppression of any type 
2. Any significant abnormality altering the anatomy or function of the nose 
or nasopharynx in a substantial way (including loss of or alterations in 
smell or taste), a clinically significant history of epistaxis (large 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
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nosebleeds) within the last 3 months, nasal or sinus surgery within 6 
months of screening. 
3. Clinically active rhinitis (including hay fever) or history of moderate to 
severe rhinitis, or history of seasonal allergic rhinitis likely to be active 
at the time of inclusion into the study and/or requiring regular nasal 
corticosteroids on at least a weekly basis, within 30 days prior to 
screening. 
4. History of anaphylaxis and/or a history of severe allergic reaction or 
significant intolerance to any food or drug, as assessed by the PI. 
5. History or presence of alcohol addiction, or excessive use of alcohol. The 
subject has a history of consuming more than 7 units of alcoholic 
beverages per week for male subjects and more than 5 units for females 
or has a history of alcoholism or drug/chemical/substance abuse within 
the past 2 years prior to screening (Note: one unit = 330 mL of beer, 110 
mL of wine, or 28 mL of spirits), or use of drugs of abuse. 
6. Psychiatric illness, including subjects with a history of depression and/or 
anxiety with associated severe psychiatric comorbidities, for example 
psychosis. Specifically, (a) Subjects with history of anxiety-related 
symptoms of any severity within the last 2 years if the Generalized 
Anxiety Disorder-7 score is ≥4; (b)Subjects with a history of depression 
of any severity within the last 2 years if the Patient Health Questionnaire-
9 score is ≥4 
7. Subjects who have smoked ≥5 pack years at any time [5 pack years is 
equivalent to one pack of 20 cigarettes a day for 5 years]). 
• Subjects who have smoked <5 pack years - at any time in the 3 
months prior to screening, have used tobacco in any form (e.g., 
smoking or chewing) or other nicotine-containing products in any 
form (e.g., gum, patch) or electronic cigarettes. 
Measurements and investigations 
8. A Body Mass Index (BMI) ≤18 Kg/m2 and ≥28 Kg/m2. The upper limit 
of BMI may be increased up to 30 Kg/m2 at the PI’s discretion, in the 
case of physically fit muscular individual. 
9. Venous access deemed inadequate for the phlebotomy and cannulation 
demands of the study. 
10. At the discretion of the PI, any clinically significant abnormal finding on 
screening biochemistry, hematology, serology , microbiology blood tests 
or urinalysis  or 
a. 
Positive HIV, active/chronic hepatitis B or C test. 

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b. 
Positive β -HCG or positive alcohol test  
11. Confirmed positive test for drugs of abuse and/or urinary cotinine at 
screening and on admission (Day 1). 
12. Twelve-lead ECG recording with clinically relevant abnormalities as 
judged by the study physician/PI. 
Recent respiratory infection 
13. Presence of cold-like symptoms and/or fever (defined as subject 
presenting with a temperature reading of >37.9ºC) at screening or on 
admission (Day 1). 
Receipt of medications and interventions 
14. Receipt of blood or blood products, or loss (including blood donations) 
of 550 mL or more of blood during the 3 months prior to screening. 
15. Medications 
a. Use of any medication or product (prescription or over-the-
counter) for symptoms of hay fever, nasal congestion or 
respiratory tract infections, or dermatitis/eczema including the 
use of regular nasal or medium-high potency dermal 
corticosteroids, antibiotics and First Defence™ (or generic 
equivalents) within 7 days prior to screening. The sporadic use of 
paracetamol or other medications will be acceptable only as 
agreed by the Principal Investigator. 
b. Receipt of any investigational drug within 3 months prior to 
screening. 
c. Receipt of three or more investigational drugs within the previous 
12 months prior to screening. 
d. Receipt of systemic (intravenous and/or oral) glucocorticoids or 
systemic antiviral drugs within 6 months prior to screening. 
e. Over the counter medications (e.g., paracetamol or ibuprofen) 
where the dose taken over the preceding 7 days prior to screening 
had exceeded the maximum permissible 24-hour dose (e.g., >4g 
per day of paracetamol over the preceding week). 
f. Chronically used medications, including any medication known 
to be a moderate/potent inducer or inhibitor of cytochrome P450 
enzymes, within 21 days prior to screening. 
g. Subjects who have received any systemic chemotherapy agent, 
immunoglobulins, or other cytotoxic or immunosuppressive 
drugs at any time. 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 21 of 81                                                           Version 4.0 
                                                                                                                                                                 Nov 6,2024 
 
Other 
16. Subjects who are currently employed by or are first-degree relative of 
someone employed by the Sponsor or participating clinical trial site, or 
any Contract Research Organization involved in this study. 
17. Any other reason that the Investigator considered made the subject 
unsuitable to participate. 
 
Safety and 
Tolerability 
Endpoints 
• 
Frequency and severity of Adverse Events (AEs), including Serious Adverse 
Events (SAEs) and Treatment-emergent AEs (TEAEs) occurring at any time 
during the study. 
• Change from Baseline to End of Study (EOS) in: 
o Laboratory tests including urinalysis and blood tests 
o Vital signs 
o Physical examination 
o TNSS  

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 22 of 81                                                           Version 4.0 
                                                                                                                                                                 Nov 6,2024 
Systemic 
Exposure 
Measurements 
 
Systemic exposure will be determined by measuring concentrations of serum 
Apo-Si-K170A obtained from subjects who receive Apo-Si-K170A in each dose 
cohort, at specific time points. Based on the results of the systemic exposure of 
Cohort 5, the levels of systemic exposure for all or part of Cohorts 1-4  samples 
will be  analyzed as well. 
Pharmacokinetic (PK) analysis will be considered if required, according to the 
concentrations measured. In case required, the following PK variables will be 
determined using serum samples: 
• Cmax - Maximum concentration achieved. 
• Tmax - Time to reach maximum concentration (hours). 
• AUClast – The area under the concentration vs. time curve, calculated as 
sum of AUCs using linear trapezoidal summation from time 0 to the last 
measurable data point. 
• AUCpartial – The area under the concentration vs. time curve, calculated 
as sum of AUCs using linear trapezoidal summation from time 0 to the 
maximal measurement (Tmax). 
• z (Lambdaz)- Individual estimate of the terminal elimination rate 
constant, was calculated using log-linear regression of the terminal 
portions of the plasma concentration-versus-time curves.  
• AUCinf - The area under the serum concentration-time curve 
extrapolated to infinity, calculated as:  
AUCinf was calculated as AUClast + Clast/z, where Clast is the last 
measurable concentration. 
• T1/2 - Apparent terminal elimination half-life time (hours), defined as 
0.693/z. 
Statistical 
Methods 
 
Sample size rationale and justification 
This is a Phase 1 safety study designed to evaluate the safety, tolerability, and 
systemic exposure of Apo-Si-K170A-C76. The sample size is not based on 
power calculations. It is chosen based on clinical experience and typical SAD 
and multiple administration designs and considered to be adequate to fulfil the 
objectives of the study.   
General: 
Tabulation of descriptive statistics, calculation of inferential statistics (if 
relevant), and graphical representations (if relevant) will be performed using 
SAS® version 9.4 or higher for Windows. 
All demography, baseline characteristics and safety analyses will be performed 
on the Safety Analysis Set.  
All measured variables will be listed individually. 
All measured variables and derived variables will be tabulated by dose cohort 
and overall (for all treatment arms, not including placebo) for the following 
descriptive statistics: 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 23 of 81                                                           Version 4.0 
                                                                                                                                                                 Nov 6,2024 
 
 
• 
Continuous variables will be summarized by the number of observations 
(n), mean, standard deviation, median, minimum, and maximum and 95% 
CI for means of variables if appropriate, by dose group (cohort) and 
treatment arm.  
• 
Categorical variables will be summarized by frequency counts and 
percentages [n (%)] for each category. Unless otherwise stated, 
percentages will be calculated out of the number of subjects in the 
relevant Analysis Set (Safety Analysis Set), by dose group (cohort) and 
treatment arm.  
No data imputation will be performed. 
 
Safety Endpoints: 
Adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA, most updated version) terminology and presented in tables 
by System Organ Class (SOC) and Preferred Term (PT).  
AE data will be listed individually and summarized by SOC and by PT within a 
system organ class. 
Frequency of TEAEs (Treatment-Emergent Adverse Events) and drug-related 
adverse events will be summarized in tables by SOC, PT and by seriousness. 
Concomitant medications entered into the database will be coded using the public 
World Health Organization (WHO) Drug Reference List, which employs the 
Anatomical Therapeutic Chemical classification system.  
Change from Baseline to EOS in safety laboratory, vital signs and physical 
examination will be summarized in appropriate tables. 
 

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
CONFIDENTIAL                                                  Page 24 of 81                                                              Version 4.0 
                                                                                                                                                                   Nov 6 2024 
 
Table 1  Schedule of Assessments: Cohorts 1, 2 and 3 (single dose) 
 
Screening1 
-21 to Day 1 
 
Treatment 
administration 
Day 12 
Day 2  
 
EOS: 
Day 8 
(± 2 day) 
F/U 
Visit No. 
1 
2 
3 
4 
Informed consent3 
X 
 
 
 
Complete medical history 
X 
 
 
 
Height4, weight, and BMI calculation 
X 
 
 
 
Vital signs5  
X 
X 
X 
X 
TNSS6 
X 
X 
X 
X 
Complete physical examination7 
X 
 
 
 
Focused physical examination8 
 
X 
X 
X 
12-lead safety ECGs9 
X 
X 
X 
X 
Blood and urine for safety analyses10 
X 
 
 
X 
SARS-CoV-2 screening test11 
X 
X 
 
 
Blood sampling for systemic 
exposure12 
 
X 
X 
 
Blood for hep B, hep C, HIV 
serology 
X 
 
 
 
 
1 Screening must occur within 21 days prior to the start of dosing. Screening will take place only once for each participant. 
2 Overnight confinement to the clinic between Day 1 and Day 2 is mandatory (through 24 hours post dose); i.e., subjects will be 
discharged on Day 2 after all required assessments and procedures have been completed for that day. The PI or designee will 
confirm that the subject is fit for discharge on Day 2. 
3 Informed Consent must be obtained prior to initiating any study procedure. Subject eligibility should be confirmed also on Day 
1 prior to dosing.  
4 Height to be measured only at screening. 
5 Vital signs will be obtained at Screening, within 2 hours prior to and 1, 2, 4, and 8 hours (all ± 20 minutes) post dose on Day 1, 
at 24 hours (± 1 hour) post dose on Day 2 and at F/U. Vital signs should be captured after 5 minutes of rest while the subject is in 
a supine or seated position.   
6 Subjects will complete the TNSS scale to rate their nasal symptoms.  TNSS will be tested at screening, within 2 hours prior to 
dosing, and 1 hour (± 20 minutes) after dosing. Also, TNSS will be recorded on Day 2, 24 hours (± 1 hour) after the dose 
administered on Day 1, and at the EOS visit. 
7 A complete physical examination (i.e., general appearance, head, ears, eyes, nose, throat, dentition, thyroid, chest [heart, lungs], 
abdomen, skin, neurological, extremities, back, neck, musculoskeletal, lymph nodes) will be performed at Screening. 
8 A focused physical examination consisting of the chest (heart, lungs), abdomen, skin, neurological, and musculoskeletal 
examinations will be performed within 2 hours prior to dosing of Treatment, upon discharge on Day 2, and at the F/U visit.  
9 Safety ECGs will be obtained at Screening Visit. A single 12-lead safety ECG will also be obtained on Day 1, pre-dose (within 2 
hours prior to dosing) and at 1 hour ± 20 minutes and 24 hours (± 1 hour) post dose. Safety ECGs will be obtained at F/U. The 
ECGs should be captured after 5 minutes of rest in a semi-supine / supine position. 
10 Blood samples will be collected for chemistry, hematology, and coagulation at Screening and at F/U.  Urine samples will be 
collected for urinalysis (and urine microscopy if urinalysis is + or above for red blood cells, white blood cells, protein, or nitrite) 
at Screening and at F/U. 
11 Performed locally using a kit.  
12 On Day 1, obtain blood for systemic exposure prior to dosing (within 2 hour before), at 30 and 60 minutes (all ± 5 minutes) 
and 2, 3, and 4 hours (all ± 10 minutes), 6 and 8 hours (all ± 20 minutes) post dose. A 24-hour (± 1 hour) post dose sample will 
be collected on Day 2. 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 25 of 81                                                           Version 4.0 
                                                                                                                                                                 Nov 6,2024 
 
Screening1 
-21 to Day 1 
 
Treatment 
administration 
Day 12 
Day 2  
 
EOS: 
Day 8 
(± 2 day) 
F/U 
Visit No. 
1 
2 
3 
4 
Alcohol test and urine test for drugs 
of abuse, cotinine and pregnancy13 
X 
X 
 
 
Eligibility confirmation  
X3 
X3 
 
 
Randomization14 
 
X 
 
 
IN administration of treatment 
 
X 
 
 
Assess for AEs15 
X 
X 
X 
X 
Prior and concomitant medications16 
X 
X 
X 
X 
Examination of nasal cavity  
X 
 
X 
X 
Abbreviations: AEs = Adverse events; BMI = Body mass index; ECG = Electrocardiogram; EOS = End of Study; F/U = Follow-up; HIV = 
Human immunodeficiency virus; I.N. = Intranasal (administration); TNSS = Total nasal symptom score.  
 
 
13 At screening, alcohol and pregnancy will be tested in blood and drugs and cotinine in urine (all central lab). On Day 1 prior to 
dosing, alcohol, drugs, cotinine, and β-HCG will be tested locally in urine. 
14 Randomization to placebo or active will occur as close as possible prior to the first administration of Treatment. 
15 Adverse events will be collected from the time of informed consent through the F/U visit. 
16 Prior and concomitant medication history includes all medications (including over-the-counter medications, vitamins, and 
supplements) taken from 30 days prior to informed consent signing through the F/U visit.  

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
CONFIDENTIAL                                                  Page 26 of 81                                                              Version 4.0 
                                                                                                                                                                   Nov 6 2024 
Table 2  Schedule of Assessments: Cohorts 4 and 5 (BID dose) 
 
Screening1 
-21 to Day 1 
Day 1 
 Treatment 
administration2 
Day 2  
 
EOS:  
Day 8 
(± 2 day) 
F/U 
Visit No. 
1 
2 
3 
4 
Informed consent3 
X 
 
 
 
Complete medical history 
X 
 
 
 
Height4, weight, and BMI calculation 
X 
 
 
 
Vital signs5  
X 
X 
X 
X 
TNSS6 
X 
XX 
X 
X 
Complete physical examination7 
X 
 
 
 
Focused physical examination8 
 
X 
X 
X 
12-lead safety ECGs9 
X 
X 
X 
X 
Blood and urine for safety analyses10 
X 
 
 
X 
SARS-CoV-2 screening test11 
X 
X 
 
 
Blood sampling for systemic exposure12 
 
X 
X 
 
Blood for hep B, hep C, HIV serology 
X 
 
 
 
 
1 Screening must occur within 21 days prior to the start of dosing. Screening will take place only once for each participant. 
2 Overnight confinement to the clinic between Day 1 and Day 2 is mandatory (through 24 hours post dose); i.e., subjects will be 
discharged from the clinic on Day 2 after all required assessments and procedures have been completed for that day. The PI or 
designee will confirm that the subject is fit for discharge on Day 2. 
3 Informed Consent must be obtained prior to initiating any study procedure. On Day -1, subject eligibility should be confirmed. 
4 Height to be measured only at screening. 
5 Vital signs will be obtained at Screening, within 2 hours prior to and 1, 2, 4, 6 (but pre-2nd dose) and 8 hours (all ± 20 minutes) 
post 1st dose on Day 1, at 24 hours (± 1 hour) post 1st dose on Day 2 and at F/U. Vital signs should be captured after 5 minutes of 
rest while the subject is in a supine / seated position. 
6 Subjects will complete the TNSS scale to rate their nasal symptoms.  TNSS will be tested at screening, within 2 hours prior to the 
1st dose on Day 1, and 1 hour (± 20 minutes) after each dose. Also, TNSS will be recorded on Day 2, 24 hours (± 1 hour) after the 
1st dose administered on Day 1, and at the EOS visit. 
7 A complete physical examination (i.e., general appearance, head, ears, eyes, nose, throat, dentition, thyroid, chest [heart, lungs], 
abdomen, skin, neurological, extremities, back, neck, musculoskeletal, lymph nodes) will be performed at Screening. 
8 A focused physical examination consisting of the chest (heart, lungs), abdomen, skin, neurological, and musculoskeletal 
examinations will be performed within 2 hours prior to the 1st dose of Treatment, on Day 2 and F/U visit.  
9 Safety ECGs will be obtained at Screening Visit. A single 12-lead safety ECG will also be obtained on Day 1, pre-dose (within 2 
hours prior to 1st dosing) and at 1, 6 hours (but pre-2nd dose), 7 hours (i.e. 1 hour post 2nd dose) (all ± 20 minutes) and 24 hours 
(± 1 hour) post 1st dose. Safety ECGs will be obtained at F/U. The ECGs should be captured after 5 minutes of rest in a semi-
supine/ supine position. 
10 Blood samples will be collected for chemistry, hematology, and coagulation at Screening and at F/U. Urine samples will be 
collected for urinalysis (and urine microscopy if urinalysis is + or above for red blood cells, white blood cells, protein, or nitrite), 
at Screening and at F/U 
11 Performed locally using a kit.  
12 On Day 1, obtain blood for systemic exposure prior to 1st dosing (within 2 hour before), and then at 30 and 60 minutes (all ± 5 
minutes), and 2, 3, and 4 hours (all ±10 minutes), 6, 6.5, 7, 8, 9, and 10 hours (all ±20 minutes) after 1st dosing. A 24-hour (± 1 
hour) post 1st dosing sample will be collected on Day 2.  

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 27 of 81                                                           Version 4.0 
                                                                                                                                                                 Nov 6,2024 
 
Screening1 
-21 to Day 1 
Day 1 
 Treatment 
administration2 
Day 2  
 
EOS:  
Day 8 
(± 2 day) 
F/U 
Alcohol test and urine test for drugs of 
abuse,  cotinine and pregnancy 13 
X 
X 
 
 
Eligibility Confirmation  
X3 
X3 
 
 
Randomization14 
 
X 
 
 
IN administration of treatment 
 
XX (BID) 
 
 
Assess for AEs15 
X 
X 
X 
X 
Prior and concomitant medications16 
X 
X 
X 
X 
Examination of nasal cavity 
X 
 
X 
X 
 
Abbreviations: AEs = Adverse events; BMI = Body mass index; ECG = Electrocardiogram; EOS = End of Study; F/U = Follow-up; HIV = 
Human immunodeficiency virus; I.N. = Intranasal (administration); TNSS = Total nasal symptom score.  
 
13 At screening, alcohol and pregnancy will be tested in blood and drugs and cotinine in urine (all central lab). On Day 1 prior to 
dosing, alcohol, drugs, cotinine, and β-HCG will be tested locally in urine. 
14 Randomization to placebo or active will occur as close as possible prior to the first administration of Treatment. 
15 Adverse events will be collected from the time of informed consent through the F/U visit. 
16 Prior and concomitant medication history includes all medications (including over-the-counter medications, vitamins, and 
supplements) taken from 30 days prior to informed consent signing through the F/U visit. 

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
CONFIDENTIAL                                                  Page 28 of 81                                                              Version 4.0 
                                                                                                                                                                   Nov 6 2024 
 
Table 3  Schedule of Assessments: Cohorts 6 and 7 (repeated dose BID) 
Day / Visit 
Screening1 
-21 to Day 
1 
Day 1  
Treatment 
administration2 
Day 2 to 
Day 4 
Continued  
Dosing of  
Treatment 
Day 5  
Final  
Treatment 
administration 
Day 6 
 
EOS: 
Day 12 
(±2 day) 
F/U 
Visit No. 
1 
2 
3, 4, 5 
6 
7 
8 
Informed consent3 
X 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
Height4, weight, and BMI 
calculation 
X 
 
 
 
 
 
Vital signs5 
X 
X 
X 
X 
X 
X 
TNSS6 
X 
XX 
XX 
XX 
X 
X 
Complete physical examination7 
X 
 
 
 
 
 
Focused physical examination8 
 
X 
 
X 
X 
X 
12-lead safety ECG9 
X 
X 
X 
X 
X 
X 
Blood and urine for safety 
analyses10 
X 
 
X 
 
 
X 
SARS-CoV-2 screening test11 
X 
X 
 
 
 
 
Blood sampling for systemic 
exposure12 
 
X 
X 
X 
X 
 
 
1 Screening must occur within 21 days prior to the start of dosing. Screening will take place only once for each participant. 
2 Confinement to the clinic between Day 1 and through 24 hours post 1st dose of last treatment day, is mandatory; i.e., subjects will 
be confined from Day 1 through the morning of Day 6 in the research unit and will be released after all required assessments and 
procedures have been completed on Day 6. The PI or designee will confirm that the subject is fit for discharge. 
3 Informed Consent must be obtained prior to initiating any study procedure. On Day 1 subject eligibility should be also confirmed. 
4 Height to be measured only at screening. 
5 Vital signs will be obtained at Screening, within 2 hours prior to and 1, 2, 4, 6 and 8 hours (all± 20 minutes) after the 1st dose of 
study drug on Days 1 to 5, at 24 hours (± 1 hour) post the 1st dose of study drug on the previous day on Day 6, and at F/U. Vital 
signs should be captured after 5 minutes of rest while the subject is in a supine/ seated position. 
6 Subjects will complete the TNSS scale to rate their nasal symptoms.  TNSS will be tested at screening, within 2 hours prior to the 
1st dose of each treatment day, and 1 hour (± 20 minutes) after each dose. Also, TNSS will be recorded on Day 6, 24 hours (± 1 
hour) after the 1st dose administered on Day 5, and at the EOS visit. 
7 A complete physical examination (i.e., general appearance, head, ears, eyes, nose, throat, dentition, thyroid, chest [heart, lungs], 
abdomen, skin, neurological, extremities, back, neck, musculoskeletal, lymph nodes) will be performed at Screening. 
8 A focused physical examination consisting of the chest (heart, lungs), abdomen, skin, neurological, and musculoskeletal 
examinations will be performed within 2 hours prior to the 1st dose of Treatment on Day 1, on Days 5 and 6, and at the F/U visit. 
9 Safety ECGs will be obtained at Screening Visit. A single 12-lead safety ECG will also be obtained on Day 1, pre-dose (within 2 
hours prior to 1st dosing) and at 1, 6 hour (but pre-2nd dose), 7 hours (i.e. 1 hour post 2nd dose) (all ± 20 minutes). On Days 2-5, 
ECG will be recorded pre-dose (within 2 hours prior to 1st dosing) and 1 hour post 2nd dosing of the same day. On Day 6, ECG will 
be recorded 24 hours (± 1 hour) post 1st dose of Day 5. Safety ECGs will be obtained at F/U. The ECGs should be captured after 5 
minutes of rest in a semi-supine / supine position. 
10 Blood samples will be collected for chemistry, hematology, and coagulation at Screening, on Day 3 (prior to 1st dosing), and at 
F/U. Urine samples will be collected for urinalysis (and urine microscopy if urinalysis is + or above for red blood cells, white blood 
cells, protein, or nitrite) at Screening, on Day 3 (prior to 1st dosing) and at F/U. 
11 Performed locally using a kit.  
12 On Day 1, obtain blood for systemic exposure prior to 1st dosing (within 2 hour before), and then at 30 and 60 minutes (all ± 5 
minutes), and 2, 3, and 4 hours (all ±10 minutes), 6, 6.5, 7, 8, 9, and 10 hours (all ±20 minutes) after 1st dosing. A 24-hour (± 1 
hour) post 1st dosing sample will be collected on Day 2 (this will be the pre-dose sample of Day 2). On Days 2-5, the same time 
points as on Day 1 will be collected. A 24-hour (±1 hour) post Day 5-1st dosing sample will be collected on Day 6. 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 29 of 81                                                           Version 4.0 
                                                                                                                                                                 Nov 6,2024 
Day / Visit 
Screening1 
-21 to Day 
1 
Day 1  
Treatment 
administration2 
Day 2 to 
Day 4 
Continued  
Dosing of  
Treatment 
Day 5  
Final  
Treatment 
administration 
Day 6 
 
EOS: 
Day 12 
(±2 day) 
F/U 
Blood for hep B, hep C, HIV 
serology 
X 
 
 
 
 
 
Alcohol test and urine test for 
drugs of abuse, cotinine and 
pregnancy13 
X 
X 
 
 
 
 
Eligibility Confirmation  
X3 
X3 
 
 
 
 
Randomization14 
 
X 
 
 
 
 
IN administration of treatment15 
 
XX (BID) 
XX (BID) 
XX (BID) 
 
 
Assess for AEs16 
X 
X 
X 
X 
X 
X 
Prior and concomitant 
medications17 
X 
X 
X 
X 
X 
X 
Examination of nasal cavity  
X 
 
X 
X 
X 
X 
Abbreviations: AEs = Adverse events; BMI = Body mass index; ECG = Electrocardiogram; EOS = End of Study; F/U = Follow-up; HIV = 
Human immunodeficiency virus; I.N. = Intranasal (administration); TNSS = Total nasal symptom score.  
 
13 At screening, alcohol and pregnancy will be tested in blood and drugs and cotinine in urine (all central lab). On Day 1 prior to 
dosing, alcohol, drugs, cotinine, and β-HCG will be tested locally in urine. 
14 Randomization to placebo or active will occur as close as possible prior to the first administration of Treatment. 
15 The 1st Treatment dosing will occur on Day 1. Subjects will receive IN study drug twice a day (q6h) on Days 1 through 5. 
16 Adverse events will be collected from the time of informed consent through the F/U visit. 
17 Prior and concomitant medication history includes all medications (including over-the-counter medications, vitamins, and 
supplements) taken from 30 days prior to informed consent signing through the F/U visit. 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 30 of 81                                                           Version 4.0 
                                                                                                                                                                 Nov 6,2024 
1. 
INTRODUCTION AND BACKGROUND 
1.1 Interna Therapeutics  Ltd. Technology 
SARS-CoV-2 remains a Public Health Emergency of International Concern [as determined by the 
World Health Organization (WHO)] over three and a half years after the first cases of atypical 
pneumonia were identified in Wuhan, China. An unprecedented global effort to contain the virus 
has so far failed to consistently prevent its spread. The virus’s remarkably high replication rate and 
highly mutagenic nature have greatly limited the efficacy of nation-scale lockdowns, rapid 
development, and massive deployment of novel vaccine technologies, as well as the rapid 
development of novel treatments. As of this writing, and despite 4.62 billion individuals having 
been fully vaccinated, 2023 has seen over 868,000 new COVID-19 cases and over 3,700 deaths 
were reported in July 2023 (26 June to 23 July 2023). As of 23 July 2023, over 768 million 
confirmed cases and over 6.9 million deaths have been reported globally (WHO report 27Jul2023).  
In addition to vaccines, whose efficacy against the Wuhan strain and corresponding decrease in 
efficacy against Omicron has been well established, numerous novel antiviral treatments have been 
developed in record time. Due to the monumental efforts to develop SARS-CoV-2 vaccines and 
antiviral therapies in response to the COVID-19 pandemic, SARS-CoV-2 is to the view of pas 
emerging pandemics, such as MERS, SARS and SARS-CoV-2, a possible emergence of novel 
strains and new pandemic potential.  Numerous novel antiviral treatments were developed over 
the course of the SARS-CoV-2 pandemic. However, the most significant of these, LAGEVRIO 
(molnupiravir) and PAXLOVID (nirmatrelvir and ritonavir), also suffer from significant 
limitations, including low efficacy and the potential for significant adverse events. Furthermore, 
molnupiravir is an isopropylester prodrug of a nucleoside analogue and thus has the potential to 
cause mutations in both the SARS-CoV-2 virus and the patients using the drug. Nirmatrelvir, based 
on unpublished studies by Pfizer, has exhibited greater efficacy than molnupiravir. However, 
nirmatrelvir must be co-administered with ritonavir, which is used to extend the serum half-life of 
PAXLOVID. Ritonavir, as a potent inhibitor of a human protease, will also interfere with the 
metabolism of many other drugs, including anticoagulants and immunosuppressive medications 
used in organ transplant patients and patients being treated for autoimmune diseases. In these 
patients, who are also vulnerable to SARS-CoV-2 infections, the dosage of these other drugs will 
need to be modified. In addition, the combined use of nirmatrelvir and ritonavir requires a total 
dose of 30 pills given over a 5-day period. 
The limitations of these therapeutics, the limited long-term efficacy of vaccines in preventing the 
spread of new variants, and the corresponding magnitude of the ongoing pandemic, all highlight 
the critical need for the continued development of novel antiviral treatments. New treatment 
options orthogonal to existing vaccination and treatment approaches, with prophylactic as well as 
therapeutic capabilities, and which are efficacious against all currently known variants, would 
doubtless prove as critical tools in the ongoing efforts to mitigate the pandemic.  
-Interna Therapeutics Ltd. has developed a unique delivery modality (Molecular Nano Motors 
(MNMs)) that harnesses the dipole potential present within all cell membranes. The potential is 
large (108-109 V/m), and can be leveraged for the delivery of genetic cargo. The Interna 
Therapeutics Ltd. delivery modality exploits this universal property of phospholipid bilayer 
membranes for medical applications for the first time. 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 31 of 81                                                           Version 4.0 
                                                                                                                                                                 Nov 6,2024 
Two MNMs are attached to a Small interfering RNA (siRNA) through a linkage that is cleaved 
only upon entry into cells, thereby releasing the siRNA and trapping it in the cytoplasm. Once 
released, the siRNA can exert its biological effect, while the remnant MNM is metabolized and 
excreted. 
Once inside the cytoplasm, the siRNA guide strand associates with the RISC (RNA-induced 
silencing complex) machinery to direct targeted mRNA degradation.  The siRNA-RISC complex 
can remain active for many days and even weeks, meaning that this therapeutic approach is 
targeted, potent and durable. 
The sequence of the siRNA can be tailored to target universally conserved viral genes and can be 
rapidly modified to keep pace with mutagenesis. This same approach can be used to rapidly 
generate drug candidates for all 23 human respiratory viruses. 
 
1.2 Investigational Therapy (Apo-Si-K170A-C76)  
Apo-Si-K170A-C76 is a double-stranded short interfering RNA (dsiRNA), which is specifically 
designed to target mRNA of the RNA-dependent RNA polymerase (RdRp) gene of SARS-CoV-2. 
The RdRp protein is crucial for the replication and transcription of SARS-CoV-2, and the RdRp 
gene is the most conserved region in the SARS-CoV-2 viral genome. RdRp plays a crucial role in 
the viral life cycle and is essential for viral survival; hence, targeting the corresponding mRNA 
sequence to hinder its translation or induce its enzymatic degradation may be an effective 
therapeutic strategy.  
Therapeutic oligonucleotides have attracted great interest due to their potency and potential for 
changing the therapeutic landscape of many pathological conditions, including those of viral 
origin. Targeting conserved SARS-CoV-2 RNA sequences essential for viral replication offers a 
rational approach to inhibit viral infection, thereby halting disease progression. Bioinformatics 
analysis of approximately 6,000,000 viral genome sequences showed full coverage of all current 
variants; therefore, Apo-Si-K170A-C76 is expected to be efficacious for treatment of disease 
caused by all known mutations and probably emerging variants in the future. The efficacy of 
several variants has recently been experimentally confirmed. 
The method by which siRNA causes the silencing of genes is as follows: 
1. The dsiRNA enters the cell and is cleaved by the Dicer enzyme within the cytosol, producing 
siRNA. 
2. The duplex separates, to form the sense and the antisense single-stranded siRNA. 
3. The antisense strand of the siRNA interacts with cellular proteins to form an RNA-induced 
silencing complex (RISC). 
4. RISC scans all mRNA in the cytoplasm for complementary sequences.  
5. Once mRNA bearing complementary sequence(s) is identified, cleavage of the mRNA is 
induced, and the gene translation is silenced. 
Despite the great promise of siRNA-based therapy and the significant resources that have been 
committed in efforts to bring such therapies into the clinic, only six siRNA-based drugs have been 

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approved to date. The primary hurdle on the road to the widespread use of siRNA therapy is the 
difficulty in efficiently delivering siRNA into the cytoplasm. The obstacle preventing siRNA 
duplexes from gaining entry into cells is an energetic barrier inherent to all interactions between 
large, charged molecules, such as nucleic-acids, and the phospholipid bilayer of cell membranes. 
This energetic barrier is the result of the low dielectric constant of the hydrocarbon interior of all 
phospholipid bilayers, which prevents the penetration of polar molecules, especially those bearing 
fixed charges. 
Various approaches for delivery have been developed, including transfection, viral-mediated 
delivery, 
chemical 
modifications 
of 
the 
nucleic 
acid 
backbone, 
conjugation 
to 
N-Acetylgalactosamine (GalNAc), as well as formulations encapsulating the RNA cargo into lipid 
nanoparticles (LNP) or DNA nanostructures. However, all these approaches suffer from significant 
limitations. The most widely applied approach is transfection, which is limited to use in-vitro. 
Viral-mediated delivery is often inefficient, requiring large doses of virus, which result in toxicity. 
LNPs have been employed to great effect in delivery of mRNA cargo, but they are unstable and 
thus require ultra-low temperature storage conditions. Additionally, LNP siRNA particles (such as 
patisiran) require that the patient be premedicated with steroids and antihistamines to prevent 
unwanted immune response. To date, only GalNAc has a proven clinical track-record, meaning 
that the applications of siRNA therapy have been mainly limited to the targeting of disease drivers 
present in the liver. Consequently, realization of the true therapeutic potential of siRNA-mediated 
gene silencing has awaited the establishment of a siRNA-delivery mechanism capable of safe and 
efficient delivery into any cell type. 
The development of Apo-Si-K170A-C76, a modified oligonucleotide, addresses the challenge of 
delivery of siRNA therapeutics via a novel mechanism of action. The active drug is a construct of 
a double strand dsiRNA sequence attached to two Molecular Nano-Motors (MNM), one on each 
5'-end of the RNA. The two MNMs interact with the strong electric field inherent in all 
phospholipid bilayer membranes and effect trans-membrane delivery of the “cargo” dsiRNA. In 
the cytoplasm, the MNMs are detached, leaving the siRNA free to exert its biological function of 
gene silencing. The MNM delivery platform is universal and can be applied to any oligonucleotide 
sequence. 
Following intracellular delivery, the “cargo” dsiRNA targets the mRNA responsible for the 
production of RdRp of the SARS-CoV-2 virus, inhibiting viral replication. RdRp is the main 
enzyme involved in the replication and transcription of viral RNA genomes, including that of 
SARS-CoV-2, and is highly conserved across viral genomes. The sequence was carefully designed 
to be specific to viral RdRp, taking attention of exclusion of potentially common bases in the core 
sequence (Alvarez, 2009). To ensure the specificity of the target sequences, it was verified by Blast 
homology and tested against Homo sapiens and Mus musculus mRNA reference sequence. The 
designated sequences had maximal 16 bases match in the final siRNA with Homo sapiens genome. 
The selected sequence was structurally modified and elongated according to M.A. Behlke 
publications and IDT design manual to created dicer substrate (25/27 dsiRNA). 
 
1.3 Non-Clinical Studies 
The Apo-Si-K170A-C76 Construct has been characterized in terms of establishing the drug 
substance and drug product specifications, including the acceptance criteria. The efficacy has been 

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evaluated in vitro, using a rapid bioassay for antiviral drug screening in Vero-E6 cells and 
inhibition of SARS-CoV-2 induced cytopathic effects (CPE), showing a 3 order of magnitude 
reduction of CPE at 24 hours post-infection. In addition, the efficacy of Apo-Si-K170A-C76 
showed a long-lasting inhibition of up to a 3-log reduction in SARS-CoV-2 viral load in the nostrils 
of non-human primates, African green monkeys. 
A series of range-finding and pivotal toxicology studies has been conducted in Sprague-Dawley 
(SD) rats using intranasal (IN) dosing. The Apo-Si-K170A-C76 Construct was administered in all 
studies. 
The following toxicology studies were conducted:  
• A 7-day dose-range toxicology study has been conducted in rats using once-daily IN 
instillation of Apo-Si-K170A-C76 and a follow-up 7-day toxicology study using twice a day 
(BID) intranasal instillation was conducted in rats.  
• A 14-day GLP BID IN instillation toxicology study in the rat has been recently completed. In 
all studies, all animals survived and there were no Study Drug-related effects on any parameter, 
including histopathology. 
• We have evaluated the toxicity of the construct in African green monkey, following repeated 
IN and IT administration. There was no evidence of toxicity following the IN, intratracheal 
(IT) or inhalation administration of Apo-Si-K170A-C76.  
• The target of Apo-Si-K170A-C76 Construct is viral-specific and not found in the mammalian 
genome. Because of this, and following the procedure adopted for biotechnology-derived 
products with foreign targets (ICH S6 R1), a single-species is considered to be acceptable.  
• The local target tissue, i.e., the nasal cavity’s exposure to Apo-Si-K170A-C76 Construct in 
rats involved the maximum achievable dose based on administering the maximum feasible 
concentration at the maximum feasible dose volume; therefore, the derived toxicity data, which 
has confirmed the safety of the compound, represents a worst-case scenario. Also, no local 
irritation in the nasal cavity and respiratory tract were observed in these studies. 
• Pharmacokinetic studies, conducted in mice following a single IN administration, have 
revealed that limited circulatory exposure is obtained. 
• A GLP-compliant respiratory safety pharmacology study was conducted in male SD rats 
following a BID IN administration. There were no effects on any of the respiratory parameters 
at any dose. All measurements were comparable to the pre-dose values and/or to the concurrent 
control. 
• AMES study indicated that the Study Drug has no mutagenic activity in the tested bacterial 
strains (Salmonella typhimurium TA98, Salmonella typhimurium TA1535, Salmonella 
typhimurium TA1537, and Escherichia coli WP2 uvrA).  
• hERG and in vitro micronucleus tests will also be conducted shortly.  
 

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1.4 Rationale for the Use of Apo-Si-K170A-C76 and Study Design 
Based on non-clinical studies with Apo-Si-K170A-C76, IN administration of Apo-Si-K170A-C76 
is predicted to result in minimal systemic exposure. In the absence of infection with SARS-CoV-
2, the pharmacology of Apo-Si-K170A-C76 will also not be engaged. The study is therefore 
designed to provide a preliminary assessment of safety and systemic exposure of IN administration 
of Apo-Si-K170A-C76. This will be achieved by an exploration of three dose levels, the first 
expected to be associated with minimal pharmacology and the highest dose (‘target dose’) is 
expected to be pharmacologically active. These dosages will be first administered once. In the 
second phase of the study (Cohorts 4, 5), subjects will receive a twice-daily (BID) administration 
of the 2nd and 3rd dosage levels. Finally, for the third phase (Cohorts 6, 7), subjects will receive a 
twice-daily dosage (2nd and 3rd dosage levels) for 5 consecutive days. This will represent 5 days of 
treatment with repeated BID dosing at the target dose level and at one-level lower dosage. Given 
the route of administration and anticipated limited systemic exposure, conduct of this part in a 
single cohort of volunteers is considered appropriate. The transition between dosing cohorts will 
be performed following adequate review of safety data before the next dosing cohort. The 
transition from cohort 5 to cohort 6 will also involve reviewing of systemic exposure results 
obtained from the previous cohorts 1-5. Cohort size is not based on a formal powered comparison 
but 6 subjects on active treatment are considered adequate for a preliminary assessment of safety 
and systemic exposure. Two additional subjects will be randomized to placebo to maintain the 
blindness of this part of the study. 
  
1.5 Risk Assessment 
This is the first Human study with Apo-Si-K170A-C76. Although similar and higher doses of Apo-
Si-K170A-C76 have been tested in several animal studies and results support the dose levels to be 
tested in humans, this will be the first clinical exposure of the drug and thus there may be risks 
which are unknown at this time. 
The potential risks which may be associated with Apo-Si-K170A-C76 are based on theoretical 
considerations, and findings from non-clinical studies. The 14 days BID toxicology study in rats, 
safety pharmacology studies in rats, and the African green monkey efficacy studies did not reveal 
potential signs for safety concern. At the present time, no significant risk has been identified. 
However, a safety framework is applied in the proposed study: 
The study will be conducted in healthy volunteers. The proposed inclusion/ exclusion criteria have 
been selected to minimize the risk to participants from any potential risks associated with the 
investigational product.  
Also, a double-blind design is proposed to facilitate objective assessment. Sentinel dosing will be 
employed in all parts. 
Safety review will be performed between each dosing cohort.  

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The review will be conducted by the Safety Steering Committee (SSC). This will consist of the PI, 
the Sponsor’s Medical Monitor (MM), and chaired by a senior clinician independent of the study 
team. The SSC will review blinded data (systemic exposure data will not identify specific 
subjects). If the SSC considers that an unblinded review of data is required to make a decision, 
then the independent Data Safety Monitoring Committee (DSMC) will be asked to undertake this 
review and make their recommendation. The chair of the SSC may also refer to the DSMC if 
unblinding is required. 
 

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 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
The objectives of this study are to assess the safety, tolerability, and systemic exposure of Apo-
Si-K170A-C76 in healthy adult subjects.  
 
2.1 Study Objectives 
 
Objectives 
Endpoints 
Primary 
• To evaluate the safety and 
tolerability of single, BID doses, 
and repeated BID ascending doses 
of Apo-Si-K170A-C76 
administered intranasally (IN) in 
healthy adult subjects. 
• Incidence, nature, and severity of 
AEs, and SAEs 
• Use of concomitant medication  
• Changes from baseline in vital signs, 
clinical laboratory values, ECG and 
physical examination 
• Changes from baseline in TNSS score 
Secondary 
• To evaluate the systemic exposure 
of Apo-Si-K170A-C76 following 
intranasal administration in 
healthy adult subjects. 
• Characterize the systemic exposure 
based on concentration in serum.  
• PK analysis will be considered in case 
required. 
 
2.2 Safety Endpoints 
• Frequency and severity of Adverse Events (AEs), including Serious Adverse Events 
(SAEs) and Treatment-emergent AEs (TEAEs) occurring at any time during the study.  
• Change from Baseline to End of Study (EOS) in: 
o Laboratory tests including urinalysis and blood tests 
o Vital signs 
o Physical examination 
o TNSS 

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3. 
OVERALL STUDY DESIGN 
This is a first-in-human, phase 1, single-center, randomized, double-blind, placebo-controlled 
study aimed to evaluate the safety, tolerability, and systemic exposure of Apo-Si-K170A-C76 in 
healthy adult subjects following intranasal administration of single ascending doses (SAD), twice 
daily (BID) ascending dosing, and repeated BID ascending doses. 
Subjects will participate in 7 dosing cohorts, see also Figure 1:  
• Cohort 1 will involve an initial administration of a single (low) dose of 
Apo-Si-K170A-C76 (on Day 1) to both nostrils, 2mg/nostril.  
• Cohort 2 will involve a single alternately dose administration of Apo-Si-K170A-C76 at a 
double dose of the first dose (on Day 1) to both nostrils, 4mg/nostril.  
• Cohort 3 will involve a single alternately  dose administration of Apo-Si-K170A-C76 at 
the target dose (x3 of the first dose, on Day 1) to both nostrils, 6mg/nostril.  
• Cohort 4 will involve BID administration (on Day 1) of Apo-Si-K170A-C76 at the same 
dose as cohort 2, separated by6 hours (+15 min)  : 4mg/nostril BID to both nostrils.  
• Cohort 5 will involve BID administration (on Day 1) of Apo-Si-K170A-C76 at the same 
dose as cohort 3, separated by 6 hours (+15 min)-: 6mg/nostril BID to both nostrils.  
• Cohort 6 will involve administration of repeated doses of Apo-Si-K170A-C76 twice daily 
(BID on Days 1-5), at the same dose level or lower than that administered in Cohort 4: 
4mg/nostril BID to both nostrils, for 5 days. 
• Cohort 7 will involve administration of repeated doses of Apo-Si-K170A-C76 twice daily 
(BID on Days 1-5), at the target dose level or lower than that administered in Cohort 5: 
6mg/nostril BID to both nostrils, for 5 days. 
 
Figure 1: Apo-Si-K170A-C76 First-In-Human Dosing Study – Study Design 
 
5-Day Repeated BID Administration
Cohorts: 6, 7
Endpoints: Safety and Systemic Exposure Review
BID Administration
Cohorts: 4, 5
Endpoints: Safety and Systemic Exposure Review
Single Dose Administration
Cohorts: 1, 2, 3
Endpoints: Safety and Systemic Exposure Review

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IN administration is performed to both nostrils of all participants. The nasal spray device contains 
the Study Drug at 20 mg/mL and delivers 0.1 mL volume per actuation. After each actuation, an 
inspiration will be performed, and around a 5-second delay will be introduced between each new 
actuation. The subjects will receive 1-3 actuations per nostril in an alternately manner according 
to dosing group. Thus, during each administration cohort, dosages registered as dose/nostril are 
received twice per subject one dose to each nostril. An examination of the nasal cavity will be 
performed by a study physician at screening, 24 hours (+1hr) after each dose  and at the  last follow 
up visit for all subjects in all cohorts. 
 
Subjects will be randomized to receive either placebo or active treatment on each dosing cohort 
and sentinel dosing will be employed. Staggered dosing will be employed in all cohorts, i.e., 2 
sentinels will always be dosed before the remaining 6 subjects. 
The initial dose for this study is based on the non-clinical No-Observed-Adverse-Effect Level 
(NOAEL). The starting dose (Cohort 1) and the proposed subsequent doses are shown in Table 4. 
 
Table 4  Study Dosing Plan 
Part 1 
Dose Concentration 
 
Number of Subjects 
Apo-Si-K170A-C76 
Placebo 
Cohort 1 
2mg/nostril, 4mg/both nostrils 
6 
2 
Cohort 2 
4mg/nostril, 8mg/both nostrils 
6  
2  
Cohort 3 
6mg/nostril, 12mg/both nostrils 
6 
2 
Cohort 4 
4mg/nostril, 8 mg/both nostrils BID 
(16mg/day/both nostrils) 
6 
2 
Cohort 5 
6mg/nostril, 12 mg/both nostrils BID 
(24mg/day/both nostrils) 
6 
2 
Cohort 6 
4mg/nostril, 8 mg/both nostrils BID 
(16mg/day/both nostrils) for 5 days 
6 
2 
Cohort 7 
6mg/nostril, 12 mg/both nostrils BID 
(24mg/day/both nostrils) for 5 days 
6 
2 
Total Subjects 
42 
14 
 
 
All study staff (with the exception of specified unblinded pharmacy staff), each subject, and the 
Sponsor will remain blinded to study drug allocation. Subjects will be screened and randomized 
to treatment of active Apo-Si-K170A-C76 or matching placebo, in a 3:1 ratio. 

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Randomization will be performed as close as possible prior to the 1st administration of study drug 
(preferably on Day 1) in a staggered manner: initially, two sentinel subjects (one active and one 
placebo) will be randomized and dosed with blinded treatment prior to the remaining subjects. One 
sentinel subject will be dosed with active drug (Apo-Si-K170A-C76) and the other with matching 
placebo. The remaining 6 subjects in the dose cohort will be randomized and dosed if no safety 
concerns (without clinically significant AEs) are identified in the sentinel subjects; The decision 
to proceed and dose additional subjects following the first 2 sentinel subjects, according to the 
randomization schedule, will be at the discretion of the investigator and following his review of 
all their medical data.   
The decision to escalate to the next dose level, to investigate lower, intermediary, or higher doses, 
will be done by the Safety Steering Committee (SSC) which will review blinded emerging data of 
subjects of a given cohort including safety and tolerability. A minimum of 7 days post-dose safety 
data will be reviewed by the SSC to determine the next dose level. All dose escalation decisions, 
except for the transitions between cohort 3 to cohort 4 and cohort 5 to cohort 6, will be taken 
by the SSC. If the SSC considers that an unblinded review of data is required to make a decision, 
then the independent DSMC will be asked to undertake this review and make their 
recommendations. As mentioned above, the transition between cohort 3 to cohort 4 and between 
cohort 5 to cohort 6 will be reviewed and confirmed by the DSMC.  In addition, the transition from 
cohort 5 to cohort 6 will also involve (in addition to safety data) reviewing of the systemic exposure 
results obtained from the previous cohorts 1-5. 
In all cohorts, subjects will be admitted to the Research Unit (RU) on Day 1 at a time designated 
by the RU. Randomization in each dose cohort will occur as close as possible prior to the 1st 
administration of study treatment, preferable on Day 1. Treatment administration will occur on 
Day 1.  
 
In cohorts 1-5:  
Overnight confinement to the clinic between Day 1 and Day 2 is mandatory ( i.e., subjects will be 
discharged from the clinic on Day 2 after all required assessments and procedures have been 
completed for that day). The PI or designee will confirm that the subject is fit for discharge. 
Subjects will return to the RU for the follow-up (F/U)/EOS visit on Day 8 (± 2 days).   
 
In Cohorts 6 and 7: 
Treatment administration (BID) will occur on Day 1 and continue twice daily up to Day 5. 
Confinement to the clinic between Day 1 and through the 24 hours post 1st dose of last treatment 
day, is mandatory; (i.e., subjects will be confined from Day 1 through morning of Day 6 in the 
research unit) and will be released after all required assessments and procedures have been 
completed on Day 6. The PI or designee will confirm that the subject is fit for discharge.  
Subjects will return to the RU for the follow-up (F/U) / EOS visit on Day 12 (± 2 days).  

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Subjects in all cohorts will receive treatment after standardized meals. Water will be freely 
available at all other times. Grapefruit juice and caffeine containing beverages should be avoided 
until after the 24-hour (± 1 hour) post last dose blood sample. 
  
Study Periods and Visits 
The study will consist of three periods: Screening, Treatment and Follow up, with the following 
visits: 
Cohorts 1-5 
Screening Up to 21 days prior to dosing: 
1. 
Visit 1 / Screening 
Screening will take place only once for each participant.  
 
Treatment Period: 
2. 
Visit 2 / Day 1, admission to the RU and treatment administration single dose (cohorts 1-
3) or BID (cohorts 4-5)) 
3. 
Visit 3 / Day 2, 24h post dose assessments 
Discharge from the RU will occur on Day 2  
 
Follow Up 
4. 
Visit 4 / Day 8 (± 2 days), FU / EOS 
 
Cohorts 6-7 
Screening Up to 21 days prior to dosing: 
1. 
Visit 1 / Screening 
 
Treatment Period: 
2. 
Visit 2 / Day 1, admission to the RU and treatment administration (BID) 
3. 
Visit 3 / Day 2, treatment administration (BID) 
4. 
Visit 4 / Day 3, treatment administration (BID) 
5. 
Visit 5 / Day 4, treatment administration (BID) 
6. 
Visit 6 / Day 5, treatment administration (BID) 
7. 
Visit 7 / Day 6, 24h post Day 5 assessments 
Discharge from the RU will occur on Day 6.   
 
Follow Up (EOS) 
8. 
Visit 8 / Day 12 (± 2 days), FU / EOS 
 

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Investigational Plan 
For the complete schedule of assessments to be performed in each visit, please see Table 1, Table 
2 and Table 3 for cohorts 1-3, 4-5 and 6-7, respectively. 
 
 
End of Study 
A subject is considered to have completed the study if he has completed all periods of the study 
including the last visit (F/U), EOS, for the cohort he was assigned to. 
The end of the study is defined as the date of the last EOS visit of the last subject in the study. 
 
Drinks, Meals and Other Restrictions 
Subjects in all cohorts will receive treatment after standardized meals (breakfast and lunch (lunch 
in case of BID administration). Water will be freely available at all other times.  
 
Subjects will be required to abstain from alcohol for 48 hours before the start of dosing until after 
the 24h post last dose blood sampling. 
 
In addition, subjects will be required to abstain from grapefruit juice and caffeine products until 
after the 24h (±1 hours) post last dose blood sampling.  
 
Physical activity while staying in the RU is prohibited. 
 
Early Discontinuation Visit 
If a subject discontinues prematurely from the study for the reasons specified in Section 4.3, the 
same procedures planned for EOS visit will be conducted. Additional procedures and evaluations 
will be completed as deemed necessary by the PI. Reasons for withdrawals and discontinuation of 
any subject from the protocol will be recorded in the eCRF. The DSMC will be systematically 
involved in every important decision concerning conduct of the study, including discontinuation.  
 
Unscheduled Visit 
An unscheduled visit may be performed at any time during the study at the subject's request or as 
deemed necessary by the PI. The date and reason for the unscheduled visit will be recorded. AE 
monitoring and concomitant medication recording will be performed by the PI during the visit. 
Other procedures and evaluations will be completed as deemed necessary by the PI and may 
include (but will not be limited to) laboratory tests, vital signs and a physical examination. The 
date, reason, and procedures conducted during the unscheduled visit will be recorded in the 
subject's file and the eCRF. 
 

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Data Safety Monitoring Committee (DSMC) 
The DSMC as described in the DSMC charter, found in the Safety and Medical Monitoring Study 
Plan, will review unblinded emerging data of subjects in a given cohort including safety and 
tolerability at the transition between cohort 3 to cohort 4 and between cohort 5 to cohort 6, i.e, the 
transition between single to BID dosing and from BID to repeated BID dosing. A minimum of 7 
days post-dose safety data will be reviewed by the DSMC to determine the next dose level. The 
DSMC will also review the systemic exposure results of cohorts 1-5 (in addition to safety data) 
prior to confirming the transition between cohort 5 to cohort 6.   
Also, if the SSC considers that an unblinded review of data is required to make a decision, then 
the independent DSMC will be asked to undertake this review and make their recommendations. 
Unblinding will take place if needed, as according to the Blinding and Unblinding section of the 
Safety and Medical Monitoring Study Plan. 
Members of the committee will be established before initiation of study screening. Details for the 
committee will be outlined in a separate charter in the Safety and Medical Monitoring Study Plan, 
the governing document that will supersede this section of the protocol. 
Safety data to be reviewed by the committee will include details on any clinically significant events 
experienced on study-related safety parameters, with a table listing an aggregate of AEs reported 
during the study. 
At each decision stage (i.e., dose escalation or at other times), the committee will review safety 
data, including those from previous cohorts, and together make one of the following 
recommendations: 
• To continue the study as planned. 
• To continue the study with modifications. 
• To temporarily suspend or terminate the study. If, at any time, the study is terminated, a 
written statement fully documenting the reasons for study termination will be provided to 
the IRB/IEC. 
 

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4. 
STUDY POPULATION 
This study will be conducted in healthy adult subjects.  
 
4.1 Inclusion Criteria 
Subjects may participate in the study if they meet all the following criteria: 
 
1. Male and female participants; must be ≥ 18 years old. 
2. Understands the study procedures described in the Informed Consent Form (ICF), be willing 
and able to comply with the protocol, and provides written consent. 
3.  Not pregnant or lactating and willing to comply with the contraceptive requirements from 
enrolment to 3 months post last dose. Contraceptive requirements include the following: 
a. Use a condom with a spermicide to prevent pregnancy in a female partner or to prevent 
exposure of any partner (male and female) to the study intervention treatment.  
b. Male sterilization with the appropriate post vasectomy documentation of the absence of 
sperm in the ejaculate (please note that the use of condom with spermicide will still be 
required to prevent partner exposure). This applies only to males participating in the study.  
c. In addition, female partners and female participants of child-bearing potential, must use 
another form of contraception such as one of the highly effective methods (pills, Intra 
Uterine Device (IUD)) 
d. True abstinence - sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated with 
the study treatments. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the subject.  
e. In addition to the contraceptive requirements above, male subjects must agree not to donate 
sperm for 3 months post last dose. 
4. In good health with no history of clinically significant medical conditions (as described in 
Exclusion criteria) that would interfere with subject safety, as defined by relevant medical 
history, physical examination and routine laboratory tests, ECG, and determined by the 
Investigator at an admission evaluation. 
5. Subjects will have a documented relevant medical history either prior to entering the study 
and/or following relevant medical history review with the study physician at screening. 
 
4.2 Exclusion Criteria 
Any potential subject who meets any of the criteria below will be excluded from participating in 
this study: 
 

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Clinical History 
1. History or evidence of any clinically significant or currently active cardiovascular, 
(including thromboembolic events), respiratory, dermatological, gastrointestinal, 
endocrine, 
hematological, 
hepatic, 
immunological, 
rheumatological, 
metabolic, 
urological, renal, neurological, or psychiatric illness. Specifically: 
a. Subjects with any history of physician diagnosed and/or objective test-confirmed 
asthma, chronic obstructive pulmonary disease, pulmonary hypertension, reactive 
airway disease, or chronic lung condition of any etiology or who have experienced: 
o Significant/severe wheeze in the past 
o Respiratory symptoms including wheeze which has ever resulted in hospitalization 
o Known bronchial hyper-reactivity to viruses 
b. History of thromboembolic, cardiovascular, or cerebrovascular disease 
c. History or evidence of diabetes mellitus 
d. Any concurrent serious illness including history of malignancy that could interfere 
with the aims of the study or a subject completing the study. Basal cell carcinoma 
within 5 years of treatment or with evidence of recurrence is also an exclusion. 
e. Migraine with associated neurological symptoms such as hemiplegia or vision loss.  
Cluster headache/migraine or prophylactic treatment for migraine. 
f. History or evidence of autoimmune disease or known immunodeficiency of any cause. 
g. Other major disease that, in the opinion of the Investigator, could interfere with a 
subject completing the study and necessary investigations. 
h. Immunosuppression of any type. 
2. Any significant abnormality altering the anatomy or function of the nose or nasopharynx 
in a substantial way (including loss of or alterations in smell or taste), a clinically 
significant history of epistaxis (large nosebleeds) within the last 3 months, nasal or sinus 
surgery within 6 months of screening. 
3. Clinically active rhinitis (including hay fever) or history of moderate to severe rhinitis, or 
history of seasonal allergic rhinitis likely to be active at the time of inclusion into the study 
and/or requiring regular nasal corticosteroids on at least a weekly basis, within 30 days 
prior to screening. 
4. History of anaphylaxis and/or a history of severe allergic reaction or significant intolerance 
to any food or drug, as assessed by the PI. 
5. History or presence of alcohol addiction, or excessive use of alcohol. The subject has a 
history of consuming more than 7 units of alcoholic beverages per week for male subjects 
and more than 5 units for females or has a history of alcoholism or 

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 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 45 of 81                                                           Version 4.0 
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drug/chemical/substance abuse within the past 2 years prior to screening (Note: one unit 
= 330 mL of beer, 110 mL of wine or 28 mL of spirits)), or use of drugs of abuse. 
6. Psychiatric illness including subjects with a history of depression and/or anxiety with 
associated severe psychiatric comorbidities, for example psychosis. Specifically, (a) 
Subjects with history of anxiety-related symptoms of any severity within the last 2 years 
if the Generalized Anxiety Disorder-7 score is ≥4; (b)Subjects with a history of depression 
of any severity within the last 2 years if the Patient Health Questionnaire-9 score is ≥4 
7. Subjects who have smoked ≥5 pack years at any time [5 pack years is equivalent to one 
pack of 20 cigarettes a day for 5 years]). 
• Subjects who have smoked <5 pack years - at any time in the 3 months prior to 
screening, have used tobacco in any form (e.g., smoking or chewing) or other nicotine-
containing products in any form (e.g., gum, patch) or electronic cigarettes. 
Measurements and investigations 
8. A Body Mass Index (BMI) ≤18 Kg/m2 and ≥28 Kg/m2. The upper limit of BMI may be 
increased up to 30 Kg/m2 at the PI’s discretion, in the case of physically fit muscular 
individual. 
9. Venous access is deemed inadequate for the phlebotomy and cannulation demands of the 
study. 
10. At the discretion of the PI any clinically significant abnormal finding on screening 
biochemistry, hematology, serology  microbiology blood tests or urinalysis  or 
a. Positive HIV, active/chronic hepatitis B or C test. 
b. Positive β -HCG or positive  alcohol test 
11. Confirmed positive test for drugs of abuse and/or urinary cotinine at screening and on 
admission (Day 1). 
12. Twelve-lead ECG recording with clinically relevant abnormalities as judged by the study 
physician/PI. 
Recent respiratory infection 
13. Presence of cold-like symptoms and/or fever (defined as subject presenting with a 
temperature reading of >37.9ºC) at screening or on admission (Day 1). 
Receipt of medications and interventions 
14. Receipt of blood or blood products, or loss (including blood donations) of 550 mL or more 
of blood during the 3 months prior to screening. 
15. Medications 
a. Use of any medication or product (prescription or over-the-counter), for symptoms 
of hay fever, nasal congestion or respiratory tract infections or dermatitis/eczema 
including the use of regular nasal or medium-high potency dermal corticosteroids, 
antibiotics and First Defence™ (or generic equivalents) within 7 days prior to 

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screening. The sporadic use of paracetamol or other medications will be acceptable 
only as agreed by the Principal Investigator. 
b. Receipt of any investigational drug within 3 months prior to screening. 
c. Receipt of three or more investigational drugs within the previous 12 months prior 
to screening. 
d. Receipt of systemic (intravenous and/or oral) glucocorticoids or systemic antiviral 
drugs within 6 months prior to screening. 
e. Over the counter medications (e.g., paracetamol or ibuprofen) where the dose taken 
over the preceding 7 days prior to screening had exceeded the maximum 
permissible 24-hour dose (e.g., >4g per day of paracetamol over the preceding 
week). 
f. Chronically used medications, including any medication known to be a 
moderate/potent inducer or inhibitor of cytochrome P450 enzymes, within 21 days 
prior to screening. 
g. Subjects who have received any systemic chemotherapy agent, immunoglobulins, 
or other cytotoxic or immunosuppressive drugs at any time. 
Other 
16. Subjects who are currently employed by or are first-degree relative of someone employed 
by the Sponsor or participating clinical trial site, or any Contract Research Organization 
involved in this study. 
17. Any other reason that the PI considered made the subject unsuitable to participate. 

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
CONFIDENTIAL                                                  Page 47 of 81                                                              Version 4.0 
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4.3 Subject Withdrawal Criteria 
 
Subjects will be withdrawn from the study for the following reasons:  
 
• A subject may withdraw from the study at any time at his own request or may be withdrawn 
at any time at the discretion of the investigator for safety, behavioral, or compliance reasons.  
• Reasons for withdrawing subjects from the study might include, but are not limited to, AEs, 
withdrawal of consent, administrative decision by the investigator or the Sponsor, protocol 
deviation, or subject noncompliance. 
• At the time of withdrawing from the study, if possible, an EOS visit (FU visit) should be 
conducted. See Table 1, Table 2 and Table 3 for data to be collected at the time of study 
withdrawal and follow-up and for any further evaluations that need to be completed. 
• Subjects who withdraw from the study will be permanently discontinued from the study 
intervention. 
•  If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
• If a subject withdraws from the study, he may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records. 
 
4.4 Discontinuation of Study Intervention 
In some cases, it may be necessary for a subject to permanently discontinue study treatment. Please 
also refer to stopping rules described in Section 11.6. 
A subject may discontinue study intervention for reasons including but not limited to: 
• Adverse event 
• Death 
• Non-compliance with study intervention 
• Physician decision 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal by subject 
The reason for subject discontinuation from study intervention will be recorded in the eCRF. If a 
subject discontinues study intervention because of an AE, the investigator must arrange for the 
subject to have appropriate follow-up care until the AE is resolved or has stabilized. Unresolved 
AEs will be followed until the last scheduled follow-up visit or until the investigator, and study 
MM (and/or designee) determine that further follow-up is no longer indicated. 
 

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4.5 Lost to Follow Up 
A subject will be considered lost to follow-up if he fails to return for the scheduled FU visit and is 
unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the RU for a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• Before a subject is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he will be considered to have withdrawn 
from the study. 
 
4.6 Subject Identification 
A unique screening number will be assigned when an individual subject signs an informed consent 
from. The subject will also be identified with this number and/or randomization number if found 
eligible to participate in the study and randomized to receive either placebo or active.  
 
4.7 Subject Replacement 
Subjects who discontinue from the study after randomization without receiving any treatment will 
be replaced. Subjects discontinuing the study before the full course of treatment will be replaced 
by a subject who will be assigned the same treatment/dose as the subject being replaced. 
Dose administration will be considered incomplete if subject has not received all the scheduled 
dosing.  
If treatment was not completed due to an AE, subject replacement should be discussed with the 
relevant Study Committee. 
Subjects that were replaced after receiving an incomplete course of treatment will still complete 
the rest of the study protocol procedures. 

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5. 
STUDY PROCEDURES 
 
Subject Informed Consent 
Information about the study, including the objectives, procedures, and potential risks versus 
benefits, will be given to the subject in writing and verbally.  
The study personnel will review the Institutional Review Board (IRB) approved ICF with each 
subject and give the subject an opportunity to have all questions answered before proceeding.  The 
IRB/IEC-approved Informed consent will be signed prior to any study related procedure.  A copy 
of the signed ICF will be given to every subject and the original will be maintained within the 
subjects’ records.  
 
Demographics/Medical History/Prior and Concomitant Medications 
A demographic profile (birth date, race, and ethnicity) and complete relevant medical history will 
be recorded at screening and prior to study procedures.  The relevant  medical history will include 
a complete review of all current diseases and past medical conditions. Their respective medical 
treatments will be recorded as prior and/or concomitant medications. This information will be 
collected at screening to ensure suitability of the subject per the inclusion and exclusion criteria.  
 
All medications (including prescription and over-the-counter medications, supplements, and 
vitamins) taken within 30 days prior to signing the ICF and throughout the last F/U visit will be 
recorded as prior and/or concomitant medications (using their generic name, if known) with the 
corresponding indication. 
 
Safety Procedures 
 
General note: Where study procedures coincide at the same time point, order of collection is 
suggested to be: ECGs, vital signs, and blood draws and nasal cavity examination where possible, 
provided that systemic exposure samples are collected within permitted windows. When ECG and 
vital signs occur at the same time, the rest time may be shared between the assessments. If the 
procedures are completed within the window outlined in the tables included in the protocol, 
variances to the suggested order of procedures are not considered protocol deviations. 
 
Physical Examination 
• A Complete physical examination will be performed at screening to ensure suitability per the 
inclusion and exclusion criteria. Complete physical examination will include general 
appearance, head, ears, eyes, nose, throat, dentition, thyroid, chest (heart, lungs), abdomen, 
skin, neurological, extremities, back, neck, musculoskeletal, and lymph nodes.   

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• In cohorts 1-5, brief physical examinations will be performed within 2 hours prior to the first 
dose of study treatment, on Day 2 and at the F/U visit. In cohort 6-7, the brief examination will 
be performed within 2 hours prior to the first dose of study drug on Day 1, on Days 5 and 6, 
and at the F/U visit. The brief, focused physical examination will include chest (heart, lungs), 
abdomen, skin, neurological, and musculoskeletal examinations.  
• Any clinically relevant changes occurring from screening until the last study visit will be 
recorded on the Adverse Event Sections of the eCRF. 
  
Vital Signs 
Vital signs will be measured at each visit (screening, treatment days, 24h post last dose and EOS 
visits) and will include: blood pressure and heart rate at all time points. Oral temperature and 
respiratory rate will be measured only prior to dosing and before discharge from the research unit 
on treatments days  
• Cohorts 1-5: on dosing days, vital signs will be obtained within 2 hours prior to and 1, 2, 4 and 
8 hours (all ±20 minutes) post first dose on Day 1 and on Day 2 at 24 hours (±1 hour) post 1st 
dose. In cohorts 4-5, vital signs will also be measured 6 hours post 1st dose (but pre-2nd dose) 
• Cohorts 6-7: on dosing days, vital signs will be obtained within 2 hours prior to and 1, 2, 4, 6 
(but pre-2nd dose), and 8 hours (all± 20 minutes) after the first dose of treatment on Days 1 to 
5, and on Day 6 at 24 hours (± 1 hour) post the Day 5-1st dose of treatment. 
• Vital signs should be captured after 5 minutes of rest while the subject is in a supine or seated 
position.   
Vital signs should be checked prior to blood draws when blood draws and vital signs occur at the 
same time, provided that blood samples for systemic exposure are collected within permitted 
windows. 
If deemed appropriate by the investigator, clinically significant findings in the vital signs will 
exclude a subject from study participation. Any abnormal finding related to vital signs that the 
investigator considers to be clinically significant must be recorded as an AE. 
In addition, height will be collected only at screening and weight will be collected at screening and 
upon admission to the RU. 
  
12-Lead ECG 
ECG recording will be performed at screening, on treatment days, on Day 2 / Day 6 (depending 
on the cohort) and at the EOS visit. The ECGs should be captured after 5 minutes of rest in a semi-
supine/supine position. 
 
• Cohorts 1-3: A single 12-lead safety ECG will be obtained on Day 1, pre-dose (within 2 hours 
prior to dosing) and at 1 hour ± 20 minutes and 24 hours (± 1 hour) post dose.   

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• Cohorts 4-5: A single 12-lead safety ECG will be obtained on Day 1, pre-dose (within 2 hours 
prior to 1st dosing) and at 1, 6 hours (but pre-2nd dose), 7 hours (1 hour post 2nd dose) 
(all ± 20 minutes) and 24 hours (± 1 hour) post 1st dose.   
• Cohorts 6-7: A single 12-lead safety ECG will be obtained on Day 1, pre-dose (within 2 hours 
of dosing) and at 1, 6 hours (but pre-2nd dose), 7 hours (1 hour post 2nd dose) (all ± 20 minutes) 
after the 1st dose of treatment on Day 1. On days 2-5, ECG will be recorded pre-dose (within 
2 hours prior to 1st dosing) and 1 hour post 2nd dosing of the same day. On Day 6, ECG will be 
recorded 24 hours (± 1 hour) post 1st dose of Day 5.   
The Investigator will record in eCRF if ECG is normal, abnormal (not clinically significant) or 
abnormal (clinically significant, with description of findings). In all cases in which an ECG has a 
potentially clinically significant finding, it will be repeated in triplicate within about 30 minutes 
and reviewed by the investigator or designee prior to subsequent dosing or study disposition 
decisions that do not constitute a subject emergency.  
Clinically significant findings in the ECG obtained at screening should exclude a subject from 
study participation (as deemed appropriate by the investigator). Any clinically significant change 
following enrollment into the study will be reported as an AE. 
 
Safety Clinical Laboratory  
Laboratory testing will be performed in AML laboratories.  
For the timing and frequency of each laboratory panel, see the schedule of assessments for all 
cohorts (see Table 1, Table 2 and Table 3 for cohorts 1-3, 4-5 and 6-7, respectively.) In brief, 
urinalysis and blood samples will be collected at screening and at the F/U visit. For subjects 
participating in cohorts 6 and 7 - also pre-1st dosing on Day 3. 
The following safety parameters will be tested: 
SERUM BIOCHEMISTRY 
ALP 
Total bilirubin, Indirect/direct bilirubin 
Calcium 
Sodium 
Chloride 
Blood urea nitrogen (BUN) 
Magnesium 
Potassium 
Phosphorus 
Glucose  
Total cholesterol 
SGPT/ALT 
SGOT/AST 
 
 
HAEMATOLOGY 
Red Blood Cell (RBC) Count 
Hemoglobin (HGB) 
Hematocrit (HCT) 
Mean Cell Hemoglobin (MCH) 
Mean Cell Hemoglobin Concentration (MCHC) 
Mean Corpuscular Volume (MCV) 
White Blood Cell (WBC) Count and Differential 
(Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils – absolute and %) 
Platelet Count 
C-reactive protein (CRP) 
 
URINALYSIS  

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The investigator must review the laboratory report, document this review, and record any clinically 
significant adverse changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. All laboratory tests with values 
considered clinically significant during participation in the study or on or before the last follow-
up visit (EOS) should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or study MM. 
 
 
GGT 
Albumin 
Urea 
Creatinine (estimated glomerular filtration rate 
[eGFR] calculated based on standard equation) 
 
Creatine kinase 
Bicarbonate 
Total protein 
Uric acid 
Lactic dehydrogenase (LDH), 
Triglycerides 
 
COAGULATION TESTS  
PT 
aPTT 
INR 
 
PREGNANACY TEST 
blood testing at screening (central) 
urine testing on Day 1 (local)  
Dipstick, including microscopic and macroscopic 
analysis: appearance, bilirubin, occult blood, 
color, glucose, ketones, leukocyte esterase, 
nitrite, pH, protein, specific gravity, 
urobilinogen 
Microscopic examination of the sediment if 
blood, protein, nitrites or leukocytes esterase 
are positive on the dipstick 
 
SEROLOGY (at inclusion only) 
HBsAg, HCV antibody 
HIV antibody or antigen 
SARS-CoV-19 PCR test* 
 
SUBSTANCE ABUSE SCREENING (at 
inclusion only) 
 
Urine drugs, cotinine** and blood alcohol 
Drugs including: AMP, Amphetamine 
BAR, Barbiturates 
BZD, Benzodiazepines 
COC, Cocaine 
MDMA, Methylenedioxy methamphetamine 
MET, Methamphetamine 
MOR/OPI, Morphine/Opiate 
MTD, Methadone 
TCA, Tricyclic Antidepressants 
THC, Marijuana 
 
* Will be locally performed using a kit. 
** At screening, alcohol and pregnancy will be tested in blood, and drugs and cotinine in urine, all by a central 
laboratory. On Day 1 prior to dosing, alcohol, drugs cotinine and pregnancy will be tested locally in urine.  

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TNSS 
Total Nasal Symptom Score (TNSS) (Downie 2004) will be completed at each visit. On dosing 
days, it will be completed prior to and post dosing (applies for all cohorts). The TNSS is a 4-item 
questionnaire used to rate the symptoms of rhinitis. The total score is the sum of scores for each 
of nasal congestion, runny nose, nasal itching and sneezing at each time point, based on the degree 
of quality of life interference rated subjectively on a 4-point Likert scale: (0 = no interference / no 
symptoms, 1 = mild interference / mild symptoms that are easily tolerated, 2 = moderate 
interference / symptoms which are bothersome but tolerable, 3 = severe interference / hard to 
tolerate and interfere with daily activity). TNSS will be tested at screening, within 2 hours prior to 
the 1st dose of the day, and 1 hour (± 20 minutes) after each dose. Also, TNSS will be recorded 24 
hours (± 1 hour) after the 1st dose administered on the previous day (on Day 2 or Day 6 for cohorts 
1-5 or cohorts 6-7, respectively) and at the EOS visit. 
 
 
Adverse Events 
AEs will be collected starting from signing the ICF until the end of the study. 
Any AEs that occur throughout the study will be recorded. Any new AE that occurs between 
scheduled visits should be brought to the attention of the Investigator and recorded in the subject’s 
medical file and on the appropriate eCRF page. 
Any AEs or clinically significant out of range lab/test results related to study drug administration 
should be followed until resolution. Unrelated AEs should only be followed until the end of the 
study. 
 
Concomitant Medications 
Relevant information about all concomitant medications (including prescribed, over-the-counter, 
or dietary supplements) taken prior to (i.e., within 30 days of Screening) and during the study must 
be recorded in the source documents and eCRF. 

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
CONFIDENTIAL                                                  Page 54 of 81                                                              Version 4.0 
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Systemic Exposure 
Systemic exposure will be determined by analyzing blood serum samples for concentration of 
Apo-Si-K170A-C76 obtained from subjects who receive Apo-Si-K170A-C76 in each dose Cohort. 
The actual 24-clock time and date of each sample collection will be recorded. A more detailed 
description of serum sample preparation will be provided in the laboratory manual. Blood samples 
for systemic exposure will be analyzed with validated methods.  
Blood (serum) for systemic exposure analysis will be collected at the following time-points: 
 
Cohorts 1, 2 and 3:  
Blood 
• On Day 1, obtain blood for systemic exposure prior to dosing (within 2 hour before), at 30 
and 60 minutes (all ± 5 minutes) and 2, 3 and 4 hours (all ± 10 minutes), 6 and 8 hours (all 
± 20 minutes) post dose. A 24-hour (± 1 hour) post dose sample will be collected on Day 
2.   
 
Cohorts 4 and 5:  
Blood 
• On Day 1, obtain blood for systemic exposure prior to dosing (within 2 hour before and 
then at 30 and 60 minutes (all ± 5 minutes), and 2, 3, and 4 hours (all ± 10 minutes), 6 (pre-
2nd dose), 6.5, 7, 8, 9, and 10 hours (all ± 20 minutes), after 1st dosing. A 24-hour (± 1 hour) 
post 1st dosing sample will be collected on Day 2.   
 
Cohorts 6 and 7:  
Blood 
• On Day 1, obtain blood for systemic exposure prior to dosing (within 2hour before and 
then at 30 and 60 minutes (all ± 5 minutes), and 2, 3 and 4 hours (all ± 10 minutes), 6 (but 
pre-2nd dose), 6.5, 7, 8, 9, and 10 hours (all ± 20 minutes), after 1st dosing. A 24-hour (± 1 
hour) post 1st dosing sample will be collected on Day 2 (this will be the pre-dose sample 
of Day 2). On Days 2-5, the same time points as Day 1 will be collected. A 24-hour (± 1 
hour) post Day 5-1st dosing sample will be collected on Day 6.   
 
 

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6. 
INVESTIGATIONAL PRODUCT 
 
6.1 The Investigational Products administered 
Table 5  Study Products administered: 
ARM Name 
Active 
Control 
Drug Name 
Apo-Si-K170A-C76 
Placebo 
Dose Formulation 
5% glucose, 0.5% benzyl alcohol in 
RNase free water 
5% glucose, 0.5% benzyl 
alcohol in RNase free water 
Unit Dosage Strength(s) 
2 mg/100 µL/nostril 
 
100 µL/nostril 
Nasal Spray Device 
The Nemera SP270+ multi-dose pump system was selected as a nasal 
spray device. This is a commercially available product 
(https://www.nemera.net/products/ear-nose-throat/multidose-
pumps/sp270-sp370/). 
Pump:   White plastic nasal pump with 100 µL metered delivery  
Bottle:   Amber glass, containing 1.2 mL 
Daily dose Level(s) (both 
nostrils) 
Cohort 1: 4 mg 
Cohort 2: 8 mg 
Cohort 3: 12 mg 
Cohort 4: 16mg, BID dosing 
Cohort 5: 24mg, BID dosing 
Cohort 6: 16mg, BID for 5 days 
Cohort 7: 24mg, BID for 5 days 
Not applicable (NA), however, 
dosing schedule is the same 
Route of Administration 
Intranasal 
Intranasal 
Administration 
instruction 
Pharmacy staff will be unblinded to subject treatment assignment (as 
assigned by the designated randomization system for the study). All 
other study site staff, including the investigator and subjects, will be 
blinded to study intervention assignment. 
Study intervention doses will only be administered by study staff in the 
clinic setting. No at-home dose administration will be allowed. 
The study drug (or placebo) will be administered to both nostrils via a 
ready-to-use nasal spray device, while the subject is seated. After 
each actuation, an inspiration will be performed, and around a 5-
second delay will be introduced between each new actuation. To 
note: In cases  where more than 1 actuation in each nostril is required 
(Cohorts  2-7), the actuations will be performed  in an alternately  
manner.   It is necessary to prime the pump bottle by spraying it into 
the air four times prior to each new bottle. In case of failure by the 
fourth prime actuation, up to 2 more actuations are allowed. If by the 

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6th priming actuation no or minimal liquid is delivered the bottle will 
be discarded and replaced with another bottle.  
A separate bottle will be used for each dosing, i.e., 2 bottles will be 
used for each subject in cohorts 4-5 and 10 bottles will be used for each 
subject in cohorts 6-7. Subjects will remain in bed for at least 2 hours 
post administration.  
In cohorts 1-5, subjects will be discharged from the clinic on Day 1 or 
on Day 2. In cohorts 6-7, subjects will be confined to the research clinic 
throughout all treatment days and will be discharged on Day 6, after 
all required assessments and procedures for that day have been 
completed including assessment of safety laboratory values. In all 
cases, the PI or designee should confirm that the subject is fit for 
discharge.   
Sourcing 
Study intervention will be provided to the site centrally by the Sponsor 
or designated representative. 
Manufacturing 
Intertek Inc., UK. 
Packaging and Labeling 
Ready-to-use nasal application devices will be packed, 60 per box, 
with appropriate label. Each bottle will be labeled with the following 
text:  
Protocol: Sir-001 
One bottle of Apo-Si-K170A-C76 
20mg/ml or placebo; 1.2 ml 
Intranasal spray 
Batch number: XXXXXX 
Expiry date: December 2024 
Subject No.: _______________ 
Kit no. XXX 
Sponsor: / Interna Therapeutics Ltd. (former Sirvir Ltd. /ApoSense 
Ltd.) 
5 Odem St., P.O. Box 7119, 
Petach Tikva 4917002, Israel 
Tel: 972-73-2397600 
Storage Condition 
Ready-to-use nasal spray bottles and devices will be stored at 2-8oC. 
About half an hour before use, they will be put at room temperature 
for temperature equilibration. 
 
6.2 Dispense and Return of the Investigational Product 
The study pharmacist will acknowledge receipt of all shipments of Apo-Si-K170A-C76 to the site. 
The investigator or pharmacist should keep all the records relating to how much of the 
Investigational Product (IP) was used by each subject. The study monitors must periodically check 
the supplied Apo-Si-K170A-C76 to ensure expiration date and sufficient amount of the IP. 

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Apo-Si-K170A-C76 must be kept in a secured area with access limited to designated study 
personnel. Only personnel under the supervision of either the Investigator or the local pharmacist 
are authorized to handle Apo-Si-K170A-C76.  
The Investigator (or designee) must return all used and unused IP or discard it, according to site 
regulations, and the Sponsor’s and/or delegate’s instructions. A copy of the clinical supplies return 
or destruction documentation will be forwarded to the Sponsor (or designee). Drug/placebo 
accountability records, clinical drug/placebo supply receipts, and returns must be maintained by 
the Investigator (or designee). 
6.3 Accountability of the Investigational Product 
Apo-Si-K170A-C76 accountability records must be maintained by the clinical investigation site at 
all times. All used and unused Apo-Si-K170A-C76 will be assessed for accountability by the study 
monitor. 
The subject number, date, kit number as well as the correct randomization allocation and quantity 
of Apo-Si-K170A-C76 used for each subject will be checked for correctness and recorded on the 
appropriate accountability forms. At the end of the study, a copy of all the clinical supply and the 
corresponding accountability forms will be accounted for reconciliation and destruction. The 
original records will be kept at the clinical investigation site. 
 
6.4 Measures to Minimize Bias: Randomization and Blinding  
Subjects who complete the screening visit and meet all the inclusion and none of the exclusion 
criteria will be randomized to receive either placebo or active on Day 1 prior to the first 
administration of treatment (8 subjects per cohort; within each cohort, randomization ratio - 6 Apo- 
Si-K170A-C76: 2 placebo). One of the first two subjects (sentinel subjects) enrolled in each cohort 
will be randomized to receive Apo-Si-K170A-C76 and the second will receive placebo. 
Randomization assignments will be provided by electronic data capture (EDC) to the study site 
pharmacist(s) who will access the EDC. Following randomization, study intervention will be 
dispensed in a double-blind manner. The Sponsor and all clinical unit personnel except the 
Pharmacist, designated pharmacy staff and unblinded study personnel (if employed), will be 
blinded to the treatment group for each subject. Subjects will also be blinded to the treatment they 
receive. 
In the event of a medical emergency, the investigator will be able to receive the treatment 
assignment, if required to provide optimal care of the subject. The Sponsor or designee should be 
contacted prior to breaking the blind unless the subject is in immediate risk. Any occurrence of 
unblinding should be reported to the Sponsor and documented. In the case of unblinding, 
disclosure of the cohort/dose should be limited to only those site personnel required to know 
treatment assignment for the care of the subject. 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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6.5 Disallowed Medication 
Medications specifically prohibited in the exclusion criteria (see Exclusion criterion #15) are not 
allowed during the ongoing study up to EOS. 
The study PI (and/or designee) should be contacted if there are any questions regarding 
concomitant medications. 

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
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7. 
SAFETY AND PHARMACOVIGILANCE 
 
7.1  Adverse Event 
Definition  
An Adverse Event (AE) is defined as any untoward medical occurrence in a subject administered 
a medicinal product whether or not considered related to the investigational medicinal product.  
An AE can therefore be any unfavorable and unintended sign, including an abnormal laboratory 
finding, symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to this IP. 
 
Events meeting the AE definition: 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (i.e., not related to progression of underlying disease) 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition 
• New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
 
In this study, any event occurring after the subject has signed the study informed consent and until 
the end of the Follow-up visit (up to the EOS) will be collected (or until AE is resolved or no 
further follow-up is required). From consent to dosing, only collect AEs related to study 
procedures).  
 

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 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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The reporting of abnormal laboratory values should be avoided unless considered clinically 
significant by the investigator. 
 
AEs occurring during the study, whether or not attributable to the study treatment, observed by the 
Investigator or reported by the subject spontaneously, or in response to a direct question, will be 
recorded in the subject’s source documents and eCRF as long as they occurred after signing the 
ICF and until last F/U visit.  
 
Each AE should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as additional 
AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as AE(s). 
 
Suspected adverse reaction is “any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.” AEs that are related or possibly related would be suspected 
adverse reactions; AEs that are not related or unlikely related would not be suspected adverse 
reactions. 
 
The Investigator will document, according to his/her opinion, the AE term of each event, start and 
end date, whether the event is serious, severity grade, action taken in response to the event, 
outcome and relationship to the IP.  
  
AE severity will be recorded and graded by the investigator in accordance with the NCI CTCAE 
v5.0. For AEs that are not adequately addressed in the NCI CTCAE, the investigator should 
classify the intensity of the AE using the following guidelines: 
 
Description 
Grade  1: Mild: Aware of sign or symptom, but easily tolerated; no intervention needed. 
Grade 2: Moderate: Discomfort enough to cause interference with usual activity, minimal non-
invasive intervention indicated (e.g., short course of antibiotics) 
Grade 3: Severe: Medically significant but not immediately life-threatening; incapacitation with 
inability to work or do usual activity 
Grade 4: Life-threatening: Refers to an event in which the subject was at risk of death at the time of 
the event, as judged by the investigator; urgent/emergent intervention indicated. This category should 
not be used for an event that hypothetically might have caused death if it were more severe. 
Grade 5: Fatal outcome 
 
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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Relationship to the IP (Assessment of causality) will be classified as follows: 
 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. The investigator will use clinical judgment to determine the 
relationship. 
• Related – There is a plausible temporal relationship between the onset of the AE and 
administration of study intervention, and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows 
a known pattern of response to study intervention; and/or the AE abates or resolves upon 
discontinuation of study intervention or dose reduction and, if applicable, reappears upon 
re-challenge. 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
- 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
- 
Alternative causes, such concomitant therapy, and other risk factors, as well as the temporal 
relationship of the event to study intervention administration, will be considered and 
investigated. 
- 
The investigator will also consult the Investigator's Brochure (IB) and/or product information, 
for marketed products, in his/her assessment. 
- 
For each AE/SAE, the investigator must document in the medical notes that he has reviewed 
the AE/SAE and has provided an assessment of causality. 
 
Adverse Events outcome will be classified as follows: 
• Recovered: The subject has fully recovered from the AE with no residual effects 
observable 
• Recovered with Sequelae: The subject has recovered from the AE with residual effects 
observable 
• Recovering: The subject status improved but has not been fully recovered 
• Not Recovered (ongoing): The subject status has not recovered from the AE 
• Fatal: Termination of life as a result of the AE 
• Unknown: Not known, not observed, not recorded, lost for follow-up or refused 
 
All entries must be clearly documented in the source documents and the source documentation 
should be signed and dated by a physician Investigator. AEs documented in the eCRF without a 
stop date should be reviewed at subsequent visits. Documentation on AEs should be updated as 
necessary. In case of worsening of an AE (i.e. AE grade increase) the event should be captured 
with the maximal severity observed providing that the AE is ongoing while the AE grade increased. 
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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7.2 Serious Adverse Event 
An SAE is defined as an AE that results in any of the following: 
• Death 
• Life-threatening (at the time of the event) 
• Requires inpatient hospitalization or prolongs existing inpatient hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• An important medical event that requires medical intervention to prevent any of the above 
outcomes 
Important medical events are those that may not be immediately life-threatening, but may 
jeopardize the subject and may require intervention to prevent one of the other serious outcomes 
listed above. Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital inpatient 
admission and/or prolongation of hospital stay were required for treatment of AE, or that they 
occurred as a consequence of the event. It does not refer to pre-planned elective hospital admission 
for treatment of a pre-existing condition that has not significantly worsened, or to diagnostic 
procedure. 
The term “life-threatening” in the definition of “serious” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe. 
Any SAE occurring after the subject has signed the ICF and up to the EOS should be reported (Or 
until SAE is resolved or no further follow-up is required). 
 
7.3 Unexpected Adverse Event 
An unexpected adverse drug experience (event) is any adverse event, the specificity or severity of 
which is not consistent with information in the current Investigator’s brochure for an unapproved 
investigational product or package insert/summary of product characteristics for an approved 
product. 
 
7.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is a serious adverse reaction assessed as unexpected by the Sponsor and that is judged 
by either the reporting investigator or the Sponsor to have a reasonable causal relationship to a 
medical product. AEs that are not related or unlikely related would not be suspected adverse 
reactions. 
Since this is a first-in-human clinical trial with Apo-Si-K170A-C76 and the efficacy and safety of 
the IP has not been yet established - in this clinical study all serious adverse reactions will be 
considered unexpected for the purpose of safety reporting.  
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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7.5 Serious Adverse Events/SUSAR Reporting 
Each SAE must be reported by the Investigator to the pharmacovigilance group within 24 hours 
of its occurrence, even if it is not considered to be treatment-related.  
Follow-up information about a previously-reported SAE must also be reported within 24 hours of 
the Investigator receiving it.  
 
The primary mechanism for reporting an SAE to the Sponsor will be a paper SAE report form 
and the corresponding event will be recorded in EDC. 
 
All SAE forms should be sent to the Chief Medical Officer (CMO) and/or appropriate contacts 
mentioned in the Safety and Medical Monitoring Study Plan: 
CMO: Prof. Gary K. Schoolnik 
Email: gks007@stanford.edu  
 
Any fatal or life-threatening event should be reported immediately to the pharmacovigilance 
representative. These preliminary reports will be followed within 24 hours by detailed descriptions 
that include a completed SAE form, copies of hospital case reports, autopsy reports and other 
documents, when requested and applicable. 
The Investigator must complete the SAE Report Form, assess the relationship to study treatment 
and submit it via fax or email within 24 hours to the pharmacovigilance group listed above. 
Follow-up information is to be submitted on a new SAE form. The new form should clearly state 
that it is a follow-up to the previously-reported SAE and give the date of the original report. The 
follow-up SAE report should describe whether the event has resolved or continues, if and how it 
was treated and whether the subject continued or discontinued study participation. 
 
The following information should be provided in the SAE form to accurately and completely 
record the event: 
1. Investigator name and site address 
2. Subject study identification number 
3. Subject demographics (gender, year of birth or age, weight, height) 
4. Clinical Event: 
• Description 
• Date and time of onset, stop date, or duration 
• Severity 
• Treatment (including hospitalization) 
• Relationship to the IP (causality) 
• Action(s) taken regarding the IP 
• Information on recovery and any sequelae 
• If the SAE resulted in death, cause of death (whether or not the death was related to the IP) 
and Autopsy findings (if available) 
• Medical History case report form (copy) 
• Concomitant Medication case report form (copy) 
• Any relevant reports (laboratory, discharge, etc.) 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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Accompanying documentation, such as copies of hospital case reports, autopsy reports and other 
documents when applicable, should be summarized on the SAE form and a copy of the source 
document may be sent if required. The subject's personal details will be removed and replaced 
with study identifiers i.e. study number and initials, if applicable. 
 
The Sponsor and/or delegate will notify the appropriate regulatory agencies and participating 
Investigator Expedited Safety Reports that occur during the trial within the time frames required 
by each regulatory agency. 
 
In addition, all AEs / SAEs / SUSARs will be reported to the local ethics committee (EC / IRB) 
and regulatory authorities as required by local regulations and International Conference on 
Harmonization (ICH)-GCP guidelines. 
 
Documentation of the submissions to IRBs / IECs and health authorities (as applicable) must be 
retained in the appropriate trial file(s). As instructed by the Sponsor, Safety Reports/Expedited 
Safety Reports should be retained in the appropriate Investigator site trial files, or with the IB. 
 
7.6 SAE & AEs Requiring Discontinuation of Investigational Product 
Any SAE, which occurs after a subject has signed the ICF, whether or not related to study product, 
must be reported to the Sponsor or its designee immediately (within 24 hours) via telephone, email 
or facsimile. If initially reported via telephone, this must be followed-up by email or a facsimile 
of the written SAE report within 24 hours of the call to the sponsor or its designee.  
 
Non-serious events that require discontinuation of IP (including laboratory abnormalities) should 
be reported to the Sponsor or its designee immediately and within 24 hours.  
 
Subjects who discontinue study participation due to experiencing IP related AE(s) should be 
followed-up clinically until the adverse event has resolved, becomes clinically insignificant, is 
stabilizes, or the subject is lost to follow-up.   
 
A subject who experiences an SAE related to IP will be discontinued from the study.  Regardless 
of the duration of the study participation, subject who exhibit an SAE, will be followed up by the 
Investigator until the SAE has resolved, becomes clinically insignificant, is stabilizes, the subject 
is lost to follow-up or is considered to be chronic (stabilized for at least 30 days) based on the 
Investigator’s medical judgment.  For safety reporting instructions see SAE and Pregnancy Form 
Report Instructions.  
 
 
 

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 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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7.7 Pregnancy 
Female subjects who become pregnant or male subjects with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any female or male subject’s 
female partner who becomes pregnant while participating in this study. With regard to male 
subjects with partners who become pregnancy - this applies only to male subjects who receive 
study intervention. 
• The investigator will record pregnancy information on the appropriate Pregnancy Form and 
submit it to the Sponsor within 24 hours of being notified of the pregnancy (for female partners 
- after obtaining the necessary signed informed consent from the pregnant female partner 
directly).  
• The female will be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and should be reported to the Sponsor or its 
designee within 24 hours of being notified of the outcome. 
 
 
7.8 Adverse Events Follow up 
Subjects who have had an AE during the treatment period must be followed up clinically until all 
parameters (including laboratory) have either returned to normal or have stabilized or are otherwise 
explained. In exceptional cases, it may be defined as “ongoing without further follow-up” by the 
Investigator and Sponsor’s decision.  
SAEs that are identified on the End of Treatment visit (or the Early Termination visit) or End of 
Study visit, must be recorded on the AE eCRF page and reported to the Sponsor or its designee 
according to the procedures outlined above. Subjects with unresolved previously reported SAE(s), 
or any new SAE(s) identified on the End of Study visit, should be followed-up until the event has 
resolved, becomes clinically insignificant, is stabilized, or the Subject is lost to follow-up, based 
on the Investigator’s medical judgment. Resolution means the subject has returned to the baseline 
state of health, or all parameters have stabilized, and the PI does not expect any further 
improvement or worsening of the SAE.  The PI should continue to report any significant follow-up 
information to the Sponsor or its designee up to the point that the event has resolved.  Any SAE 
or AE reported by the subject to the Investigator or study personnel that occurs within 30 days 
after the last subject's last IP dose and is determined by the PI to be reasonably associated with the 
use of the IP, should be reported to the Sponsor. In case of an SAE, the SAE should be reported 
within 24 hours of when the Investigator or the site personnel first learns of the occurrence of the 
event. 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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7.9 Emergency Unblinding 
In the event of a medical emergency, when knowledge of treatment assignment is needed for 
immediate medical management of the subject’s health, investigators can obtain unblinded 
treatment assignment through the EDC system at any time, according to the Blinding and 
Unblinding section of the Safety and Medical Monitoring Study Plan. Thorough documentation of 
the rationale for unblinding is required. Consultation of the study MM is recommended for all 
unblinding requests. 
 
 

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
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8. 
STATISTICAL METHODOLOGY 
 
Sample size considerations 
This is a Phase 1 safety study designed to evaluate the safety, tolerability, and systemic exposure 
of Apo-Si-K170A-C76. The sample size is not based on power calculations. It is chosen based on 
clinical experience and typical SAD and repeated dose designs and considered to be adequate to 
fulfill the objectives of the study.  
 
General 
Tabulation of descriptive statistics, calculation of inferential statistics (if relevant), and graphical 
representations (if relevant) will be performed using SAS® version 9.4 or higher for Windows. 
All demography, baseline characteristics and safety analyses will be performed on the Safety 
Analysis Set.  
All measured variables will be listed individually. 
All measured variables and derived variables will be tabulated by dose cohort and overall (for all 
treatment arms, not including placebo) for the following descriptive statistics: 
• 
Continuous variables will be summarized by the number of observations (n), mean, 
standard deviation, median, minimum, and maximum and 95% CI for means of variables 
if appropriate, by dose group (cohort) and treatment arm.  
• 
Categorical variables will be summarized by frequency counts and percentages [n (%)] for 
each category. Unless otherwise stated, percentages will be calculated out of the number 
of subjects in the relevant Analysis Set (Safety Analysis Set), by dose group (Cohort) and 
treatment arm.  
No data imputation will be performed. 
 
Safety Analysis  
 
Adverse Events 
An overall summary of the number and percentage of subjects in each of the categories listed 
below will be presented by dose group and treatment arm and for the pooled dose groups.  
• All Treatment Emergent AE (TEAE) 
• Serious TEAEs 
• Study intervention related TEAEs 
• TEAEs with NCI CTCAE ≥ Grade 3 
• Study intervention related serious TEAEs  
• Study intervention related TEAEs with NCI CTCAE ≥ Grade 3 
• TEAEs leading to discontinuation  
• TEAEs leasing to death 
For each of the above categories data will be further summarized by MedDRA system organ 
class and preferred term. 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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All AEs will be listed in subject listing. 
If there is insufficient data to create a meaningful summary (e.g. for SAEs, AEs leading to 
death), data will be listed only. 
 
Vital Signs 
All data recorded in the eCRF will be listed. Vital signs data and relative changes from baseline 
will be summarized descriptively by time point and by dose cohort and overall.  
 
Clinical Laboratory Values  
All laboratory data recorded provided from the central lab will be listed. Out-of-reference range 
values will be flagged as high (H) or low (L) in the listings. Laboratory assessments will be 
categorized as high/normal/low and whether clinically significant or not by visit and by dose 
cohort and overall. Relative changes from baseline will be calculated and summarized. 
 
Electrocardiogram (ECG)  
Abnormalities identified from ECG data recorded in the eCRF will be listed. ECG will be 
categorised as normal/abnormal and whether clinically significant or not by visit and by dose 
cohort and overall.  
 
Physical Examination  
Abnormalities identified from physical examination will be listed. Physical Examination will be 
categorized as normal/abnormal and whether clinically significant or not by body system, by visit 
and by dose cohort and overall.  
 
Concomitant medications  
Prior medications recorded at screening will be listed separately from concomitant medications 
given post-treatment.A summary of the number of subjects receiving concomitant medications 
given at any time post treatment will be produced by WHO generic name (ATC level 5). 
 
Other Safety Endpoints  
TNSS score  
The scores for nasal congestion, rhinorrhea, nasal itching, and sneezing are summed to obtain the 
Total Nasal Symptom Score for a subject at a specific time point. 
All data recorded in the eCRF will be listed. TNSS scores data and relative changes from baseline 
will be summarized descriptively by time point and by dose cohort and overall.  
  
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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Systemic Exposure Analysis 
The systemic exposure will be based on the serum concentrations of Apo-Si-K170A-C76 
measured in serum at specific time points. A PK analysis will be considered if required. In case 
required, the following PK parameters will be calculated : 
• Cmax - Maximum concentration achieved. 
• Tmax - Time to reach maximum concentration (hours). 
• AUClast – The area under the concentration vs. time curve, calculated as sum of AUCs 
using linear trapezoidal summation from time 0 to the last measurable data point. 
• AUCpartial – The area under the concentration vs. time curve, calculated as sum of AUCs 
using linear trapezoidal summation from time 0 to the maximal measurement (Tmax). 
• z (Lambdaz)- Individual estimate of the terminal elimination rate constant, was calculated 
using log-linear regression of the terminal portions of the plasma concentration-versus-
time curves.  
• AUCinf - The area under the plasma concentration-time curve extrapolated to infinity, 
calculated as:  
AUCinf was calculated as AUClast + Clast/z, where Clast is the last measurable 
concentration. 
• T1/2 - Apparent terminal elimination half-life time (hours), defined as 0.693/z. 
 
Individual serum concentrations (or PK parameters if required) will be listed by dose group and 
summarized in tables presenting sample size (N), mean, Standard deviation, Standard Error, 
Median, minimum and maximum values, Coefficient of variation (CV%) and 95% CI (Confidence 
Interval) for means of variables by treatment.  
Graphical displays will be generated presenting mean concentration by treatment as well as 
individual graphs per subject. 
Samples with plasma concentrations below the LLOQ at early time-points will be set to as zero.  
 

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
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9. 
ETHICS 
 
9.1 Institutional Review Board or Ethics Committee (IRB/EC) 
Prior to initiation of the study, the Investigator will submit the study protocol, sample ICF and any 
other documents that may be requested to the Institutional Review Board (IRB) or Ethics 
Committee (EC) for review and approval. The Investigator will request that the IRB/EC provide 
written approval of the study and will keep on file records of approval of all documents pertaining 
to this study. The Investigator will not begin the study until the protocol and ICF have been 
approved by the IRB/EC. The Investigator must agree to make any required progress reports to the 
IRB, as well as reports of SAEs, life-threatening conditions, or death. 
 
9.2 Ethical Conduct of the Study 
All clinical work conducted under this protocol is subject to GCP guidelines. This includes an 
inspection by Sponsor or its designee, health authority or IRB/IEC representatives at any time. The 
Investigator must agree to the inspection of study-related records by health authority 
representatives and/or Sponsor or its designee.  
The study will be conducted in accordance with Sponsor’s and delegate standards operating 
procedures and the following guidelines: 
• ICH-GCP 
• Declaration of Helsinki  
• Local Israeli laws, regulations and guidelines for conducting clinical trials 
 
9.3 Protocol Revisions and/or Deviations 
Changes to the protocol may be made only by the Sponsor (with or without consultation with the 
Investigator). All protocol modifications must be submitted to the IRB/IEC in accordance with 
local requirements and, if required, to Regulatory Agencies, either as an amendment or a 
notification. Approval for amendments must be awaited before any changes can be implemented, 
except for changes necessary to eliminate an immediate hazard to trial subjects, or when the 
changes involve only logistical or administrative aspects of the trial. No approval will be required 
for notifications. 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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9.4 Subject Information and Consent 
Prior to screening for the study each subject will be informed in detail about the study drug to be 
administered and the nature of the clinical investigation with its risks and discomforts to be 
expected. The basic elements of informed consent as specified by the FDA (21 CFR 50.25) and 
ICH-GCP will be followed. Written consent will be obtained from each subject to be involved in 
the clinical trial by using the IRB/IEC-approved ICF/ Patient Information Sheet (PIS) prior to the 
conduct of any study-related activity. Each subject will be given a copy of the signed ICF/PIS. The 
subjects will also be instructed that they are free to withdraw their consent and discontinue their 
participation in the study at any time without prejudice. Each subject’s chart will include the 
original signed ICF/PIS for study participation. The ICF/PIS will be kept in the Investigator’s 
central study file for the required period of time. Regulatory authorities may check the existence 
of the signed ICF/PIS in this central study folder if not having done so during the study. If the 
ICF/PIS is modified during the study, in a way that can affect the subject judgment to participate, 
all subjects still ongoing will be re-consented and the original re-consent forms will be included in 
the subject’s chart. 
 
9.5 Subject Insurance 
The Sponsor has an insurance policy for the total duration of the study and for at least 30 days 
after the end of the study covering the subjects and Investigators in respect of the risks involved in 
conducting this study according to this protocol. The insurance policy will be filed in the 
Investigator's file or can be made available to the Investigator and to the IRB/IEC upon request. 
 
9.6 Personal Data Protection 
The Sponsor complies with the principle of subject's right to protection against invasion of privacy. 
Throughout this trial, all data will be identified only by the subject's identification number. The 
data will be blinded in all data analyses. The subject must be informed and written consent is 
required that authorized personnel of the Sponsor and/or designee (Study Monitor, Auditor, CRO, 
Sponsor’s Strategic Partner, etc.) and relevant health regulatory agency may have direct access to 
personal medical data to assure a high-quality standard of the study, and/or to obtain regulatory 
approvals. The data will be de-identified where appropriate and consistent with study needs. If 
results of this study are published, only numbers or symbols will be used to identify the subjects. 
  

-Interna Therapeutics  
 
 
 
 Study intervention: Apo Si 
K170A C76 
 
 
Protocol Number: Sir-001 
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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
10.1 Audits and Inspections 
The Investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from the Sponsor Quality Assurance or its designees or to 
regulatory authority inspectors after appropriate notification. The verification of the CRF data must 
be by direct inspection of source documents. These audits or inspections may take place at any 
time, during or after the study and are based on the national regulations, as well as ICH guidelines. 
 
10.2 Study Monitoring 
Monitoring of the study is the responsibility of the Sponsor and may be delegated to a CRO or a 
contract monitor. The study monitor will advise the Investigator regarding the practical conduct of 
the study and maintaining compliance with the protocol, GCP and all applicable regulatory 
requirements. Throughout the course of the study, the study monitor will oversee the conduct and 
the progress of the study by frequent contacts with the Investigator. This will include telephone 
calls and on-site visits. During the on-site visits, the CRF will be reviewed for completeness with 
corresponding source documents. As part of the data audit, source documents must be made 
available for review by the study monitor. The study monitor will also perform drug accountability 
checks and may periodically request review of the Investigator’s study file to ensure completeness 
of documentation in all respects of clinical study conduct.  
Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period. The Investigator or 
appointed delegate will receive the study monitor during these on-site visits; cooperate in 
providing the documents for inspection and respond to inquiries. 
 
10.3 Source Documents 
The Investigator will permit study-related monitoring, audits by or on behalf of the Sponsor, 
IRB/IEC review and regulatory inspections providing direct access to source data documents 
whether they are in paper or electronic form. Source documents are original records in which raw 
data is first recorded. These may be office/clinic/hospital records, charts, diaries, x-rays and 
laboratory results, printouts, pharmacy records, care records, completed scales for each study 
participant. Source documents should be kept in a secure and limited access area. All source 
documents must be accurate, clear, unambiguous, permanent and capable of being audited. The 
subject study file should contain all relevant historic and contemporary records in a permanent 
form of recording (ink, typing, printing, optical disc etc.). They should not be obscured by 
correcting fluid or have temporary attachments (such as removable self-stick notes). Source 
documents that are computer generated and stored electronically must be printed, signed and dated 
by the Investigator.  

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
CONFIDENTIAL                                                     Page 74 of 81                                                           Version 4.0 
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Source data for subjects registered to the study should indicate date informed consent was signed, 
participation in clinical protocol number and title, treatment number, evidence that 
inclusion/exclusion criteria have been met. 
 
10.4 Electronic Case Report Form (eCRF) 
eCRFs will be used to capture data for all subjects and must be completed for all subjects who 
have signed an ICF. The eCRFs will be monitored against source documents. 
The eCRF must be reviewed and electronically signed and dated by the Investigator. Access to the 
eCRF will be password protected and limited to authorized personnel only. Data should be entered 
into the eCRFs by the treating personnel or the study coordinator. The eCRF must be completed 
as soon as possible after any subject assessment or communication, but not longer than 5 business 
days afterwards. If data is to be changed due to erroneous input or any other reason, an electronic 
audit trail will track these changes. 
 
10.5 Quality Laboratory Standards 
Laboratory tests or evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards as described in the SOPs of the lab. 
 
10.6 Data Management 
An eCRF will be used for the current study to capture the data according to the protocol and 
sponsor requirements and a data management plan will be prepared by -Interna Therapeutics Ltd. 
and/or its designated representative. 
Data will be transcribed directly from the clinic source documents into the eCRF system. 
AEs will be coded using the MedDRA (latest version available). Prior and concomitant 
medications will be coded according to the public WHO Drug Dictionary. 
The Investigator is responsible for the final review, approval and sign-off of all the eCRFs for the 
study. 
Database lock will be conducted after all data reviews have been completed, all queries have been 
resolved and appropriate approvals have been obtained. 
Data management processes will be described in detail in the Data Management Plan. 
 
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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11. 
STUDY ADMINISTRATION 
 
11.1 Participating Centers 
This is a single-center study in Israel. The participating center is Hadassah Clinical Research 
Center (HCRC), Israel. 
 
11.2 Required Documents Prior to Study Initiation 
Prior to the start of this study, all pre-investigational requirements must be met by the Investigator 
and study site. These may include: 
1) Appropriate local health authority documentation, properly signed and dated by the required 
Investigators (i.e., the submission package) 
2) Signed copy (original) of the approved protocol 
3) Completed and signed statement of the Investigator 
4) A signed Clinical Trial Agreement 
5) Curriculum vitae for the Investigator and sub-Investigators 
6) IRB/EC name and address and membership lists 
7) Letter of approval from the IRB/EC / MOH / Director of Hospital (DOH) for study 
documentation (protocol, ICF, IB and all subject facing documents)  
Upon satisfactory receipt of all required regulatory documents, I Interna Therapeutics Ltd. will 
arrange that the IP be delivered to the study site. Supply of all other study materials will be the 
responsibility of Interna Therapeutics  Ltd. and/or its designee. Subject recruitment should not 
begin until after the required regulatory documents are confirmed as received. All personnel 
expected to be involved in the conduct of the study will undergo orientation to include review of 
study protocol, instructions for eCRF completion, AE reporting and overall responsibilities 
including those for the IP accountability and study file maintenance. 
 An Investigator's study file will be in place and should be used for all trial-related documents. The 
Investigator will be responsible for keeping the Investigator's file updated and ensuring that all 
required documents are filed. The file will be inspected periodically during monitoring visits. 
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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11.3 Clinical Trial Supplies 
The Sponsor and/or designated representative will be responsible for supplying clinical trial 
supplies. The Investigator will be responsible for inventory and accountability of all clinical trial 
supplies at his/her site, exercising accepted medical and pharmaceutical practices. An accurate and 
timely record of the disposition of all clinical supplies must be maintained. The supplies and 
inventory record must be made available for inspection upon request. Upon completion or 
termination of the study the Investigator will keep a copy of the inventory record, destruction 
record (if relevant) and a record of the clinical supplies returned. Study drugs are to be used only 
as directed by this protocol.  
Clinical trial supplies include, however, are not limited to study drugs. 
 
11.4 Investigator’s Site File 
The investigator’s site file will be provided by the Sponsor and/or delegate up to the initiation visit. 
All documents required for the conduct of the study as specified in the ICH-GCP guidelines will 
be maintained by the Investigator in an orderly manner in the investigator’s site file and made 
available for monitoring and/or auditing by the Sponsor and/or delegate and regulatory agencies. 
 
11.5 Study Completion 
The end of the study is defined as the date of the last EOS visit of the last subject in the study. 
Data and materials that are required for the study to be considered complete and/or terminated are: 
• Laboratory findings, clinical data and all special test results from screening through to the end of 
the follow-up period 
• eCRF properly completed by appropriate study personnel and signed by the Investigator 
• Completed Drug Accountability Records 
• Statement of outcome for each serious adverse event reported to the sponsor and/or delegate and 
IRB/IEC 
• Copies of protocol amendments and IRB/IEC as well as relevant health authority 
approval/notification (if applicable) 
All collected data whether it is in paper or electronic form must be reviewed, signed and dated by 
the investigator or appropriate designee before study completion. 
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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11.6 Study Termination and Stopping Rules 
The RU reserves the right to terminate the study or to terminate an individual subjects’ 
participation in the interest of subject welfare. 
The Sponsor reserves the right to suspend or terminate the study at any time. 
The SMG and DSMC will monitor safety throughout the study. The SMG and DSMC will meet 
periodically to review available safety data to make decisions regarding continuation, 
modification, suspension, or termination of the study. 
Dose escalation or administration of study intervention in a dose cohort may be stopped and 
additional subjects will not receive study intervention until a consultation has taken place among 
the SMG and DSMC members, investigator, and the Study Medical Monitor (or designee), if one 
of the following circumstances occurs in subjects treated with study intervention, unless it is 
determined by the SMG/DSMC in consultation with the study investigator/medical monitor that 
the occurrence is not related to the administration of the study intervention: 
• Two or more subjects in a cohort experience a common terminology criteria for adverse 
events (CTCAE) Grade 3 or higher clinical or laboratory abnormality that is considered to 
be related to study intervention by the investigator. 
• An AE or group of AEs that singularly or in aggregate suggests to the investigator or 
Sponsor that the study intervention is poorly tolerated and further treatment per protocol 
may not be safe. 
• If one or more subject(s) in a cohort experience any treatment-related, treatment-emergent 
SAEs, dose escalation will be stopped to re-evaluate the dose in question. 
If any of these criteria occur, the SMG/DSMC will review all available data; if an event is 
determined to be related to a specific dose level, doses in subsequent cohorts may be either 
modified, the current dose level can be expanded, or dose escalation may be terminated. Prior to 
any required dose level adjustment, the clinical and laboratory safety parameters from the previous 
dosing cohort(s) will be reviewed and discussed by the SMG/DSMC to allow a recommendation 
on advancing to the next dose level. The suggested next doses may be the protocol-defined 
escalation dose, an equivalent dose, an intermediate dose, or an adjusted-downward dose based on 
evaluation of safety and tolerability data from previous cohorts. 
The Sponsor, investigator and the institutional review board (IRB) / independent ethics committee 
(IEC) reserve the right to terminate or suspend the study at any time; however, this should be 
discussed between the relevant parties beforehand and the reason for such decision recorded. 
Should this occur, all data available will also be recorded in eCRFs. The investigator should notify 
the IRB/IEC in writing of the study’s completion or early termination. 
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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11.7 Final Report 
A final study report will be generated at the completion of data analysis. This report will be a 
clinical and statistical integrated report, according to ICH E3 guidelines. 
 
11.8 Retention of Study Records 
 
The Investigator will retain copies of the approved protocol, completed CRF, ICFs, relevant source 
documents, and all other supporting documentation related to the project for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by Interna Therapeutics Ltd. or designee, whichever is longer, in a secure and safe facility 
with limited access. 
If the Investigator is unable to retain the study documents for the required amount of time, Sponsor 
or designee must be informed of the individual who will be assuming this responsibility. 
Further retention, if required, will be negotiated at the end of this retention period. In that case, 
Interna Therapeutics Ltd. will notify, in writing, the Investigator when the clinical study data may 
be discarded. The Investigator will take measures to prevent accidental or premature destruction 
of these documents. 
These files must be made available for inspection upon reasonable request by authorized 
representatives of Sponsor and/or the relevant regulatory agencies. 
At the end of the minimum period, the Investigator should obtain written authorization from the 
Sponsor prior to the destruction of any records. 
 
11.9 Confidentiality and Publication 
Subject medical information obtained by the study is confidential and disclosure to third parties 
other than those noted below in this section is prohibited. Throughout the study, all data will be 
identified only by the subject identification number. 
Subject to, and dependent upon, the subject's written request, subject medical information from 
the study may be given to his personal physician or other appropriate medical personnel 
responsible for his welfare. In accordance with local regulations, when appropriate, the personal 
physician of the study participant will be notified by the Investigator of subject participation in the 
study. 
All information supplied by the Sponsor and/or delegate. in association with this study and not 
previously published, is considered confidential information. This information includes, but is not 
limited to, the Investigator’s Brochure, the protocol, CRFs and other scientific data. Any data 
collected during the study is also considered confidential. 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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This confidential information shall remain sole property of the Sponsor, shall not be disclosed to 
others without the prior written consent of the Sponsor and shall not be used except in the 
performance of this study. 
11.10 Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
Neither the Sponsor nor the site is financially responsible for further testing or treatment of a 
subject for any medical condition that may be detected during the screening process. 
 
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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12. 
REFERENCES 
 
 
https://www.who.int/docs/default-source/coronaviruse/situation-
reports/20230727_weekly_epi_update_153.pdf?sfvrsn=de3d47d_3&download=true 
 
Alvarez R, Elbashir S, Borland T, Toudjarska I, Hadwiger P, John M, Roehl I, Morskaya SS, 
Martinello R, Kahn J, Van Ranst M, Tripp RA, DeVincenzo JP, Pandey R, Maier M, Nechev 
L, Manoharan M, Kotelianski V, Meyers R. RNA interference-mediated silencing of the 
respiratory syncytial virus nucleocapsid defines a potent antiviral strategy. Antimicrob Agents 
Chemother. 2009 Sep;53(9):3952-62. 
 
 
Stanojevic, S., Kaminsky, D. A., Miller, M., Thompson, B., Aliverti, A., Barjaktarevic, I., et 
al. (2021). "ERS/ATS technical standard on interpretive strategies for routine Pulmonary 
function tests." Eur Respir J. 
Downie SR, Andersson M, Rimmer J, Leuppi JD, Xuan W, Akerlund A, Peat JK, Salome CM. 
Symptoms of persistent allergic rhinitis during a full calendar year in house dust mite-sensitive 
subjects. Allergy. 2004 Apr;59(4):406-14. 
 
 

Interna Therapeutics  Ltd.  
 
 
 Study intervention: Apo-Si-K170A-C76 
 
                                                                                       
   Protocol Number: Sir-001 
 
 
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13. 
APPENDICES 
NA