Phase 3 Gene Therapy for Painful Diabetic Neuropathy

Peripheral neuropathy is a serious complication of diabetes. This form of neuropathy carries
a high risk of pain, trophic changes and autonomic dysfunction. Treatment of diabetic
peripheral neuropathy (DPN) is 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. The results from previous studies suggest that VM202 provides the same magnitude
of pain relief as reported with pregabalin or gabapentin.

Inclusion Criteria:

1. Age ≥ 18 years to 75 years;

2. Documented history of Type I or II diabetes with current treatment control
(glycosylated hemoglobin A1c of ≤ 10.0% at Screening) and currently on oral medication
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 (VAS) score of ≥ 40 mm at Initial Screening (0 mm = no pain - 100
mm very severe pain);

8. Symptoms from the Brief Pain Neuropathy Screening (BPNS) 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 (MNSI) is ≥ 3 at Initial Screening;

11. Subjects on gabapentin (Neurontin), pregabalin (Lyrica), duloxetine (Cymbalta) for
painful DPN at study entry must be on stable regimen of these treatments for at least
3 months prior to study entry; and

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 DPN;

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 (SBP) > 200
mmHg or diastolic BP (DBP) > 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 and patches, isosorbide dinitrate (ISDN)
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 6 months of the study. Subjects on these medications
at study entry must maintain a stable dose for the first 6 months 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 for the first
6 months 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 for the first 6 months of the
study;

21. Major psychiatric disorder within last 6 months that would interfere with study
participation;

22. Body mass index (BMI) > 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 VM202; and

25. Unable or unwilling to give informed consent.