Development of Plasmid DNA Gene Medicine with Regenerative Capacities for Diabetic Neuropathy and Foot Ulcer

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1 Keynote, BioJAPAN Development of Plasmid DNA Gene Medicine with Regenerative Capacities for Diabetic Neuropathy and Foot Ulcer Sunyoung Kim Seoul National University ViroMed Co Ltd.

2 VM202 is a DNA medicine. Plasmid DNA designed to simultaneously express two isoforms of HGF, HGF 723 and HGF 728, at high levels in vivo as well as in vitro. Freeze Dried DNA HCMV IE promoter IM Injection Exon 1 Intron 1 ColE1 Exon 2 Intron 4 Alternative splicing HGF 723 HGF 728 HGF-X7 Kan r pck + HGF-X7 Exon number pa HGF-X7 Special Features Therapeutic Gene: HGF Two isoforms: HGF HGF 728 Expression Level: Promoter UTR Intron Formulation ViroMed has a strong patent position with VM202. Patents issued in US, Japan, Europe, China, Singapore and Korea and filed in Brazil. #2

3 Simple intramuscular injections of VM202 can create new blood vessels and repair damaged neurons. Angiogenesis Targets: cardiovascular diseases (e.g. ischemic diseases) Atherosclerosis (narrowed or blocked blood vessels) Pain Control and Regeneration of Damaged Nerves Formation of New Blood Vessels Targets: neurological diseases Nerve Occluded Vasa Nervorum* ( * small arteries & microvasculature ) Damaged nerve cells Blood vessel Nerve Regenerated nerve cells #3

4 We target 4 major human diseases, based on these biological activities. Cardiovascular Coronary Artery Disease Acute Myocardial Infarction Phase II (Korea) ongoing Spinal Cord Neurological Amyotrophic Lateral Sclerosis Lou Gehrig s Disease Phase II (US) approved Motor neuron Spinal Cord Responsive muscle Peripheral Artery Disease Chronic Non-Healing Foot Ulcer Phase III (US) ongoing Diabetic Peripheral Neuropathy Painful Diabetic Peripheral Neuropathy Phase III (US) ongoing #4

5 Painful Diabetic Peripheral Neuropathy (DPN) One of the most frequently observed neuropathies associated with 5~12% of all diabetes patients Patients suffer from sensory loss, dysesthesia, and night time pain * Blood vessel damage Hyperglycemia Normal Blood vessel Normal Narrowed or Blocked Nerve * Nerves shrivel when blood vessels disappear Throbbing, Tingling, Burning, Stabbing #5

6 Current Treatment Methods There are 3 major drugs just for DPN prescription, forming a $ 4 ~ 5 billion market. Anticonvulsants: Antidepressants: Pregabalin (Lyrica, Pfizer) $ ~5.1 Billion (2014), Neuropathic pain market: 30~50% Gabapentin (Neurontin, Pfizer) $ ~ 210 Million (2014) Duloxetine (Cymbalta, Eli Lilly) $ 5 Billion (2013), Neuropathic pain market: > $1 Billion NSAIDs Opioids: Tapentadol (Nucynta ER, J&J/Depomed) Overall sales: $ 190 Million (US, 2015) #6

7 There is a huge medical need in the area of painful DPN Current prescription drugs provide symptom relief only, and produce not-so-trivial side effects. Most importantly, 60% ~ 70% of PDPN patients do not or cannot follow these medication options. #7

8 Study Outline of Phase II A Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 1. Indication Painful Diabetic Peripheral Neuropathy 2. Treatment groups (Total: 103 subjects) 16 mg VM202 (8mg/leg) : 40 subjects 32 mg VM202 (16mg/leg) : 42 subjects Placebo (0.9% normal saline) : 21 subjects Principal Investigator JOHN (JACK) A. KESSLER, M.D. (Northwestern Medical School) 3. Injection scheme Bilateral 2 injection cycles along the calf line (day 0 & 14) (~ 2cm deep) (~ 2cm distance) 4. Follow-up period : 9 months 5. Efficacy Pain score (Daily Pain and Sleep Interference Diary)* VAS*, BPI-DPN*, MNSI, PGIC* and histological findings on skin biopsy 6. Safety * These methods were used in Pfizer s clinical studies for Lyrica. #8

9 Changes in severity from baseline Effect on Pain Severity (Daily Pain Diary) 2 Rounds of IM injection of VM All Subjects (n=84) Simplified from Kessler et al. Annals of Clinical and Translational Neurology, 2: (2015) *(Δ=-1.5) (Δ=-1.03) Months after the first injection (Δ=-1.19) Placebo VM mg (8 mg/leg) [*p<0.05, vs. placebo, p<0.05, vs. baseline, Δ VM202 16mg Placebo] (Drug-Placebo) Value -1.5 vs -1.2 vs -1.4 VM202 Lyrica Nucynta -1.1 Neurontin -1.3 Cymbalta Significant pain-relieving effects were observed over a long period. #9

10 Changes in severity from baseline Most strikingly, VM202 produced record-high pain-relieving effects in patients who could not or did not take currently available drugs. 2 Rounds of IM injection of VM Subjects NOT on Lyrica and/or Neurontin (n=49) Simplified from Kessler et al. Annals of Clinical and Translational Neurology, 2: (2015) Placebo vs VM202 Lyrica * (Δ=-2.37) * (Δ=-2.29) Months after the first injection [*p<0.05, vs. placebo, p<0.05, vs. baseline, Δ VM202 16mg Placebo] (Δ=-1.47) VM mg (8 mg/leg) #10

11 50% Responder Analysis *Simplified from Kessler et al. (2015) NOM = patients not taking Lyrica and/or Neurontin in the present study 3 months 6 months 9 months NOM 1) Total NOM 1) Total NOM 1) Total Placebo 18.2% 17.6% 9.1% 17.6% 27.3% 23.5% VM mg Lyrica * * 68.4% 48.4% 52.6% 38.7% 52.6% 41.9% VM202 [*p<0.05, vs. placebo group] 300 mg, 2 times/day Duration of effect: 12 ~ 24 hours 50% responders: 32.9 ~ 38.3% Note: Lyrica values were obtained using BOCF imputation rule, while VM202 used no imputation 16 mg, mg, 2 wks interval Duration of effect: 3 ~ 9 months 50% responders: 38.7 ~ 68.4% VM202 showed much greater percentage of 50% responders than Lyrica. #11

12 Key Discoveries of Phase II Trial 1. VM202 has shown an excellent safety profile compared to current prescription drugs. 2. The 16 mg dose of VM202 (8 mg/leg) gave significant improvements in all pain measurements for a long period of time. (Daily pain diary, BPI-DPN, VAS, PGIC) 3. Pain relieving effects were more pronounced in patients who are not taking Lyrica and/or Neurontin. 4. Data from monofilament tests suggests that VM202 may aid in recovery of sensory functions and has the potential to be a disease-modifying drug. #13

13 #1 Phase III for DPN Phase III ongoing in US (184 randomized & 479 enrolled, as of June. 27 th, 2017) 1. Target disease : Painful Diabetic Peripheral Neuropathy 2. Dosing Scheme Placebo: 159, VM202: 318 Total: 477 subjects. Repeated injections 16mg (Days 0 and 14) + 16mg (Days 90 and 104) 3. Follow-up period: 9 months #14

14 VM202 for Ischemic Diseases Blood vessel damage Normal Targets: cardiovascular diseases Narrowed or Blocked Formation of New Blood Vessels Simple intramuscular injections of VM202 can create new blood vessels and repair damaged neurons. #16

15 2nd Target Disease of VM202 Chronic, non-healing, ischemic foot ulcer in diabetes patients Ischemic foot ulcer results from narrowing or blockage of peripheral arteries in the legs. Many diabetes patients suffer from chronic, non-healing foot ulcer. Blocked / Occluded Peripheral Artery Vessels Claudication Rest Pain Ulcer (Chronic) Gangrene Amputation Atherosclerosis Hyperglycemia Diabetes 26 million Peripheral Neuropathy 15 million Chronic Foot Ulcer 4.5 million CLI 0.85 million Peripheral Artery Disease 8.5 million Total Number Chronic Foot Ulcer ~ 4.5 Million CLI Critical Limb Ischemia ~ 0.85 Million Amputation 82, ,000 Medical Costs $ 9~13 Billion ~ $ 8 Billion There is a huge unmet medical need in the area of diabetic foot ulcer #17

16 Phase II Trial for CLI as a POC model A Phase II, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 1. Indication : Critical Limb Ischemia (Rutherford class 4 and 5) (one of the most extreme forms of diabetic foot ulcer) 2. Treatment arms (Total : 52 subjects) Placebo (0.9% normal saline) : 11 subjects Low dose of VM202 (2 mg/visit) : 21 subjects High dose of VM202 (4 mg/visit) : 20 subjects 30/52 (57.6%) subjects had diabetes. Principal Investigator EMERSON C. PERIN, M.D. (Stem Cell Center Texas Heart Institute) (~ 2cm distance) 3. Injection scheme : 4 injection cycles along the calf line (days 0, 14, 28, & 42), unilateral IM injection 4. Follow-up period : 12 months 5. Efficacy 6. Safety #18

17 Dramatic Healing Effects on Ulcer Were Observed. Placebo (Screening) Placebo (Day 90) Low dose (Screening) Low dose (Day 365) High dose (Screening) High dose (Day 365) Group (Number of ulcers) Placebo (n = 9) Low dose (n = 27) High dose (n = 13) Completely healed 11% (1/9) 52% (14/27) 62% (8/13) Improved 1) 11% (1/9) 70% (19/27) 69% (9/13) (Kibbe et al., Gene Therapy (2016) 1-7) 1) Reduction of ulcer area > 50% * * * [* p < 0.05, vs. placebo (Fischer Exact Test)] A higher % of completely healed ulcers was observed in the high dose group during 12-month follow-up period. #19

18 Phase III for Diabetic Foot Ulcer (US) 1. Indication: Chronic Non-Healing Ischemic Diabetic Foot Ulcers ( Ulcer(s) on or around the foot area that is unresponsive to standard therapies and persists despite 4 weeks of appropriate care) 2. Treatment arms: (Total 300 subjects) 16 mg VM202 + Standard of Care: 200 subjects Placebo (VM202 vehicle) + Standard of Care: 100 subjects 3. Injection scheme: Unilateral 4 injection cycles in the ipsilateral calf of the affected foot (day 0, 14, 28, and 42) 4. Follow-up period: 7 months 5. Efficacy endpoints: Primary: Complete wound closure, 4 months 6. Safety endpoints SilhouetteStar Ulcer size is measured using 3D camera to determine ulcer depth or volume #20

19 ViroMed s Position in Gene Therapy [ Approved gene therapy product] [Phase III (currently ongoing)] Year Country Product Company Target Indication 2016 Europe Strimvelis GKS ADA-SCID 2015 US Imlygic Amgen Malignant Melanoma 2012 Europe Glybera UniQure LPLD 2011 Russia Neovasculgen 2007 Philippines Rexin-G Human Stem Cell Institute Epeius Biotechnologies Critical Limb Ischemia Metastatic malignant tumor 2005 China Oncorine Shanghai Sunway Head and neck cancer Company Indication Material Kite Pharma B-cell non-hodgkin lymphoma CAR-T Novartis B-cell acute lymphoblastic leukemia CAR-T Bluebird bio Hereditary disease Lentivirus BMS / Bavarian Nordic inc Prostate Cancer Virus-PSA antigens GenSight Biologics Hereditary disease AAV virus-nd4 MolMed S.p.A. Acute leukemia Herpes virus-tk Sillajen, Korea Hepatocellular carcinoma Oncolytic Spark Therapeutics Hereditary disease AAV-SPK-RPE56 Taxus Cardium Pharm. Cardiovascular Adenovirus-FGF-4 Tissuegene (Kolon) Degenerative arthritis Cell & Gene therapy 2003 China Gendicine Shenzhen Sibiono GeneTech Co., Ltd Head and neck cancer Vical & Astellas Viral infection during organ transplant DNA Vaccine ViroMed Painful Diabetic Peripheral Neuropathy DNA-HGF ViroMed Diabetic Foot Ulcer DNA-HGF Only three phase III s use DNA. BLA submission #22

20 Our DNA Platform Technology Our proprietary DNA platform is designed to produce much needed therapeutic effects in various diseases. Expression Platform Therapeutic Gene HGF X + Y Her2/neu Non-disclosed genes VM202 DPN PAD ALS CAD Next Generation DNA Medicines for Cardiovascular and Neurological Diseases VM206 Her2+ cancers Breast Cancer Stomach Others Tumor antigens Antigens in infectious pathogens Allergens Genes with regenerative potentials By inserting a different gene, a variety of different drugs are being developed. #23

21 Conclusion 1. Naked plasmid DNA can be a powerful tool for gene delivery, depending on the nature of genes and target indications. 2. VM202 has produced significant efficacy in diabetic peripheral neuropathy and ischemic foot ulcer. 3. VM202 has strong potential to be applied to a number of other neuromuscular and neuroischemic diseases. 4. Should the phase II data be reproduced in phase III studies, VM202 is likely to become the first regenerative medicine for these major human diseases. #24