Polaris Group 2016/07/05

Transcription

1 Polaris Group 2016/07/05

2 Polaris Group Main Asset (ADI PEG 20) Has Great Market Potential A novel biologic for a wide variety of cancers Late Stage Clinical Development Already in multiple global Phase II, III clinical studies Fully Integrated Pharmaceutical Company Early stage R&D, worldwide clinical trials, cgmp production

3 Arginine Metabolism A Major Metabolic Difference In Normal and Cancer Cells Arginine Metabolism in Normal Cells Arginine Metabolism in Cancer Cells Without Urea Cycle Arginine is an amino acid that the human body needs to maintain normal metabolic functions and survive In normal cells, arginine can be obtained via two different routes: 1. External nutritional intake 2. Internal synthesis via urea cycle Some cancer cells lack an urea cycle enzyme: argininosuccinate synthetase (ASS) and cannot make arginine internally These cells rely exclusively on external supplies of arginine for survival and growth It was reported in the 1990s that many hepatocellular carcinoma and melanoma cell lines are deficient in ASS More recent publications have reported many additional cancer types to also have deficiency in ASS

4 ADI PEG 20 A Novel Treatment For ASS deficient Cancer Cells Arginine deiminase (ADI) is a microbial enzyme that catalyzes arginine into citrulline ADI kills ASS deficient cancer cell effectively in vitro and in vivo Native ADI is highly antigenic and has a short half life in vivo ADI PEG 20 is ADI conjugated with polyethylene glycol of 20,000 M.W.; pegylation increases the circulating half life and decreases immunogenicity ADI PEG 20 is administered intra muscularly (IM) once a week and it can efficiently depletes external supplies of arginine from circulation within minutes ASS deficient cancer cells are fatally affected by ADI treatment because they cannot obtain arginine internally and externally Normal cells are not affected by ADI because they can produce arginine internally via the urea cycle

5 ADI PEG 20 should be effective if 1. Cancer cells do not have ASS, cannot make arginine internally 2. Extended depletion of circulating arginine can be achieved by ADI PEG 20

6 ADI PEG 20: Monotherapy

7 ADI PEG 20 As A Monotherapy in Clinical Studies Cancer Type Hepatocellular Carcinuma Clinical Study Phase Lead Institute Lead Principal Investigator Number of Countries Number of Sites Patient Number Completion Date I/II MD Anderson Cancer Center Steven Curley Mar 06 I/II Pascale National Cancer Institute, Italy Francesco Izzo Jun 03 IIB Pascale National Cancer Institute, Italy Francesco Izzo Apr 09 II National Health Research Institut, Taiwane Leo Chen Oct 08 II National Taiwan University Hospital Pei Jer Chen Jun 16 III Memorial Sloan Kettering Ghassan Abou Alfa Jul 15 I Indiana University Ted Logan Jun 04 Melanoma I/II Pascale National Cancer Institute, Italy Paolo Ascierto Jun 04 I/II Memorial Sloan Kettering Jedd Wolchok Sep 12 II University of Miami Lynn Feun Feb 13 Mesothelioma II Barts, UK Peter Szlosarek Dec 12 Small Cell Lung II Memorial Sloan Kettering Lee Krug Aug 13 Leukemia (AML) II Cheng Kung University Hospital, Taiwan T. S. Chen Jul 16 Lymphoma (NHL) II Cheng Kung University Hospital, Taiwan T. S. Chen Jul 16 Pediatric Cancers I MD Anderson Cancer Center Cynthia E. Herzog Aug 13

8 ADI PEG 20 Summary of Efficacy As Monotherapy Prolonged Overall Survival (OS), prolonged Progression free Survival (PFS), high Disease Control Rate (DCR); improved Overall Response Rate (ORR) have been observed in HCC, melanoma, mesothelioma and other solid tumors Overall survival correlates well with deficiency of Urea Cycle enzyme ASS Overall survival correlates well with the duration of arginine depletion in circulation

9 ADI PEG 20 Overall Survival Correlates with ASS Level in HCC A Phase II HCC study enrolled 71 patients with unresectable, Stage III/IV HCC at 8 cancer centers in Taiwan Retrospective analysis of ASS protein expression level was conducted on available pre treatment tumor specimens obtained from 44/71 patients by immuno histochemical (IHC) staining 33 of 44 (75%) were ASS deficient 11 of 44 (25%) were ASS positive Median OS of ASS deficient patients: 252 days Median OS of ASS positive patients: 99 days OS in ASS( ) patients is 2.5X longer than ASS(+) patients (p = 0.065)

10 ADI PEG 20 Overall Survival Correlates with ASS Level in Melanoma A Phase II study enrolled 39 patients with metastatic melanoma at the University of Miami Retrospective analysis of ASS protein expression level was conducted on available pretreatment tumor specimens obtained from 27/39 patients by immuno histochemical (IHC) staining 17 (63%) patients were ASS( ) Median OS = 13.5 months 9/17 patients had partial response (4) or stable disease (5) 8/17 patients had progressive disease (2 had mixed response) 10 (37%) patients were ASS(+) Median OS = 8.5 months 1/10 patients had stable disease 9/10 patients had progressive disease

11 ADI PEG 20 Progression Free Survival Correlates with ASS Level in Mesothelioma Prospective analysis of ASS protein expression level was performed to enrich for an ASSdeficient patient population. Only patients with > 50% ASS deficiency were study eligible Patients who received ADI PEG 20 (44/67) had prolonged PFS (3.2 months, or by 68%) compared to patients received only best supportive care (BSC, 1.9 months) Hazard ratio: % CI 0.30 to 0.86, p=0.012 Median PFS (67 events): BSC = 1.9 months BSC + ADI PEG20 = 3.2 months Patients with higher level of ASS deficiency (>75%) benefited even more than patients with lower level of ASS deficiency (50 75%)

12 ADI PEG 20 Safety Comparison with Nexavar In HCC Patients Since normal cells can synthesize arginine internally via Urea Cycle, the depletion of arginine by ADI PEG 20 should not affect the metabolism of normal cells Limited toxicity was expected, and observed, with ADI PEG 20 as a treatment for cancer patients Adverse Events (All Grades) Asia Pacific (Cheng 2009) (n=150, %) Nexavar (Sorafenib) ADI PEG 20 SHARP (Llovet 2008) (n=297, %) Hong Kong (Yau 2009) (n=51, %) Italy (Glazer 2010) (n=76, %) Taiwan (Yang 2010) (n=71, %) Hand Foot Syndrome Diarrhea Alopecia Fatigue Rash/Desquamation NA NA Rash NA NA NA 3 23 Hypertension Anorexia Hyperuricemia Injection Site Reaction Dose Reduction

13 SO. ADI PEG 20 appears to be an effective and safe treatment for a variety of cancers THEN Why did the Phase III HCC study fail? Did we learn anything from the study? Is ADI PEG 20 still a project worth pursuing? With lessons learned, do we know what to do next? Do we have a solid plan moving forward?

14 Lesson #1 Nexavar (Sorafenib) induces the expression of ASS in cancer cells This Phase III study was designed as a second line study that treats HCC patients who have failed a systemic therapy Nexavar is the only globally approved treatment for HCC 87% of the enrolled patients has failed Nexavar, 13% have failed other systemic treatment

15 Nexavar (Sorafenib) Induces ASS Expression Makes ADI PEG 20 Monotherapy Ineffective Sorafenib-treated patients Sorafenib-naïve patients Median in months (95% CI) ADI-PEG 20: 7.4 (6.4, 8.2) Placebo: 7.8 (6.5, 9.5) P=0.469 Median in months (95% CI) ADI-PEG 20: 6.5 (4.9, 9.3) Placebo: 5.7 (2.9, 6.5) P=0.106 Presented by: Ghassan K. Abou-Alfa on behalf of the ADI-PEG 20 HCC Phase III Study Investigators team

16 Lesson #2 Overall Survival (OS) correlates with the duration of arginine in the circulation

17 ADI PEG 20 OS Correlates with Duration of Arginine Depletion Global Phase III HCC study 422 patients received 18 mg/m 2 ADI PEG patients received >7 treatments 88 had complete depletion of circulating arginine at wk7; OS = 12.5 months 217 did not have complete depletion of circulating arginine at wk7; OS = 8.6 months Significant correlation (P=0.0003) observed between Overall Survival and duration of arginine depletion Treatment duration (wk) (median) Total Patient Number Median OS (month) [95% CI] P value Duration of Arginine Depletion 7 weeks [7.4, 9.7] Duration of Arginine Depletion > 7 weeks [10.0, 16.3] Total 305

18 Lesson #3 ADI PEG 20 is a very very safe treatment

19 ADI PEG 20 Safety Summary From Phase III HCC Global Study Parameter ADI PEG 20 (n=424) Placebo (n=211) Grade 5 Events 16% (68) 17% (36) Cardiac arrest 0.2% (1) 0 GI Hemorrhage 1% (4) 1% (3) Liver failure 1% (5) 1% (2) Brain infarction/bleed 0.2% (1) 0.5% (1) Respiratory failure 0.5% (2) 1% (2) Anemia 4% (19) 6% (12) Liver Function: AST 10% (42) 9% (18) Skin Pruritus and Rash: Grade 1&2 34% (142) 25% (52) Skin Pruritus and Rash: Grade 3 1% (5) 1% (2)

20 ADI PEG 20 should be effective if 1. Cancer cells have no ASS, cannot make arginine internally Lesson #1: Nexavar induces ASS expression Conduct a first line study, Nexavar will be the control arm and ADI PEG 20 treats patients who are naive to therapies 2. Extended depletion of circulating arginine can be achieved by ADI PEG 20 Lesson #2: Arginine need to be depleted for >7 weeks Use a higher dose of ADI PEG 20 Combination with other drugs

21 ADI PEG 20: Combination Therapy

22 ADI PEG 20 Combination Therapy: Rationale and Approach For patients with advanced stage of cancers, their window of opportunity to find effective treatment options narrows rapidly. It is logical and ethical to provide a combination of effective treatments as early as possible. An ideal combination should include treatments that have: Proven efficacy Significant safety to maintain patients quality of life Different/complementary mechanism of action to provide synergy ADI PEG 20 has demonstrated apparent efficacy, unprecedented safety in multiple clinical trials with a mechanism of action that can potentially be complementary to a wide variety of cancer therapies. All combinations are first tested pre clinically in cell based assays and animal models. Effective combinations are selected for further investigation in clinical studies. All combination clinical studies are to be conducted at well established clinical centers: Memorial Sloan Kettering, MD Anderson, University of California, Barts (UK) and University of Washington

23 ADI PEG 20 Combination Therapy: Selections Combinations that have advanced to clinical studies includes the following classes of chemotherapies: Platinum based compounds: Cisplatin, Oxaliplatin Anti folates: 5 Fu, Pemetrexed Nucleoside analogs: Gemcitabine, Cytarabine Taxenes: Docetaxel, nab Paclitaxel The following class of compounds have demonstrated synergy with ADI PEG 20 in animal models: BRAF inhibitors MEK1 inhibitors mtor inhibitors Many of the selected combinations combines ADI PEG 20 with the current standard first line or second line therapies for specific cancers Recent in vitro and in vivo studies have demonstrated potential synergy combining ADI PEG 20 with immunotherapy compounds. Clinical studies and potential collaborations are being considered.

24 Clinican Study Phase I/IB Combined Treatment + Docetaxel ADI PEG 20 Combination Studies Planned Cancer Type Patient Number Proatate Cancer 17 Non Small Cell Lung Cancer 21 Cutaneous Melanoma 25 Hepatocellular Carcinoma 25 Ovarian Cancer 20 Lead Institute Lead Principal Investigator Initiation Date I/IB + Cisplatin Biliary Cancer 14 MD Anderson Siquing Fu November 2012 Uveal Malanoma 14 Sarcoma 14 I/IB + Doxorubicin Breast Cancer 9 MD Anderson Siquing Fu April 2014 I/IB + Sorafenib Hepatocellular Carcinoma 8 Univ. of Washington William Haris December 2014 Hepatocellular Carcinoma 40 I/IB + FOLFOX Gastric Cancer 15 MSKCC Ghassan Abou Alfa January 2015 Colorectal Cancer 15 I/IB + Gemcitabine + nab Paclitaxel Pancreatic Cancer 18 MSKCC Eileen O'Reilly January 2015 I/IB II/III + Cisplatin + Pemetrexed + Cisplatin + Pemetrexed Mesothelioma 30 Nonsmall Cell Lung Cancer 30 Uveal Melanoma 10 Glioblastoma 10 University of California, Davis Mesothelioma 140/372 Barts Lucky Lara August 2011 Barts Peter Szlosarek July 2014 Peter Szlosarek March 2016 A Phase I/IB study combining ADI PEG 20 with Cytarabine for AML is to be initiated in Q A Phase I/IB study combining ADI PEG 20 with immunotherapy is being designed for Q1/2017

25 ADI PEG 20 Median Duration of Arginine Depletion Monotherapy vs. Combination Therapies Extended duration of arginine depletion leads to prolonged Overall Survival Comparing with monotherapy, all combinations can significantly extend the duration of circulating arginine depletion (from 8 wks to >16wks). ADI PEG 20 monotherapy consists of two doses: 18 mg/m 2 and 36 mg/m 2 ; the lower dose was used in the global Phase III study and the concentration of circulating arginine was significantly elevated in ~80% of the patients.

26 ADI PEG 20 + Pemetrexed + Cisplatin Efficacy in Non Epithelioid Mesothelioma In the ongoing TRAP study, 20 of the 31 enrolled mesothelioma patients had sarcomatoid or biphasic subtypes; which are significantly more aggressive than the most common epithelioid subtype. Disease control rate in these non epithelioid patients is a perfect 100% (20/20), and the response rate is 35% (7/20).

27 ADI PEG 20 + FOLFOX Efficacy in HCC In an ongoing HCC study at Memorial Sloan kettering Cancer Center, ADI PEG 20 is used in combination with 5 Fu and Oxaliplatin (FOLFOX), the preliminary results are encouraging. 8 of 10 patients are HCC patients who have already failed Nexavar as the first line treatment. The disease control rate is 75% (6/8), and the response rate is 25% (2/8). This compares favorably with Nexavar s response rate of 3 4%.

28 ADI PEG 20 + Gemcitabine + nab Paclitaxel Efficacy in Pancreatic Cancer In a Phase I/IB pancreatic study at Memorial Sloan kettering Cancer Center, ADI PEG 20 is used in combination with Gemcitabine and nabpaclitexal, the first line treatment for pancreatic cancer. The study has completed patient enrollment. A total of 18 patients were enrolled, 17 of them are evaluable for response rate. The disease control rate is 100% (17/17), and 41% (7/17) had confirmed Partial Response (PR). This compares favorably with the historical data rate of 23% ORR with Gemcitabine and nab paclitexal alone.

29 ADI PEG 20 + Pemetrexed + Cisplatin Efficacy in Non Small Cell Lung Cancer In the ongoing TRAP study, ADI PEG 20 in combination with Pemetrexed and Cisplatin was also used to treat non small cell lung cancer (NSCLC). Pemetrexed + Cisplatin is the first line therapy for non squamous NSCLC. Disease control rate is a perfect 100% (13/13), and the response rate is 54% (7/13). This ORR is comparable with the impressive efficacy numbers generated by the new immunotherapy drugs. TRAP study will enroll up to 30 non squamous NSCLC patients

30 ADI PEG 20 Overall Observations From All Clinical Studies ADI PEG 20 has been clinically tested in 22 clinical studies globally in patients with a variety of end stage cancer types. Over 1,200 patients have received ADI PEG 20 as monotherapy or in combination with other treatment. ADI PEG 20 has demonstrated apparent anti tumor activity and excellent safety All of the clinical studies have been conducted under three US FDA INDs. Half of the studies were led by either Memorial Sloan kettering Cancer Center or MD Anderson Cancer Center, two of the most prestigious cancer centers in the world. Most patients taking ADI PEG 20 have been able to continue treatment without sacrificing quality of life. The duration of treatment is up 4 years. ADI PEG 20 is administered intra muscularly. Patients typically receive treatment once a week as out patients, and released after 1 hour of observation. No extensive hospital stays is required.

31 ADI PEG 20 Clinical Development Strategy 1. Obtain market approval via Biologics License Application (BLA) The most significant and immediate value generator in the pharmaceutical industry is to get a drug approved, for any indication 2. Expand market by testing more ASS deficient tumors in trials The value of a drug can be further increased with expanded market 3. Enhance efficacy by combination therapies Demonstrate superior efficacy and safety to the current treatment can significantly increase the market penetration within each cancer market

32 Clinical Development Plan Cancer types that have the shortest path to approval: Non Epithelioid Mesothelioma 1 Phase II (mono) completed, 1 Phase I/IB (combo) ongoing (35% PR, 100% DCR) New global pivotal Phase II/III study initiated in March 2016 Pancreatic Cancer 1 Phase I/IB (combo) ongoing At Sloan Kettering Cancer Center (41% PR, 100% DCR) New global pivotal Phase II/III is being planned for initiation in 2017 Liver Cancer (hepatocellular carcinoma, HCC) For monotherapy, 4 Phase I/II, 1 global Phase III completed For combination therapy, 3 Phase I/IB ongoing In an onging Phase I/IB FOLFOX study, PR = 25%, DCR=75% New pivotal multinational Phase II/III study will be designed for initiation in 2017

33 ADI PEG 20 Competitive Edge Late stage project with multiple ongoing clinical trials Significant de risking has already occurred as project already in Phase II, III studies ASS deficiency common across multiple cancer types An expanded market scope with multiple potential indications Unique mechanism of action perfect for combination therapy Complementary with other anti cancer treatments Well tolerated by patients as normal cells can make arginine ASS companion diagnostic personalized medicine Identify patients most likely to benefit from ADI PEG 20 In house cgmp production ensures supply and quality of drug Strong collaborations with world class cancer centers

34 SO. ADI PEG 20 IS an effective and safe treatment for a variety of cancers Especially in combination with selected drugs THEN Why did the Phase III HCC study fail? Did we learn anything from the study? YES Is ADI PEG 20 still a project worth pursuing? YES Do we know what to do next? YES Do we have a solid plan moving forward? YES

35 THANK YOU