Jun 3, 2014 - Predictive models enable more precise targeting and the ... 2000 mg/m2 IV over 24 hours/200 mg/m2 l+d race
A Fully Integrated Cancer Company. Jefferies Global Healthcare Conference June 3, 2014 Robert Mulroy, President and CEO
Forward Looking Statements To the extent that statements contained in this presentation are not descriptions of historical facts, they are forwardlooking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements include any statements about Merrimack’s strategy, future operations, future financial position and future expectations and plans and prospects for Merrimack, and any other statements containing the words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” “hope” and similar expressions. In this presentation, Merrimack’s forward-looking statements include statements about the potential effectiveness and safety profile of Merrimack’s product candidates, including MM-398 either alone or in combination, the expected timeline for seeking regulatory approval for the MM-398 combination regimen, Merrimack’s ability to translate clinical data into future clinical success, anticipated milestones, including the initiation of new trials, the timing of availability of clinical trial data, the status of and enrollment in clinical trials, the timing of availability of clinical trial data, Merrimack’s commercialization plans and strategies and the ability to enter into business development transactions. Such forward-looking statements involve substantial risks and uncertainties that could cause Merrimack's clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the initiation of future clinical trials, availability of data from ongoing clinical trials, expectations for regulatory approvals, development progress of Merrimack's companion diagnostics, availability of funding sufficient for Merrimack’s foreseeable and unforeseeable operating expenses and capital expenditure requirements, and other matters that could affect the availability or commercial potential of Merrimack's drug candidates or companion diagnostics. Merrimack undertakes no obligation to update or revise any forward-looking statements. Forward-looking statements should not be relied upon as representing Merrimack's views as of any date subsequent to the date hereof. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to Merrimack's business in general, see the “Risk Factors” section of Merrimack's Annual Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 6, 2014 and other reports Merrimack files with the SEC.
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Investment Highlights MM-398 Achieves Ph3 Endpoint in Pancreatic Cancer • Combo arm achieved mOS of 6.1 months, HR=0.67, p-value=0.012 • Preparing to file NDA • Core commercial team preparing for launch
MM-121 BM+ data in Ovarian, Breast & NSCLC • Pre-specified biomarkers identified 30-50% of patients most at risk of progression • BM+ patients showed statistically significant improvement in PFS
Technology Leadership • • • •
Systems biology R&D engine driving new insights into cancer Six novel therapeutics in clinical development with companion Dx Nanoliposomes improve drug deposition and exposure Multispecific antibody capabilities engineering novel agents 3
A Superior Approach to Drug Discovery Gene
Protein
Network
Network dynamics govern cell decisions
• Systems dynamics is a way to evolve our understanding of cancer and our ability to develop targeted therapies • Predictive models enable more precise targeting and the development of diagnostics • Simulations inform the engineering of drugs and the understanding of their pharmacodynamics • Paired with deep technological expertise, this approach enables rapid development of new therapies with a strong clinical rationale 4
Drugs Engineered to Specific Cancer Biology
PC
Phase 1
Phase 2
MM-310 undisclosed
MM-302 nano-doxorubicin
MM-121
MM-131 undisclosed
MM-151
DX-929 Nano-imaging agent
EGFR MM-141 IGF1R-ErbB3
ErbB3
Phase 3 MM-398 nanoirinotecan
MM-111 ErbB2-ErbB3
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Merrimack’s Antibody-targeted Nanoliposomal Drug Platform vs. ADCs
• 30,000+ drug molecules per nanoliposome • Many types of drugs • Many options for targeting antigens
• 2-4 drug molecules per antibody • Few drugs possible • Very few antigens have proven possible 6
Nanotherapeutics Designed for Protected Delivery and Prolonged Exposure Preclinical Data MM-398: Sustained intra-tumor levels
t1/2 (h)
AUC∞(µg*h/ml)
CPT-11
.27
6
MM-398
10.7
2134
Clinical Data
•
PK analysis of patients show extended circulation –
•
70-fold higher AUC in the blood vs. irinotecan
Local activation of MM-398 in tumor (AACR 2014) – 5-fold higher levels of SN-38 in the tumor compared to blood 7
MM-398 • Nanoliposomal encapsulation of irinotecan • Engineered for increased drug deposition, local activation of SN38 and prolonged cytotoxic effects • Recently achieved positive phase 3 results in combination arm in pancreatic cancer • Next step is to file NDA in 2014 • Has orphan drug designation • Additional studies ongoing in CRC, Ewing’s sarcoma and glioma • Imaging diagnostic also in development 8
Pancreatic cancer is difficult to treat Tumor Associated Macrophages (TAMs) • Associated with poor prognosis
Dense stroma • Drug penetration barrier • Extracellular matrix proteins
Complex intracellular signaling pathways Hypoxic micro-environment (Wilson & Hay, 2011)
• Suppresses cytotoxic drug activity gemcitabine
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MM-398 Ph3 Study Design Primary Endpoint: Overall Survival Secondary Endpoints: Progression Free Survival Safety and Adverse Event Profile
Global Principal Investigator: Daniel D. Von Hoff, M.D., F.A.C.P.
Metastatic Pancreatic Cancer Received prior gemcitabine-based therapy N = 405 (planned): 417 (actual)
RANDOMIZATION
Arm A: MM-398 120mg/m2 IV q 3 weeks
Arm B (control): 5-FU/LV 2000 mg/m2 IV over 24 hours/200 mg/m2 l+d racemic form, q weekly X 4
Arm C: MM-398 + 5-FU/LV MM-398 80 mg/m2 IV , q 2 weeks 5-FU/LV 2400 mg/m2 IV over 46 hours/400 mg/m2 l+d racemic form
1:1:1 randomization for paired-wise comparison against 5-FU/LV control arm 10
MM-398 Ph3 Top line Results MM-398 in combination with 5-FU/LV
Control arm 5-FU/LV
MM-398 monotherapy
• • • •
Median OS 6.1 months HR=0.67; p-value=0.012 1.9 month improvement over control arm Statistically significant improvement in PFS also observed
• Median OS 4.2 months
• Median OS 4.9 months • HR=0.99, p-value=0.942
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MM-398 Ph3 Top line Safety • Most common Grade 3 or higher adverse events in the combination arm – Neutropenia (14.5%) – Fatigue (13.7%) – Diarrhea (12.8%) – Vomiting (11.1%) – Sepsis (3.4%) was the only serious life threatening event that occurred with a more than 2% difference between the combination arm and the control arm • In general, patients on the monotherapy arm experienced a higher level of adverse events at this dose and treatment schedule compared to patients who received the combination of MM-398 with 5-FU and leucovorin
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Pancreatic Cancer Landscape Extremely high unmet medical need with few clinical options • 73% mortality within one year • 6% 5-year survival • Unacceptably high recurrence rates post adjuvant treatment (ACS Cancer Facts and Figures 2014)
Front line treatment in Pancreatic Cancer • FOLFIRINOX: 11.1 mo. vs. GEM - 6.8 mo. (Conroy, NEJM) • Abraxane-GEM: 8.5 mo. vs. GEM - 6.7 mo. (Impact, 2013) • GEM monotherapy: 5-6 mo. (various)
Gemcitabine is the mainstay first line treatment and a significant proportion of patients treated with gemcitabine will be eligible for further treatment.
Second line treatment (post-GEM) No approved regimens other than 5-FU & leucovorin 13
MM-398 Path Forward & Next Steps Regulatory Path: • •
Hold Pre-NDA meeting with FDA Plan to submit NDA in 2014
Commercial Next Steps: • •
Core commercial team preparing for potential launch Activities initially focused on US – Geographic clustering allows pancreatic cancer physicians to be effectively targeted by a small, focused field force
Pancreatic Cancer Geographic Location
Patients Diagnosed Annually*
US
~45,000
EU
~60,000
Japan
~30,000
China
~100,000
Expansion/Development: • Diagnostic-led expansion into other indications *Decision Resources 2013. Report on Pancreatic Cancer. Ma et al. [Trend and prediction on the incidence of pancreatic cancer in China]. 2013 Feb;34(2):160-3. Chinese.
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MM-398 Diagnostic Approach with Ferumoxytol* Pre FMX MRI
24 hours post FMX MRI
grow
• 6 patients • 23 lesions • 5 different tumor types
Best Change in Tumor Lesion Size
Presented at AACR 2014
*The use of Ferumoxytol (Feraheme®, AMAG Pharmaceuticals) in the pilot study mentioned above is for clinical investigational studies only and has not been approved by the FDA.
stable
shrink More FMX uptake
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MM-121: Addressing ErbB3-Driven Cancers
Unmet need
# patients
• MM-121 is a monoclonal antibody targeting ErbB3 About ErbB3-Driven Cancer • Promotes resistance to therapies and worsens patient outcomes • Spans many solid tumors • Works in conjunction with other pathways • Not a traditional oncogenic pathway where it is primary driver of the cancer
MM-121 Designed to Target Biomarker Positive (BM+) patients
BM+
BM-
Response •
•
Biomarker positive patients appear to respond worse to standard-of-care (SOC) than biomarker negative patients Biomarker positive patients on MM-121 may respond better than biomarker positive patients on SOC alone 16
MM-121 Ph2 Studies: HRG is the Key Biomarker • Patients with HRG respond poorly to standard-of-care • MM-121 appears to restore sensitivity in HRG positive patients Optimal benefit is observed in HER2 low patients (0+ and 1+) MM-121
• This is important to measure in ovarian cancer (~50% of HRG positive patients are HER2 2+) • This is NOT important to measure in HER2 negative breast cancer and NSCLC (very few patients are HER2 2+)
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Clinical Testing of Diagnostic Hypothesis Archived
Biopsy 140
Platinum-resistant Ovarian Cancer (N=220)
Paclitaxel + MM-121
Ovarian cancer
Paclitaxel 80 Archived 59
ER/PR+ Metastatic Breast Cancer (N=115)
Exemestane + MM-121
ER/PR+ mBC
Exemestane 56 Archived
Biopsy 85
EGFR wt NSCLC (N=129)
EGFR wt NSCLC
Erlotinib + MM-121 Erlotinib 44 18
0.2
BM-
BM+ BM-
0
10
20
30
1.0 0.8 0.6
Breast BM+
0.4
0.4
BM+
Exemestane + MM-121
0.2
0.6
Ovarian
Exemestane
BM-
40
0
10
20
1.0
Time (weeks)
30
40
50
60
Time (weeks)
Erlotinib
Study
0.8
Erlotinib + MM-121
0.6
Lung
0.2
0.4
BM+
BM-
BM+
BM-
N
HR
Prev.
N
HR
Ovarian
57
0.37
38%
93
1.81
Breast
21
0.35
37%
36
0.99
Lung
36
0.39
54%
31
2.64
BM+ 0.0
Progression-free survival
BM-
BM+
0.0
0.8
Paclitaxel + MM-121
Progression-free survival
1.0
Paclitaxel
0.0
Progression-free survival
MM-121 PFS Data in Biomarker (BM) Defined Population
BM0
10
20
30
40
Time (weeks) 19
Ovarian cancer
41% Colorectal cancer
36% Pancreatic cancer
57%
Breast cancer
Bladder cancer
Cervical cancer
56%
46%
71%
Head and Neck cancer
Liver cancer
Prostate cancer
99%
55%
48%
Melanoma
Uterine cancer
40%
SOC Combos
HRG is pervasive & Orthogonal to Other Mechanisms of Disease
Indications
28%
• HRG expression data from The Cancer Genome Atlas • Percentages based on observed threshold for MM-121 benefit in ovarian cancer
MM-111 • HER2-3 bispecific Ab • Engineered against hyperactive HER2/HER3/HRG trimer • Demonstrated superior signaling inhibition to current agents in preclinical studies • Global Ph2 trial in gastric cancer underway • Diagnostic approach: Stratifying based on HER2 and other biomarkers • Wholly owned
MM-111 + Multiple Combinations Phase 1 HER2+ Patients in Multiple Solid Tumors
42% ORR 52% CBR
* Indicates patient ongoing at time of presentation
Presented at ESMO 2012
The toxicity profile of the MM-111 combinations was consistent with that generally observed in patients receiving the underlying HER2 therapy.
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MM-111 Ph2 Second Line Gastric Study • Applied learning from MM-121 Ph2 program – Increased confidence in ErbB3 as a target and in its role across solid tumors – Added a second independent primary objective for biomarker positive population
• Updated Study Design – Enroll 120 HER2+ FISH+ Patients – Focuses resources on biomarker-driven data, increases number of patients studied in this population and is a faster path to proof of concept for MM-111
Documentation of HER2 Expression
HER2 3+ OR HER2 2+ AND FISH+
1:1 RANDOMIZATION
• Data anticipated in 2015 Experimental (60 patients) Paclitaxel + Trastuzumab + MM-111
Comparator (60 patients) Paclitaxel + Trastuzumab 22
N Complete Response (CR) Partial Response (PR) Stable Disease (SD) ORR (CR + PR) CBR (CR + PR + SD)
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PFS: 5.6 months (95% CI: 2.8, 10.9)
6
best change in tumor burden (% change)
27 1 3 6 15% 37%
progression free survival (PFS) (months)
50 01 20 01 0- 1 1 20 03 0- 3 10 30 2 0- 6 1 10 03 0- 2 1 50 02 0- 1 1 30 01 0- 8 10 10 3 0- 0 1 20 02 0- 8 10 10 2 0- 3 1 10 01 0- 0 1 10 01 0- 7 1 50 02 0- 7 1 30 03 0- 1 1 10 03 0- 4 1 50 02 0- 4 1 30 01 0- 6 1 30 02 0- 9 1 10 01 0- 2 10 50 2 0- 5 1 50 02 0- 0 1 30 01 0- 9 1 20 01 0- 3 1 50 02 0- 2 10 09
• ErbB2 Ab targeted nanotherapeutic encapsulation of doxorubicin • Engineered for local accumulation & retention (10x) and maximal potency/cell uptake • Designed to address cardiotox issues of combinations • Diagnostic approach: PET/MRI imaging with copper labeled molecule • Wholly owned 50 01 20 01 0- 1 1 20 03 0- 3 1 30 02 0- 6 10 10 3 0- 2 1 50 02 0- 1 10 30 1 0- 8 1 10 03 0- 0 1 20 02 0- 8 1 10 02 0- 3 10 10 1 0- 0 1 10 01 0- 7 10 50 2 0- 7 1 30 03 0- 1 1 10 03 0- 4 1 50 02 0- 4 1 30 01 0- 6 1 30 02 0- 9 1 10 01 0- 2 10 50 2 0- 5 1 50 02 0- 0 10 30 1 0- 9 1 20 01 0- 3 10 50 2 0- 2 10 09
MM-302 Phase 1 Monotherapy Presented at SABCS December 2013
0
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MM-302 SABCS 2013 Phase 1 Data
ROI
ROI
ROI
ROI = Region of Interest Positron emission tomography/computed tomography (PET/CT) of patients treated with MM-302 and 64Cu-labeled MM-302 indicates liposomal accumulation in difficult to treat metastatic lesions. Patients were imaged within the first hour and approximately 20 to 48 hours later. A region of interest (ROI) encompassing the site of a brain metastasis for patient 300-1049, as determined by MRI (not shown), is shown. PET signal enhancement at 44 hours indicates 64Cu-MM-302 deposition.
N CR PR SD ORR CBR
9 1 3 1 44% 56%
PFS: 10.9 months (95% CI: 1.6, NR) 12
6
0 20 01 50 03 0- 3 1 10 01 0- 8 1 10 01 0- 0 1 10 02 0- 7 1 50 02 0- 4 1 30 01 0- 9 1 20 01 0- 3 1 50 02 0- 2 10 09
ROI
best change in tumor burden (% change)
ROI
Anthracycline Naïve Response Data
merge
progression free survival (PFS) (months)
ROI
PET
44 hr
53 min
CT
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Other Merrimack ASCO Data ErbB3
MM-141
IGFR
EGFR
MM-151
• Oligoclonal anti-EGFR antibody combination
• Bispecific antibody designed to target IGF-1R and ErbB3
• Presented Phase 1 study results
• Presented Phase 1 study results
• Next step: initiation of Ph2 study in colorectal cancer in 2014
• Next step: initiation of Ph2 study in front line pancreatic cancer
• Also presented: – MM-111 Ph1 multi-arm study in combination with standard of care therapies in multiple tumor types – MM-121 Ph1 study testing safety and pharmacokinetics in patients with advanced solid cancers 25
Anticipated Milestones • Presentation of full data for MM-398 Ph3 study in pancreatic cancer at ESMO GI in June • Top line data for MM-121 Ph2 study in neoadjuvant TNBC in Q2’14 • Initiation of Ph2 studies for MM-302, MM-151 and MM-141 in 2014 • Business development transactions across pipeline in 2014
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Investment Highlights MM-398 Achieves Ph3 Endpoint in Pancreatic Cancer • Combo arm achieved mOS of 6.1 months, HR=0.67, p-value=0.012 • Preparing to file NDA • Core commercial team preparing for launch
MM-121 BM+ data in Ovarian, Breast & NSCLC • Pre-specified biomarkers identified 30-50% of patients most at risk of progression • BM+ patients showed statistically significant improvement in PFS
Technology Leadership • • • •
Systems biology R&D engine driving new insights into cancer Six novel therapeutics in clinical development with companion Dx Nanoliposomes improve drug deposition and exposure Multispecific antibody capabilities engineering novel agents 27
Nanoliposomes
Oncology Pipeline Candidate
Design
Target
Trial(1)
MM-398
Nanotherapeutic targeted irinotecan
Topo I inhibition / DNA replication
Ph2 mono: 25% 1 yr OS 5.2 mos median OS 50% DCR
MM-302
ErbB2 Ab targeted nanotherapeutic doxorubicin
Topo II inhibition / DNA replication
Ph1 mono: 15% ORR 37% CBR
Signaling Inhibitors
MM-310
Antibody targeted Undisclosed nanotherapeutic
Preclin
Ph1
Ph2
Ph3
Pre-NDA
N/A
MM-121
Monoclonal antibody
ErbB3
Ph1 combo: 39% ORR 70% CBR
MM-111
Bispecific antibody
ErbB3 & ErbB2
Ph1 combo: 40% ORR 52% CBR
MM-151
Oligoclonal antibody
EGFR
Ph1 mono: TBA
MM-141
Bispecific tetravalent antibody
IGF-1R & ErbB3
Ph1 mono: TBA
MM-131
Multispecific antibody
Undisclosed
N/A
(1) Selected trials: MM-121 plus paclitaxel in ErbB2 (HER2) negative breast, ovarian and other gynecological cancers; MM-111 plus multiple anti-cancer therapies in ErbB2 (HER2) positive solid tumors; MM-398 monotherapy in pancreatic cancer; MM-302 monotherapy in ErbB2 (HER2) positive breast cancer
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