ViroMed Overview. World leader in DNA medicine with aims to become the first mover in cardiovascular and neurological disease markets.

Transcription

1 ViroMed

2 ViroMed Overview Established: Nov. 21, 1996 Initial Public Offering (IPO): Dec. 29, 2005 (KOSDAQ: ) Number of Employees: ~ 70 (R&D >35) Location: Seoul, South Korea Webpage: World leader in DNA medicine with aims to become the first mover in cardiovascular and neurological disease markets. Yong Soo Kim CEO Vice President, Hansol Inticube Co., Ltd. CEO, Inticube Co., Ltd. COO, Locus Corporation CFO, Samsung Design America Inc. M.P.P., Harvard University Sunyoung Kim, D. Phil CSO Professor at Seoul National University Assistant Professor at Harvard Medical School D.Phil., Oxford University M.A., Harvard University M.S., MIT #2

3 ViroMed has diverse and well-balanced product portfolio. DNA Phase II Approved in US Phase III Scheduled in US VM202 - ALS VM202 - PAD Phase III Ongoing in US VM202 - DPN Biologics Phase I Completed in Korea VM206 Breast Cancer Phase III Ongoing in China VM501 Chemotherapy Induced Thrombocytopenia Protein ETC Drugs PG201 Osteoarthritis HX203 ADHD PG102 Immune Hypersensitivity Botanicals VM811 Joint Health Nutraceuticals HX106 Memory Attention Phase II Approved in Korea VM202 - CAD Antibody HX204 Lower Urinary Tract Symptoms DNA CAR-T Cell : Research & Pre-clinical : Clinical Development : Market #3

4 ViroMed's leading product VM202 targets huge medical markets. VM202, ViroMed s flagship product, is a DNA medicine targeting cardiovascular and neurological diseases with huge unmet medical needs. Main target markets are the US, Japan, and Europe. In the US, ViroMed has one phase III under way for DPN, will commence another phase III for diabetic ulcer soon, and has received phase II approval for ALS. Because of its utmost importance, I will focus my presentation on explaining VM202 #4

5 VM202 is a new and innovative DNA medicine capable of regenerating damaged blood vessels and neurons by simple intramuscular injection. 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. Special Features Expression Level: Promoter, UTR, Intron Therapeutic Gene: HGF Two isoforms: HGF HGF 728 Formulation ViroMed has strong patent position with VM202. #5

6 Simple intramuscular injections of VM202 can create new blood vessels and repair damaged neurons. Angiogenesis Formation of New Blood Vessels Atherosclerosis (narrowed or blocked blood vessels) Potential targets: cardiovascular diseases (e.g. ischemic diseases) Regeneration of nerve cells and microvasculature Damaged nerve cells Occluded Vasa Nervorum* ( * small arteries & microvasculature ) Regenerated nerve cells Potential targets: neurological diseases #6

7 We target 4 major human diseases, based on these biological activities. Cardiovascular Neurological Coronary Artery Disease Acute Myocardial Infarction Phase II (Korea) approved Spinal Cord 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) study scheduled Diabetic Peripheral Neuropathy Painful Diabetic Peripheral Neuropathy Phase III (US) ongoing #7

8 1 st Target Disease of VM202 Painful Diabetic Peripheral Neuropathy (PDPN) One of the most frequently observed neuropathies, associated with 5~12% of all diabetes patients Patients suffer from sensory loss, dysaesthesia, and night time pain Hyperglycemia High levels of Glucose Blood Vessel damage Nerve damage Blood vessel Nerve Normal Diseased blood vessels Sensory impairment Nerves shrivel when blood vessels disappear Throbbing, Burning, Stabbing, Tingling #8

9 Current prescription drugs provide symptom relief only, and also produce not-so-trivial side effects. There are 3 major drugs just for DPN prescription creating $ 4 ~ 5 billion market. Anticonvulsants: Pregabalin (Lyrica, Pfizer) $ ~5.1 Billion (2014), Neuropathic pain market: 30~50% Gabapentin (Neurontin, Pfizer) $ ~ 210 Million (2014) Antidepressants: 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) Most importantly, 60% ~ 70% of PDPN patients do not or cannot follow these medication options. #9

10 Study Outline of VM202-DPN Phase II A Double-Blind, Randomized, Placebo-Controlled, Multicenter Study (US, Korea) 1. Indication Painful Diabetic Peripheral Neuropathy Principal Investigator JOHN (JACK) A. KESSLER, M.D. (Northwestern Medical School) 2. Treatment groups (Total: 102 subjects) 16 mg VM202: 39 subjects 32 mg VM202: 42 subjects Placebo (0.9% normal saline): 21 subjects 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. #10

11 VM202 is much safer than current FDA approved medication targeting the same target disease. Lyrica 1) (Pfizer) Cymbalta 2) (Eli Lilly) Nucynta 3) (J&J/Depomed) VM202 (ViroMed) Side effects More common confusion, disorientation, ataxia, changes in walking and balance, disequilibrium, amnesia, disturbance of attention, memory impairment, blurred vision, diplopia Less common depression, agitation, mood swing, hallucinations, oneiric delirium, strabismus, loss of peripheral vision More common Diarrhea, constipation, nausea, insomnia, hypersomnia, dizziness, weakness, drowsiness, fatigue, headache, sedation, xerostomia Less common Feeling faint, anxious, chills, cough, blurred vision, feeling restless, feeling weak, head pain, weight gain, sluggishness, sleep disorder, muscle spasm More common Nausea, dizziness, vomiting, somnolence, constipation, headache, fatigue, dry mouth, hyperhidrosis, pruritus, Insomnia, diarrhea, Anxiety, Decreased appetite Less common Bladder pain, bloody urine, body aches, chills, cough, difficulty with breathing, fever, headache, loss of voice, lower back pain, muscle aches Minor pain, itching, and erythema only at injection sites 1) Pain killer, 2) Anti depressant, 3) Opioid for pain VM202 has shown an excellent safety profile compared to Lyrica, Cymbalta and Nucynta. #11

12 Changes in severity from baseline Effect on Pain Severity (Daily Pain Diary) Daily Pain Diary: Instrument for rating patient's 24-hour average daily pain intensity from 0 (no pain) to 10 (worst possible pain) 2 Rounds of IM injection of VM All Subjects (n=84) *(Δ=-1.5) (Δ=-1.19) (Δ=-1.03) Months after the first injection *p<0.05, vs. placebo, p<0.05, vs. baseline, Δ VM202 16mg Placebo Placebo 16 mg (8 mg/leg) Simplified from Kessler et al., Annals of Clinical and Translational Neurology, 2015; 2(5): vs -1.2 vs -1.4 VM202 Lyrica Nucynta -1.1 Neurontin -1.3 Cymbalta Significantly higher pain-relieving effects were observed over a long period compared to Lyrica. #12

13 Placebo Effects in Other Studies 1. Neurontin (study # ) 2. Lyrica (study # ) Placebo = -1.4 ± 1.7 Neurontin = -2.5 ± 2.5 ( = -1.1) Placebo 900 mg 1,800 mg 2,400 mg 3,600 mg Placebo = -1.9 ± 2.1 Lyrica (600 mg/d) = -2.7 ± 2.3 ( = 0.8) 3. Cymbalta (study #. HMAWa-acute) 4. Nucynta (tapentadol, J&J/Depomed) Placebo = -1.9±2.06 Cymbalta = ± 2.06 ( = -1.34) Placebo = -2.1 Nucynta = -3.5 ( = -1.4) D.J. Goldstein et al. / Pain 116 (2005) Placebo effects shown in our study are comparable to those of others. #13

14 Most strikingly, VM202 produced record-high pain-relieving effects in patients who could not or did not take currently available drugs. Changes in severity from baseline 2 Rounds of IM injection of VM202 Simplified from Kessler et al., Annals of Clinical and Translational Neurology, 2015; 2(5): Subjects NOT on Lyrica and/or Neurontin (n=49) Placebo vs VM202 Lyrica * (Δ=-2.37) * 16 mg (8 mg/leg) (Δ=-2.29) (Δ=-1.47) Months after the first injection *p<0.05, vs. placebo, p<0.05, vs. baseline, Δ VM202 16mg Placebo #14

15 50% Responder Analysis Simplified from Kessler et al., Annals of Clinical and Translational Neurology, 2015; 2(5): 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% VM202 * * 16 mg 68.4% 48.4% 52.6% 38.7% 52.6% 41.9% *p<0.05, vs. placebo group Lyrica 300 mg, 2 times/day Duration of effect: 12 ~ 24 hours 50% responders: 32.9 ~ 38.3% VM mg, mg, 2 wks interval Duration of effect: 3 ~ 9 months 50% responders: 38.7 ~ 68.4% Note: Lyrica values were obtained using BOCF imputation rule, while VM202 used no imputation VM202 showed much greater percentage of 50% responders than Lyrica. #15

16 % of patients much and very much improved % of patients much and very much improved Effect on Quality of Life - Patient s Global Impression of Change (PGIC) - Simplified from Kessler et al., Annals of Clinical and Translational Neurology, 2015; 2(5): PGIC: Questionnaire to measure a patient s perception of how treatment affected their level of activity, symptoms, emotions, and overall quality of life. 1. Very much improved 2. Much improved 3. Minimally improved 4. No change 5. Minimally worse 6. Much worse 7. Very much worse 80 All subjects (n=84) 80 Subjects NOT on Lyrica and/or Neurontin (n=49) 60 * 51.61% 60 * * 66.67% 63.16% 16 mg mg Placebo Placebo Months after the first injection Months after the first injection *p<0.05, vs. placebo group More than 50% of the patients who received VM202 have shown significant improvement in their quality of life. #16

17 % of patients improved in sensory threshold Effect of VM202 in Monofilament Test (Assessment of sensory perception) Simplified from Kessler et al., Annals of Clinical and Translational Neurology, 2015; 2(5): Subjects NOT on Lyrica and/or Neurontin 60% * 60% All Subjects 50% 40% 16 mg 50% 40% * 16 mg 30% 30% 20% 20% 10% Placebo 10% Placebo Kessler et al., Annals of Clinical and Translational Neurology, 2: (2015) 0% Months after the first injection *p<0.05, vs. placebo group 0% Left Leg Months after the first injection *p<0.05, vs. placebo group The 16 and 32 mg groups improved in sensory threshold, especially in the left leg at 9 months. Once again, patients who were not taking Lyrica and/or Neurontin responded much better to VM202, up to 9 months. #17

18 Key Discoveries of Phase II Trial 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 related factors for a long period of time. 1 Pain severity and/or interference Daily Pain Diary (Primary efficacy endpoint) Brief Pain Inventory for DPN(BPI-DPN) Visual Analogue Scale 2 Quality of life (PGIC) Patient s Global Impression of Change The effect of VM202 on pain reduction appears to be greater than Lyrica, when compared with publicly available data on Lyrica. #18

19 Key Discoveries of Phase II Trial The most striking finding is that VM202 works much better 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. VM202 has the potential to expand the current market and/or to be complementary to current prescription drugs. #19

20 Phase III plan for VM202-DPN Phase III ongoing in US (57 administered & 178 in screening, as of Nov,7 th, 2016) 1. Target disease : Painful Diabetic Peripheral Neuropathy 2. Dosing Scheme Placebo: 159, VM202: 318 Total: 477 subjects Repeated injections 16 mg (Days 0 and 14) + 16 mg (Days 90 and 104) 3. Other Phase IIIs are planned, including patients not on Lyrica and/or Neurontin #20

21 2 nd 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 #21

22 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) Principal Investigator EMERSON C. PERIN, M.D. (Stem Cell Center Texas Heart Institute) 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. (~ 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 #22

23 Dramatic Healing Effects on Ulcer Placebo (Screening) Placebo (Day 90) were observed. Group (Number of ulcers) Completely healed Improved 1) Low dose (Screening) Low dose (Day 365) Placebo (n = 9) 11% (1/9) 11% (1/9) High dose (Screening) High dose (Day 365) Low dose (n = 27) 52% (14/27) * 70% (19/27) High dose (n = 13) * 62% (8/13) * 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 were observed in the high dose group during 12-month follow-up period. #23

24 VM202-CLI Phase II Trial in China 1. Indication: Critical Limb Ischemia (Rutherford class 4 and 5) 2. Treatment arms: (Total: 200 subjects) Placebo (0.9% normal saline): Low dose of NL003 (3 mg/visit): Middle dose of NL003 (6 mg/visit): High dose of NL003 (8 mg/visit) : 72/197 (36.5%) subjects had diabetes. 3. Injection scheme: 3 injection cycles along calf line, unilateral IM injection 4. Follow-up period: 6 months 5. Primary objective: Safety of NL subjects 50 subjects 50 subjects 50 subjects 6. Secondary objectives: pain VAS, ulcer healing, ABI, TBI, TcPO2, VascuQoL, and amputation rate All clinical efficacies (VAS, ulcer healing, ABI, TBI, TcPO 2 ) have demonstrated clinical improvement. #24

25 Important Implications The US and China phase II s have produced highly similar data sets despite having distinctive trial schemes. Highlights : 1. VM202 was independently manufactured in different countries. 2. Different formulations were used in manufacturing process. 3. Participating physicians in the US and China had no chance to interact with each other. 4. Further, PI s were cardiologists and vascular surgeons. #25

26 Plan for Phase III in the US Based on phase II data, phase III was approved by US FDA for chronic non-healing ischemic foot ulcers in diabetes patients. 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 #26

27 3 rd Target Disease of VM202 Amyotrophic Lateral Sclerosis (ALS) Lou Gehrig s Disease ALS is a rare adult-onset neurodegenerative disorder characterized by the loss of upper and lower motor neurons. ALS has no cure available and the cause of the disease is still unknown. Death within 2-5 years of symptoms onset, most commonly due to respiratory failure Henry Louis Gehrig, (1903 ~ 1941) New York Yankees. Estimated 22,600 patients in the US alone [1] Prevalence: 6~8 / 100,000 persons (US) [1] Incidence: 1~2 / 100,000 persons per year (US) [1] Current Treatment Methods Only one drug approved by the US FDA: Rilutek (Sanofi) (2013 revenues = $38 million [2] ) Clinical efficacy very low with many controversies Photos from Robert Brown, MD McGuire V, et al. Neurology. 1996;47: Estimated ALS Market Size: $2~4 billion annually (Worldwide) [3] [1] ALS Association, Epidemiology of ALS and Suspected Clusters [2] GlobalData forecasts, [3] ALS Therapy Development Institute #27

28 Summary of ALS Phase I/II VM202 was well tolerated without drug-related adverse events. Reconfirmed VM202 s excellent safety profile. VM202 may stabilize disease progression of ALS patients for 2 to 3 months after initial injection. A significant fraction of subjects showed improvement in physical functions without disease progression during the first three months*: 47% in Month 1, 50% in Month 2, 24% in Month 3. Current Status * The results will be published soon A phase II IND was approved on September 30 th, 2016 VM202-ALS was designated as an orphan drug in February, US FDA granted FAST TRACK status on May 16 th, 2016 #28

29 1. Target disease : Amyotrophic Lateral Sclerosis 2. Dosing Scheme Placebo(Saline): 42, VM202: 42 Total: 84 subjects Repeated injections VM202 or Placebo 64 mg (Days 0 and 14) Group 3. Follow-up period: 9 months + 64 mg 128 mg (Days 60 and 74) (Total) 4. Efficacy endpoints: Primary: Rate changes of functional measurement (ALSFRS-R slope) at 5 Months (Day 150) 5. Safety endpoints Phase II Study Outline Day Injection site U L U L U L U L Dose (mg) ) Upper limb (U): hand and arm, 13 mg (0.25 mg of VM202 or placebo/0.5 ml/injection) 2) Lower limb (L): calf and thigh, 19 mg (0.25 mg of VM202 or placebo/0.5 ml/injection) Total DNA 128 mg #29

30 ViroMed Position: VM202 DPN Diabetic Ulcer First Mover First Mover ALS Heart Failure The only active gene therapy phase II study, if initiated. Late comer, but #30

31 5 Years Plan VM st Injection Last Injection Data Open Finish #1 (477) DPN Phase III #2 #3 BLA ` Market Entry Diabetic Ulcer Phase III #1 (300) #2 #3 BLA Market Entry ALS Phase II #31

32 Business Strategy DPN Phase III Diabetic Ulcer Phase III ALS Phase II BLA Market Entry Out-licensing before market approval (2016~2020) 1 All indications to one or more partners 2 Each indication to different partners Out-licensing after market approval (2020~2021) 3 To one or more partners depending on indications 4 Formation of SYNDICATE #32

33 Ending Remarks ViroMed aims to put at least 2 indications of VM202 on the US market by If successful, ViroMed will change the paradigm of new drug development. #33

34 ViroMed is also running other interesting programs Products in clinical development or available in market. VM206 (DNA) Therapeutic cancer vaccine Phase I: Completed in Korea. Phase II: Planned (Korea) VM501 (Recombinant protein) Chemotherapy-induced thrombocytopenia Phase I and II: Completed, Phase III: Ongoing in China. PG201 (Botanical) Osteoarthritis - PG201 approved as an ETC drug on December Licensed out to a Korean company. HX106 (Botanical) Improvement in memory and attention - Health claim approved by KFDA (Available as a nutraceutical for memory improvement) PG102 (Botanical) Allergic diseases Products in R & D stage Next generation drugs (cardiovascular and neurological diseases (aimed at market entry around 2026)) CAR-T Antibody: 1E4 Others #34

35 Major Milestones for 2016 VM202 related: ALS: US FDA granted FAST TRACK status (May 16th) DPN: Phase III initiated (US) (Jun. 28th) CAD: Phase II approved (Korea) (Aug. 1st) ALS: Phase II approved (US) (Sep. 30th) DPN: Phase III Investigator meeting (US) (Oct. 6th~7th) News to come in 2016: ALS: CLI: (China) Diabetic Food Ulcer: Ischemic Heart Disease: Releasing of phase I/II results Phase II completion & phase III IND submission Release of phase II results Phase III initiation (US) Phase II initiation (Korea) #35