MANIFEST Phase 2 Enhancement / Expansion Investor Conference Call Stellar Science, Breakthrough Medicine October 11, 2018
Forward-Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the development status of the Company s product candidates, the anticipated benefits of the changes to its clinical trial protocols and its anticipated achievement of milestones, including determination of proof of concept. All statements, other than statements of historical facts, contained in this press release, including statements regarding the Company s strategy, future operations, future financial position, prospects, plans and objectives of management, are forward-looking statements. The words anticipate, believe, continue, could, estimate, expect, intend, may, plan, potential, predict, project, should, target, will, would and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with Constellation s ability to: obtain and maintain necessary approvals from the FDA and other regulatory authorities; continue to advance its product candidates in clinical trials; replicate in later clinical trials positive results found in preclinical studies and early-stage clinical trials of CPI-1205, CPI-0610 and its other product candidates; advance the development of its product candidates under the timelines it anticipates, or at all, in current and future clinical trials; obtain, maintain or protect intellectual property rights related to its product candidates; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. For a discussion of other risks and uncertainties, any of which could cause the Company s actual results to differ from those contained in the forward-looking statements, see the Risk Factors section, as well as discussions of potential risks, uncertainties, and other important factors, in the Company s most recent filings with the Securities and Exchange Commission. In addition, the forward- looking statements included in this press release represent the Company s views as of the date hereof and should not be relied upon as representing the Company s views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments will cause the Company s views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so. CPI-1205, CPI-0610, CPI-0209, and other product candidates are investigational in nature and have not yet been approved by the FDA or other regulatory authorities. 2
CPI-0610: Differentiated BET Inhibitor in Clinical Trials for Myelofibrosis Jigar Raythatha, Chief Executive Officer
Constellation Highlights Multiple Lead Clinical Programs CPI-1205 (EZH2) and CPI-0610 (BET) Encouraging Preliminary Clinical Data Prostate cancer, solid tumors, and myelofibrosis Near-Term Milestones Proof-of-concept determination for each lead program expected in mid-2019 Expanding the EZH2 Opportunity Second-generation EZH2 inhibitor (CPI-0209) Robust Discovery Platform Novel chromatin-modifying proteins targeting tumor cells and innate immune cells 4
BET Reader Proteins Control of Key Immune, Fibrotic, and Oncogenic Pathways Leads to Opportunity in Myelofibrosis (MF) Immune Signaling NF-κB target genes Transcription Factor Fibrosis TGF-β target genes Enhancer BRD4 Cancer Genetics MYC, BCL2 TSS 5
Rationale for BET Role in Myelofibrosis BET Inhibition May Block Proliferation of Inflammatory Bone Marrow Cells and Synergize with JAK Inhibition Cytoplasm Nucleus BET Signaling BETs NF-kB Target Genes STAT P P STAT JAK/STAT Signaling Megakaryocyte Differentiation/Proliferation Pro-Inflammatory Cytokines (e.g., IL-8) 6
Myelofibrosis (MF) Background Myeloproliferative neoplasm characterized by scarring (fibrosis) of the bone marrow caused by impaired hematopoiesis 17,000-20,000 patients in US* Three main features: Symptoms of organomegaly (spleen and liver) Symptoms of systemic inflammation Anemia and thrombocytopenia Only approved therapy is ruxolitinib, which has been shown to relieve symptoms but has limited evidence of disease modification *Internal market research 7
Underserved MF Patients and MANIFEST Trial Adrian Senderowicz, Chief Medical Officer
Underserved MF Patient Population Standard of care and the only approved drug treatment is ruxolitinib (Jakafi) Significant improvement in splenomegaly and symptoms, but limited evidence of disease modifying effect 30-40% of patients respond adequately in clinical trials* Thrombocytopenia and/or anemia may lead to patients receiving sub-optimal dosing or discontinuation of treatment 57% of ruxolitinib patients required dose reductions due to adverse events in COMFORT-1** Patients may require blood transfusions, which become more frequent during ruxolitinib treatment or due to disease progression *Mesa RA, Kiladian JJ, et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis. J Clin Oncol. 2017 Dec 1;35(34):3844-3850. doi: 10.1200/JCO.2017.73.4418. Epub 2017 Sep 20Haematologica. 2015;100(4):479-488.Verstovsek S., Mesa RA. Gotlib J, et al; COMFORT-I Investigators. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55.. **Verstovsek S,, Mesa RA, Gotlib J, et al; COMFORT-I Investigators. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55. 9
Need for New Disease-Modifying Treatments in MF Ruxolitinib Spleen Response SIMPLIFY-1* Ruxolitinib TSS Response SIMPLIFY-1* 26.5% SVR35 29% SVR35 28.4% TSS50 42.2% TSS50 Transfusion Dependence SIMPLIFY-1* Inadequate response in 1L disease No approved therapy in 2L disease Patients burdened by increased reliance on transfusions Need for new disease-modifying therapies that increase response rate and improve hematopoietic function * Source: Mesa, R., et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis J Clin Oncol 2017: 35(34):3844-3850 10
IL-8 expression % change from baseline CPI-0610 Background Treated 138 patients in Phase 1 trials of hematologic malignancies Multiple objective responses observed at a range of doses below the maximum tolerated dose Demonstrated favorable PK/PD profile Activity seen in the context of NF-κB-driven diseases ABC-DLBCL (Phase 1) 7 patients at relevant doses: 1 CR, 2 PR, 1 SD (16 months) Myelofibrosis (Phase 2) Evidence of transfusion independence in one patient, reduction in spleen size, and symptom improvement Phase 1 data in 38 evaluable lymphoma patients 100% 75% 50% 25% 0% -25% -50% -75% -100% Correlation between IL-8 (NF-kB target gene) expression and CPI-0610 exposure 2.50 2.00 1.50 1.00 0.50 = ABC-DLBCL 0.00 0.00 2.00 4.00 6.00 8.00 Concentration of CPI-0610 mm 11
MANIFEST: CPI-0610 Phase 2 Trial Design in MF Prior to Amendment 2L MF patients no longer on ruxolitinib 2L MF patients on ruxolitinib despite disease progression on therapy CPI-0610 n=35 CPI-0610 + ruxolitinib n=35 CPI-0610 dosing of 125mg up to 225mg once daily in both arms Objectives: Evaluate spleen size reduction after 24 weeks of treatment Evaluate patient-reported symptom improvement Evaluate transfusion independence rate, if applicable 12
% r e d u c t io n f r o m b a s e li n e Spleen Size Reduced in All Patients as Measured by MRI MANIFEST: First Four Patients Treated B e s t S p le e n R e s p o n s e 2 0 1 0 0-1 0 C o m b i n a t i o n Ongoing > 10 months M o n o t h e r a p y Ongoing > 5 months Reduced spleen size Symptom improvement One patient with thrombocytosis and one patient transfusion-dependent at baseline both resolved -2 0-3 0-4 0-5 0 Data cutoff May 25, 2018 13
P la t e l e t c o u n t ( x 1 0 9 / L ) H e m o g l o b in ( g /d L ) Improved Hematopoiesis on CPI-0610 Patient Achieved Transfusion Independence and Improved Platelet Count T r a n s f u s io n s N o t ra n s fu s io n fo r > 2 4 w k s 3 0 0 4 w k s 4 w k s 4 w k s 6 w k s 1 2 1 1 2 0 0 1 0 1 0 0 9 8 P la te le ts 0 H e m o g lo b in 7 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 C y c le o f tr e a t m e n t ( 1 c y c le = 3 w e e k s ) Data cutoff May 25, 2018 Patient treated with CPI-0610 + ruxolitinib combination therapy 14
H e m o g lo b in ( g /d L ) Improved Hematopoiesis on CPI-0610 Hemoglobin Levels Increased in First Four Patients Treated 1 4 1 3 1 2 P a tie n t 1 ( C o m b o ) P a tie n t 2 ( C o m b o ) P a tie n t 3 (M o n o ) P a tie n t 4 (M o n o ) 1 1 1 0 9 8 7 6 0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 Data cutoff May 25, 2018 C y c le o f tr e a tm e n t ( 1 c y c le = 3 w e e k s ) 15
Clinical Trial Execution All patient data disclosed to date come from our first site We have made considerable progress in our 2018 goals of activating additional sites 7 sites in the US and 5 in Canada are active, with more to follow in US and Europe We have enrolled additional patients at these sites and look forward to providing updates at future medical meetings 16
Rationale for Protocol Amendment Preliminary signs of clinical activity in each of the evaluable 2L patients in MANIFEST* SVR and symptom improvement Potential disease-modifying effects* Improved hematopoiesis, including hemoglobin level improvement, in each patient Resolution of transfusion dependence Modifying the 2L cohorts to stratify for transfusion dependence status to better measure hematopoietic effects Initiating a 1L cohort in combination with ruxolitinib * Data cutoff May 25, 2018 17
MANIFEST: Expanded Phase 2 Trial in MF Robust Development Plan to Expand the CPI-0610 Opportunity 2L MF patients no longer on ruxolitinib 2L MF patients on ruxolitinib despite disease progression on therapy CPI-0610 Mono CPI-0610 + Rux Cohort 1A: 2L Transfusion Dependent (TD) n = up to 16 Cohort 1B: 2L Non-TD n = up to 25 Cohort 2A: 2L Transfusion Dependent n = up to 16 Cohort 2B: 2L Non-TD n = up to 25 Primary Endpoints: Transfusion independence rate in Cohorts 1A, 2A Spleen volume reduction and Total Symptom Score assessment at 24 weeks in Cohorts 1B, 2B, and 3 Note: Each cohort will implement adaptive Simon s two-stage design 1L MF patients CPI-0610 + Rux Cohort 3: 1L* n = up to 43 *Cohort 3 will enroll anemic patients, pivotal trial plans anticipated to include all comers 18
CPI-0610: Differentiated BET Inhibitor in Clinical Trials for Myelofibrosis Jigar Raythatha, Chief Executive Officer
Conclusion CPI 0610 has demonstrated clinical activity in early clinical trials with NF-κB-driven cancers, including MF, suggesting CPI-0610 may be differentiated among BET inhibitors Preliminary clinical data in 2L myelofibrosis show improvements in spleen volume, symptom scores, hematopoiesis, and transfusion independence, which may indicate the potential for disease modification We have modified MANIFEST in 2L patients to stratify for transfusion dependent status and added a 1L arm, which increases the potential opportunity for CPI-0610 Multiple new clinical trial sites initiated in US and ex-us We continue to expect determination of proof of concept by mid-2019 20
Constellation Pharmaceuticals Questions? Answers. 21