Slide 1: EMA Hutruo Findings
EMA April 20 2017 Hutruo Findings Dr. A. Hendifar MD, MPH Cedar Sinai Medical Center UCLA Medical Center Co-Director Pancreas Cancer & Medical Oncology Lead Gastrointestinal Diseases
Slide 2: Hutruo Targets Tumour-Related Inflammatory Pathways
HUTRUO Targets Tumour-Related Inflammatory Pathways which Promote Disease Progression and Debilitating Symptoms IL-1 Supports Disease Progression and Symptoms "4 ‘ ANGIOGENESIS, REMODELING Syinbioms HYPOTHALAMUS PITUITARY GROWTH, INVASION a byporHalaM Tumour Effects THROMBOEMBOLISM ANOREXIA, WASTING
Slide 3: New Treatment Approaches Are Needed for Advanced Metastatic Colorectal Cancer
New Treatment Approaches Are Needed for Advanced Metastatic Colorectal Cancer Cancer (mCRC) * Europe Has the Highest Incidence of Refractory mCRC. * Toxicities of Cytotoxic Drugs Outweigh Benefit in Refractory mCRC. * Tumour Eradication in mCRC is an Unrealistic Goal. Anti-Cancer Therapies without T
Slide 4: EMA Guidance Proposes Evaluation of Anti-Cancer Agents based on Symptom Control
Far-sighted EMA Guidance Proposes Evaluation of Anti-Cancer Agents based on Symptom Control “Symptom Control, if related to Anti-Tumour Effects, is a Valid Measure of Therapeutic Activity and may serve as a Primary Endpoint in Late Line Therapy Studies?.” 113 December 2012,EMA/CHMP/205/95/Rev.4 Onco
Slide 5: Pain, Fatigue, Appetite, and Muscle Mass Measure Symptom Control
Pain, Fatigue, Appetite, and Muscle Mass were used as Measure of “Symptom Control” in Refractory mCRC ¢ Hutruo Previously Reported to Provide “Disease Control” in Advanced Cancer Patients—including Relief from Pain, Fatigue, Anorexia; Muscle Mass Recovery; and Anti-Tumour Effects! * Symptoms COMBINE
Slide 6: Symptom Control Used to Measure Treatment Response
In Pivotal Phase III Study, “Symptom Control” was used to Measure Treatment Response to Hutruo Patient Self-Reported X-Ray Imaging (DEXA). No Worsening or Improvement + Muscle No Decrease or (at Least 2 Integrity Improvement Categories) Fatigue i ‘Symptom Control = Primary Endpoint
Slide 7: Pivotal Phase III Study
Pivotal Phase III Study Double-Blinded, Placebo Controlled Advanced, Metastatic, Inoperable, Refractory, ECOG 1,2 2:1 Hutruo + asc Placebo +ssc aa J N=102 in 8 Weeks L CT/DEXA/EORTC Primary Endpoint CT/DEXA/EORTC (4 Cycles) L Open Label Extension (For duration of benefit)
Slide 8: Phase III Study Results
Phase III Study Results Lancet Oncology: “A New Standard in the Management of Advanced Colorectal Cancer?” Intent to Treat (mITT) n=309 33% of Patients Receiving Hutruo met Primary Endpoint vs 19% treated with Placebo (p=0.0045) (relative risk 1.76, 95% Cl 1.12-2.76, one-tailed p=0.0045) Per Protoco
Slide 9: Safety
Safety Adverse Events in Hutruo arm are Consistent with Background for the Advanced mCRC Population “Blinded” Physicians Reported that 9.6% of Adverse Events in Placebo Arm were “possibly, probably or definitely” drug-related. Only 8.6% of Adverse Events in Hutruo arm were deemed Possibly Drug-Relat
Slide 10: Safety
Safety Overall Assessment by Type & Grade * No Clinically or Statistically Significant Differences in the Incidence of ANY Adverse Event, by Preferred Term or Grade, between Hutruo and Placebo. * No Deaths were Related to Hutruo. 17 (8%) Patients Died in Hutruo Arm versus 11 (11%) Patients in Placeb
Slide 11: Addressing Major Objections Relating to Clinical Efficacy & Quality
Addressing Major Objections Relating to Clinical Efficacy & Quality Reviewer Statements Related to Clinical Efficacy “The clinical relevance of this rather small difference in favour of treatment with MABp1 is questioned and not considered compelling.” “Neither the sensitivity analyses of the indivi
Slide 12: Major Clinical Objections: Clinical Relevance
Major Clinical Objections Clinical Relevance Statement 1: “The clinical relevance of this rather small difference in favour of treatment with MABp1 is questioned and not considered compelling.” Response: The Primary Endpoint is a Robust and Clinically Relevant Measure of Outcome in mCRC. For the 82%
Slide 13: Major Clinical Objections: Sensitivity Analysis
Major Clinical Objections Sensitivity Analysis Statement 2: “Sensitivity analyses of the individual co-primary endpoints and disease-related QoL symptoms) did not indicate any statistically significant or clinically relevant differences between the study arms.” Response: LBM (Lean Body Mass) Sensiti
Slide 14: EMA Requested Sensitivity Analysis: At Least 1kg LBM Increase
EMA Requested Sensitivity Analysis: At Least 1kg LBM Increase Patient Self-Reported X-Ray Imaging Primary Endpoint No Change or Improvement in at Least 2 Categories Minimum Increase + Muscle 1.0 kg ft Symptom Control i) Physical Recovery Integrity
Slide 15: At Least 1kg LBM Increase: Significant Outcome
At Least 1kg LBM Increase: Significant Outcome for Intent to Treat and Per Protocol Populations *p=0.0061 BM Hutruo MPlacebo Achieve Primary Endpoint Pearson Chi-Square test (one-tailed) 21kgCutOffintentto Treat Population _>1kg Cut Off Per Protocol Population
Slide 16: Sensitivity Analysis: LBM
Sensitivity Analysis LBM (Lean Body Mass) Signficantly More Patients on Hutruo Gained at Least 1 kg LBM Patient Self-Reported X-Ray Imaging No Change or Improvement + 21kg in Appetite & Improvement Fatigue Endpoint Hutruo 31% (64) vs Placebo 20% (20), (p=0.018)
Slide 17: Sensitivity Analysis: Self-Reported Outcomes
Sensitivity Analysis Self-Reported Outcomes Statement: “Sensitivity analyses of the individual co-primary endpoints (LBM and disease- related @et) symptoms) did not indicate any statistically significant or clinically relevant differences between the study arms.” QoL [Patient Self-Reported Outcomes
Slide 18: Sensitivity Analysis: Individual Measure of Self-Reported Outcomes
Sensitivity Analysis Individual Measure of SelfReported Outcomes Patient Self-Reported X-Ray Imaging No Change or Improvement in at Least 2 Categories rl Fatigue Endpoint [Hutruo 51% (106) vs Placebo 30% (40), (p=0.024)|
Slide 19: Sensitivity Analysis: Excluding Pain
Statement: Response: Outcomes: Sensitivity Analysis—Excluding Pain “Sensitivity analyses of the individual co-primary endpoints (LBM and disease- related @ot) symptoms) did not indicate any statistically significant or clinically relevant differences between the study arms.” QoL Symptoms: Excluding
Slide 20: Sensitivity Analysis: Excluding Pain from Self-Reported Outcomes
Sensitivity Analysis Excluding Pain from Self-Reported Outcomes Patient Self-Reported X-Ray Imaging No Change or . Improvement ai Muscle in Appetite & Integrity Fatigue No Change or Improvement Primary Endpoint
Slide 21: Primary Endpoint Excluding Pain is Significant
Achieve Endpoint Primary Endpoint Excluding Pain is Significant 35% *p=0.013 aid *p=0.015 Hutruo 25% La MiPlacebo 20% 16% 31% ms 18% o*% *Pearson Chi-Square test (one-tailed) o% Intentto Treat Population Per Protocol Population
Slide 22: Secondary & Exploratory Endpoints
Secondary & Exploratory Endpoints a Response: Outcomes: yor I y Endpoints do not Provide Any Supportive Evidence for Efficacy in Favour of MABp1.” Secondary and Exploratory Endpoints were as Follows: Secondary: Hutruo-Related Reduction in Serum IL-6; Control of Paraneoplastic platelet Expansion; and
Slide 23: Secondary Endpoint: Interleukin-6 (IL-6)
Secondary Endpoint Interleukin-6 (IL-6) Statement: “Secondary endpoints do not provide any supportive evidence for efficacy.” Background: Hutruo neutralizes interleukin-1a (IL-1), which is a potent inducer of IL-6 expression. Specific Activity of Hutruo Reduces Serum IL-6 levels. Reduction in Serum
Slide 24: Hutruo Significantly Reduces Serum IL-6 Levels
Secondary Endpoint Hutruo Significantly Reduces Serum IL-6 Levels for Intent to Treat and Per Protocol Populations pale =0.012 *p=0.026 i Hutruo MPlacebo Intent to Treat Population Per Protocol Population Wé.change,pe/mt
Slide 25: Decreasing Serum IL-6 Levels Associated with Survival
Decreasing Serum IL-6 Levels Associated with Survival Change in IL-6 Log- Serum Levels N Death % i months rank p (pg/ml) 6 ables toRnAl 1.65 fash 0.013 Median Survival (95% Cl), HR (95% Cl) R (95%
Slide 26: Secondary Endpoint: Paraneoplastic Platelet Expansion
Secondary Endpoint Paraneoplastic Platelet Expansion Statement: “Secondary endpoints do not provide any supportive evidence for efficacy.” Background: 1. Platelet Production from Megakaryocyte is regulated by interleukin-1a. 2. Specific Activity of Hutruo Reduces Paraneoplastic Expansion of Platelet
Slide 27: Secondary Endpoint—Platelets
Secondary Endpoint—Platelets Hutruo Significantly Reduces Neoplastic Expansion of Platelet Counts % ee *p=0.0041 *p=0.( - 4 ‘0 f U Eos & 8 2 Hut 2 [ Hutruo & 3 Placebo gz» £ é Intent to Treat Population Per Protocol Population
Slide 28: Secondary Endpoints—QoL
Secondary Endpoints—QoL Statement: “There is no correlation to any meaningful changes for the Qol for the subjects in the pivotal study.” Response: * The Combined Patient Self-Reported Quality of Life Outcomes used in the Primary Endpoint Did in Fact Improve in the Hutruo Compared to Placebo arms. [
Slide 29: Exploratory Endpoints: Tumour Response
Exploratory Endpoints Tumour Response Statement: “There is no evidence in support of clinically relevant efficacy from Exploratory Endpoints.” Objective Tumour Response Background: Hutruo Blocks Inflammatory Pathways Support Tumour Growth and Metastasis (Neoangiogenesis, Tissue Matrix (stromal), Par
Slide 30: Trend Toward Reduced Tumour Growth in Hutruo Treated Patients
Trend Toward Reduced Tumour Growth in Hutruo Treated Patients & Significant Reduction in Patients Meeting Primary Endpoint *p20.006 Stable Disease Hutruo vs Placebo Primary Endpoint vs Failure
Slide 31: Exploratory Endpoints
Exploratory Endpoints Clinical and Biological Outcomes Support Clinical Relevance of Primary Endpoint Improvements Observed Global QoL p<0.0001 Physical Function p<0.0001 Role Function p<0.0001 Emotional Function p<0.0001 Social Function p<0.0001 Fatigue p<0.0001 Pain p<0.0001 Paraneoplastic Platele
Slide 32: Major Clinical Objections: Safety
Major Clinical Objections Safety Statement: “Safety Database is Currently Limited, both Regarding Total Number of Patient Population and Duration of Treatment.” Response: * Hutruo Demonstrated First-in-Class Safety in 700 Patients (and Several Thousand Doses of Hutruo). * 3 Months Median Duration of
Slide 33: SAE Incidence (%)
SAE Incidence (%) Safety Reduction in SAEs—Trend in Hutruo Arm Placebo Progressed Hutruo 32% 29.3% 23% Primary End| For the 19 Most Recently Approved Anti-Cancer Agents, Overall a 77% Increase in AEs Over Comparators was Reporte Primary Hutrio vs Nal ea en, Oncology 2014 Vol 32.22 Endpoint vs Progre
Slide 34: Safety: Infections
Safety Statement: “An increased number of infections (including serious infections) was observed in MABp1-treated patients compared to placebo.” Response: Not a Single Infection or Serious Infection was Reported by Investigators to be Related to Hutruo Therapy. No Significant Difference in Number of
Slide 35: Case Report Summaries for Serious Infections
Case Report Summaries for Serious Infections CS TTA Upper respiratory Cough and subjective fever in a patient with bilateral pulmonary metastatic tract infection 2. Meus and Peritonitis 3. “Pneumonia” 4, Urosepsis 5, Pyonephrosis 6. “Pneumonitis” lesions, left upper lobe lobectomy and a history of m
Slide 36: Safety Data with Other Agents to Treat mCRC
Safety Data with Other Agents to Treat mCRC In a Phase III Study in 760 patients, Regorafenib had a 1% objective Response Rate while 93% of patients had Drug-Related Toxicities?. + A Pivotal Study for TAS-102 in mCRC showed a Tumour Response Rate of 1.6%— with 69% of Patients Experiencing Grade 3 or
Slide 37: Hutruo Fills an Unmet Need in Refractory mCRC
Hutruo Fills an Unmet Need in Refractory mCRC * Hutruo Targets Tumour Inflammatory Pathways Involved in Disease Progression and Debilitating Symptoms. * Hutruo Inhibits Tumour without Collateral Toxicity on Healthy Tissue. * Combined Endpoint—Pain, Fatigue, Appetite, and Lean Mass—is an Important an