Phase 3 Gene Therapy for Painful Diabetic Neuropathy

The purpose of this study is to determine the safety and efficacy of bilateral intramuscular injections of VM202 versus placebo in the treatment of painful diabetic peripheral neuropathy.

A total of 507 of 477 planned participants were randomized in a 2:1 ratio to one of two treatment groups. Note that 500 participants received Investigational product treatment, whereas 7 participants did not receive Investigational product treatment.

Treatments - Engensis (VM202) - 336 Engensis of 318 planned participants

Control - Placebo (VM202 vehicle) - 164 Placebo of 159 planned participants

Randomization were stratified by current use of gabapentin and/or pregabalin.

Peripheral neuropathy is a serious complication of diabetes. This form of neuropathy carries a high risk of pain, trophic changes, and autonomic dysfunction. Current treatments of diabetic peripheral neuropathy are based on either pathogenetic mechanisms or symptomatic relief. A number of clinical trials have established symptomatic treatment but for pathogenetic mechanisms, the only proven treatment strategy is strict glycemic control. Clearly, it would be desirable to prevent, impede, or reverse the disrupting and often life-threatening manifestations of peripheral neuropathy by stimulating growth or regeneration of peripheral nerve axons.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ 18 years to ≤ 75 years
2. Documented history of type I or II diabetes with current treatment control (HbA1c of ≤ 10.0% at Screening) and currently on medication for diabetes (oral, injectable, and/or insulin)
3. No significant changes anticipated in diabetes medication regimen
4. No new symptoms associated with diabetes within the last 3 months prior to study entry
5. Diagnosis of painful diabetic peripheral neuropathy in both lower extremities
6. Lower extremity pain for at least 6 months
7. Visual analog scale score of ≥ 40 mm at Initial Screening (0 mm = no pain - 100 mm very severe pain)
8. Symptoms from the Brief Pain Neuropathy Screening is ≤ 5 point difference between legs at Initial Screening
9. The average daily pain intensity score of the Daily Pain and Sleep Interference Diary completed after medication wash-out is ≥ 4 with a standard deviation ≤ 2
10. The physical examination component of the Michigan Neuropathy Screening Instrument Score is ≥ 3 at Screening
11. Subjects on gabapentin (Neurontin), pregabalin (Lyrica), duloxetine (Cymbalta) for painful Diabetic Peripheral Neuropathy at study entry must be on stable regimen of these treatments for at least 3 months prior to study entry
12. If female of childbearing potential, negative urine pregnancy test at screening and using acceptable method of birth control during the study

Exclusion Criteria:

1. Peripheral neuropathy caused by condition other than diabetes
2. Other pain more severe than neuropathic pain that would prevent assessment of Diabetic Peripheral Neuropathy
3. Progressive or degenerative neurological disorder
4. Myopathy
5. Inflammatory disorder of the blood vessels (inflammatory angiopathy, such as Buerger's disease)
6. Active infection
7. Chronic inflammatory disease (e.g., Crohn's disease, rheumatoid arthritis)
8. Positive HIV or HTLV at Screening
9. Active Hepatitis B or C as determined by Hepatitis B core antibody (HBcAb), antibody to Hepatitis B surface antigen (IgG and IgM; HBsAb), Hepatitis B surface antigen (HBsAg), and Hepatitis C antibodies (Anti HCV) at Screening
10. Subjects with known immunosuppression or currently receiving immunosuppressive drugs, chemotherapy, or radiation therapy
11. Stroke or myocardial infarction within last 3 months
12. Specific laboratory values at Screening including: Hemoglobin \< 8.0 g/dL, WBC \< 3,000 cells per microliter, platelet count \<75,000/mm3, Creatinine \> 2.0 mg/dL; AST and/or ALT \> 3 times the upper limit of normal or any other clinically significant lab abnormality which in the opinion of the investigator should be exclusionary
13. Ophthalmologic conditions pertinent to proliferative retinopathy or conditions that preclude standard ophthalmologic examination
14. Uncontrolled hypertension defined as sustained systolic blood pressure \> 200 mmHg or diastolic BP \> 110 mmHg at Screening
15. Subjects with a recent history (\< 5 years) of or new screening finding of malignant neoplasm except basal cell carcinoma or squamous cell carcinoma of the skin (if excised and no evidence of recurrence for one year); subjects with family history of colon cancer in any first degree relative are excluded unless they have undergone a colonoscopy in the last 12 months with negative findings
16. Use of the following drugs / therapeutics is prohibited. Subjects may participate in the study if they are willing to discontinue use of these drugs / therapeutics 7 days prior to starting the 7 Day Daily Pain and Sleep Interference Diary. Subjects must refrain from taking these drugs or undergoing these therapies for the duration of the study

    * skeletal muscle relaxants, opioids, benzodiazepines (except for stable bedtime dose),
    * capsaicin, local anesthetic creams (except for lidocaine cream prior to intramuscular injection) and patches, isosorbide dinitrate spray,
    * transcutaneous electrical nerve stimulation (TENS), acupuncture
17. If not using gabapentin (Neurontin) or pregabalin (Lyrica), subjects must agree not to start these drugs for the first 180 days of the study. Subjects on these medications at study entry must maintain a stable dose until Day 180 of the study;
18. If not using duloxetine (Cymbalta), any antidepressants (e.g., amitriptyline and venlafaxine), any other antiepileptics (e.g., valproic acid, carbamazepine, vigabatrin), subjects must agree not to start these drugs for the first 6 months of the study.

    Subjects on these medications at study entry must maintain a stable dose until Day 180 of the study
19. Subjects requiring \> 81 mg daily of acetylsalicylic acid; subjects may be enrolled if willing/able to switch to ≤ 81 mg daily of acetylsalicylic acid or to another medication
20. Subjects requiring regular COX-2 inhibitor drug(s) or non-specific COX-1/COX-2 inhibiting drugs, or high dose steroids (except inhaled steroids or ocular steroids) subjects may be enrolled if willing/able to undergo medication wash-out prior to the first dosing and to refrain from taking these drugs until Day 180 of the study
21. Major psychiatric disorder within the last 180 days that would interfere with study participation
22. Body mass index \> 45 kg/m2 at Screening
23. Any lower extremity amputation due to diabetic complications
24. Use of an investigational drug or treatment in past 6 months, or prior participation in any study of Engensis (VM202)
25. Unable or unwilling to give informed consent