SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of report (Date of earliest event reported): November 8, 2018
Constellation Pharmaceuticals, Inc.
(Exact Name of Registrant as Specified in Charter)
(State or Other Jurisdiction
215 First Street, Suite 200
|(Address of Principal Executive Offices)||(Zip Code)|
Registrants telephone number, including area code: (617) 714-0555
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
|Item 2.02|| |
Results of Operations and Financial Condition.
On November 8, 2018, Constellation Pharmaceuticals, Inc. (the Company) announced its financial results for the quarter ended September 30, 2018. The full text of the press release issued in connection with the announcement is being furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.
The information in this Item 2.02, including Exhibit 99.1 attached hereto, shall not be deemed filed for purposes of Section 18 of the Securities Exchange Act of 1934 (the Exchange Act) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933 or the Exchange Act, except as expressly set forth by specific reference in such a filing.
|Item 7.01|| |
Regulation FD Disclosure.
On November 8, 2018, the Company posted a Corporate Overview presentation on its website. A copy of the presentation is attached as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated herein by reference.
The information in this Item 7.01, including Exhibit 99.2 attached hereto, shall not be deemed filed for purposes of Section 18 of the Securities Exchange Act of 1934 (the Exchange Act) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933 or the Exchange Act, except as expressly set forth by specific reference in such a filing.
|Item 9.01|| |
Financial Statements and Exhibits.
The following exhibits are furnished herewith:
|99.1||Press Release dated November 8, 2018|
|99.2||Corporate Overview dated November 2018|
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|CONSTELLATION PHARMACEUTICALS, INC.|
|Date: November 8, 2018||By:||/s/ Emma Reeve|
|Name: Emma Reeve|
|Title: Chief Financial Officer|
Constellation Pharmaceuticals Announces Third-Quarter and Nine-Month 2018 Financial Results
Company Executing on Lead Programs CPI-1205 and CPI-0610
Expects to Evaluate Proof of Concept for Both Programs in Mid-2019
CAMBRIDGE, Massachusetts, November 8, 2018 Constellation Pharmaceuticals, Inc., (Nasdaq: CNST) a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, today announced its third-quarter and nine-month 2018 financial results.
We are excited about the progress we have made this year with our clinical programs and our entire epigenetics platform, said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals. In 2019, we look forward to further progress in our pipeline, as we expect to evaluate proof of concept for both our ProSTAR and MANIFEST clinical trials in mid-2019 as well as initiate clinical development of our second-generation EZH2 inhibitor CPI-0209.
Continued enrollment in ProSTAR Phase 1b/2 study of CPI-1205 in metastatic castration-resistant prostate cancer (mCRPC). As planned, 34 sites are activated and enrolling patients in each of the two cohorts of the Phase 1b portion of the study. The Company expects to determine a recommended Phase 2 dose and begin the randomized portion of the trial in the fourth quarter of 2018.
Enhanced and expanded the Phase 2 portion of the ongoing MANIFEST study of CPI-0610 in myelofibrosis (MF). Constellation modified the MANIFEST trial design to stratify for transfusion-dependent status in second-line treatment and to initiate a first-line treatment arm in combination with ruxolitinib in JAK 1/2-inhibitor-naïve patients with MF. These changes are intended to provide additional measures of potential clinical activity and to expand the potential addressable population of MF patients for CPI-0610, thereby enabling multiple potential paths to
registration. More than a dozen sites are now open for MANIFEST in the US, Canada, and Europe, with more sites expected to open in the next few months. Preliminary data in this trial as of May 25 included evidence of reductions in spleen volume, improvements in symptom scores, and increased hemoglobin levels, as well as one case of a transfusion-dependent patient achieving transfusion independence.
Announced Fast Track designation for CPI-0610 for the treatment of MF. The FDA awarded CPI-0610 Fast Track status based on preliminary results from the Phase 2 MANIFEST study. Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill unmet medical needs.
Expanded Board of Directors with experts in mCRPC and MF. Constellation announced the appointments of Dr. Elizabeth G. Tréhu and Steven L. Hoerter to its Board of Directors, bringing considerable experience working in the disease areas of mCRPC and MF.
Presenting preclinical data from EZH2 franchise in prostate cancer. Constellation will be presenting data at the upcoming EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium on November 13-16 in Dublin, Ireland, and at the AACR-KCA Joint Conference on Precision Medicine in Solid Tumors on November 15-17 in Seoul, South Korea.
Third Quarter 2018 Financial Results
Cash and cash equivalents as of September 30, 2018 grew 45% to $128.5 million compared to June 30, 2018, primarily due to capital raised in the initial public offering in July, partially offset by operating expenses.
Research and development (R&D) expenses increased 66% year over year to $12.7 million in the third quarter of 2018 mainly due to increased clinical trial expenses.
General and administrative (G&A) expenses grew 86% year over year to $3.7 million in the third quarter of 2018, primarily due to costs related to building out the organization as the Company evolved from a preclinical-stage company to a multi-candidate clinical-stage company, as well as costs associated with operating as a public company.
The net loss attributable to common stockholders increased 9% year over year to $15.9 million mainly due to increases in G&A and R&D expenses, partly offset by the inclusion of unpaid cumulative dividends in 2017 that were waived in 2018. The net loss per share attributable to common stockholders decreased 95% to $0.81 per share for the third quarter of 2018 due to an increase in shares outstanding as a result of the initial public offering and conversion of the preferred stock to common stock.
We expect that cash as of September 30, 2018, will fund planned operations into the first quarter of 2020.
The Company continues to anticipate achieving the following milestones during the upcoming twelve months:
Fourth Quarter 2018
Initiate the Phase 2 portion of the ProSTAR study with CPI-1205
Determine safety and the recommended Phase 2 dose in the ORIOn-E trial for CPI-1205 in combination with checkpoint inhibitors in solid tumors
Initiate the Phase 1 trial with CPI-0209, a second-generation EZH2 inhibitor
Evaluate proof of concept for CPI-1205 in the ProSTAR trial
Evaluate proof of concept for CPI-0610 in the MANIFEST trial
Financial Results (Unaudited)
Constellation Pharmaceuticals, Inc.
Statements of operations and comprehensive loss (unaudited)
|Nine months ended September 30,||Three months ended September 30,|
Research and development
General and administrative
Total operating expenses
Other income (expense):
Change in fair value of preferred stock tranche liability
Total other income (expense), net
Net loss and comprehensive loss
Cumulative dividends on convertible preferred stock
Net loss attributable to common stockholders
Net loss per share attributable to common stockholders, basic and diluted
Weighted average common shares outstanding, basic and diluted
Constellation Pharmaceuticals, Inc.
Balance sheets (unaudited)
|September 30, 2018||December 31, 2017|
Cash and cash equivalents
Other current assets
Convertible preferred stock
Total stockholders equity (deficit)
Note: Abbreviated financial statements; please refer to Form 10-Q for more details, including explanatory notes.
About Constellation Pharmaceuticals
Constellation Pharmaceuticals is a clinical-stage biopharmaceutical company developing novel therapeutics that selectively modulate gene expression to address serious unmet medical needs in patients with cancer. The Company has a deep understanding of how epigenetic and chromatin modifications in cancer cells and in the tumor and immune microenvironment play a fundamental role in driving disease progression and drug resistance. Constellation is driving development of the EZH2 inhibitors CPI-1205 and CPI-0209 for the treatment of metastatic castration-resistant prostate cancer and other cancers as well as the BET inhibitor CPI-0610 for the treatment of myelofibrosis. The Company is also applying its broad research and development capabilities to explore other novel targets that directly and indirectly impact gene expression to fuel a sustainable pipeline of innovative small-molecule product candidates.
This press release 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 Companys 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 Companys 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 managements 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 Constellations 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 Companys 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 Companys most recent filings with the Securities and Exchange Commission. In addition, the forward- looking statements included in this press release represent the Companys views as of the date hereof and should not be relied upon as representing the Companys views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments will cause the Companys 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.
MacDougall Biomedical Communications
Developing Treatments Targeting Epigenetic Mechanisms in Tumor and Immune Cells for Cancer Patients Corporate Overview November 2018 Exhibit 99.2
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. Forward-Looking Statements
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 Constellation Highlights
Instructions for Genetic Code Tumor Cells MDSC NK Cell T Cell Focused on Three Distinct Classes That Chemically Modify Chromatin Tumor Microenvironment Target Transcriptional Networks That Result in Cell Death Re-program Immune Cells to Overcome Resistance to Cancer Immunotherapies Transcriptional Control to Turn Genes On or Off Writers Erasers Readers
Multiple Near-Term Opportunities for Success Product Candidates Indications Preclinical Phase 1 Phase 2 Phase 3 Next Milestone EZH2 Franchise CPI-1205 mCRPC Proof of Concept Mid 2019 CPI-1205 Solid Tumors Safety and RP2D Early 2019 CPI-0209 (2nd Gen) Solid Tumors / Heme Malignancies Initiate Phase 1 Mid 2019 BET Inhibitor CPI-0610 Myelofibrosis Proof of Concept Mid 2019 Preclinical Tumor Microenvironment (Undisclosed) Solid Tumors / Heme Malignancies Immune Microenvironment (Undisclosed) Solid Tumors ProSTAR Trial ORIOn-E Trial MANIFEST Trial
CPI-1205 and CPI-0209 EZH2 Franchise
EZH2 “Writer” Activity Suppresses Gene Transcription EZH2 Inhibition Offers Broad Therapeutic Potential Polycomb Repressive Complex 2 (PRC2)… … Methylates Histone H3 at Lysine 27 (K27) EZH2 SUPPRESSED TRANSCRIPTION Acquired Drug Resistance: EZH2 mediates gene silencing that diminishes response to existing therapies Cancer Genetics: Mutations in genes which create a functional dependency on EZH2 Regulation of Immune Cells: EZH2 reprograms T cells to suppress an anti-tumor immune response
*Signature of H3K27me3-occupied EZH2 target genes repressed in metastatic relative to clinically localized prostate cancer and benign prostate tissue Model for EZH2 Role in Prostate Cancer EZH2 Gene Signature* Predicts Outcomes in Prostate Cancer Yu et al., Cancer Research 2007 Pro-tumor Signaling Enhances AR Signaling K27 OFF EZH2 Coregulators Prostate Tumor Growth Chromatin AR AR 0 2 4 6 8 10 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Time to relapse (years) Probability of survival
Evidence of EZH2 Synergy with Androgen Receptor Signaling (ARS) CPI-1205 Enhances the Gene Signature of Enzalutamide in Prostate Cancer Cells CPI-1205 is Active as Monotherapy and Synergistic with Enzalutamide in Killing Prostate Cancer Cells Enzalu- tamide CPI- 1205 Combo Theoretical concentration of each agent required to kill 90% of cancer cells if no synergistic activity Actual concentration of each agent required to kill 90% of cancer cells when combined
*ASCO 2018 Poster Khalaf, et al (Kim Chi Lab) Current Treatment Paradigm in mCRPC Metastatic Castration-Resistant Prostate Cancer (30,000–50,000 Diagnosed Annually) 1st Line Abiraterone or Enzalutamide 2nd Line Enzalutamide or Abiraterone 3rd Line Chemotherapy or Palliative Care 60–80% PSA Response 9–15 Months PSA PFS PSA50 = 4% (Abi) and 31% (Enza)* PSA PFS = 1.3 months (Abi) and 2.7 months (Enza)* No Objective Responses EZH2 inhibition may enhance the activity of ARS inhibitors
Second-Line Trial After Ineffective Treatment with Androgen Receptor Signaling (ARS) Inhibitor ProSTAR Trial Design Enzalutamide + CPI-1205 (Prior Abiraterone Progression) Abiraterone + CPI-1205 (Prior Enzalutamide Progression) Selected ARS Inhibitor + CPI-1205 (Progressed on Different ARS Inhibitor) n=35 Selected ARS Inhibitor Alone (Progressed on Different ARS Inhibitor) n=35 Testing Biomarkers for Patient Enrichment vs. Primary endpoints: MTD, RP2D Primary endpoint: Response rate PSA reduction; CTC reduction; or Objective response Selected CPI-1205 + ARSi combo RP2D Phase 1b Randomized Phase 2
Data cutoff May 25, 2018 *Continued on CPI-1205 monotherapy after cycle 1 Discontinued Treatment ProSTAR Trial: Treatment Duration 2 of 6 evaluable patients achieved PSA80 2 of 4 evaluable patients with CTCs achieved CTC reduction of > 30% 2 of 2 evaluable patients had resolution of metastatic disease C1D1 C2D1C3D1 C4D1C5D1C6D1 C7D1 Cycles of Treatment (One Cycle = One Month) Patient # 1 2 3 4 5 6 7 8 9 10 CPI-1205 + Abiraterone CPI-1205 + Enzalutamide *
*Continued on CPI-1205 monotherapy after cycle 1 Resolution of Bone Metastases Baseline Cycle 4 Day 1 CPI-1205 + Enzalutamide*
Objective Response by CT Scan February 2018 Baseline: December 2017 CPI-1205 + Enzalutamide
Significant PSA Reduction in Heavily Pre-Treated and Refractory Patient Experience with a Compassionate-Use Patient 3,000 2,500 2,000 1,500 1,000 500 12 agents prior to CPI-1205, including second-generation androgen inhibitors, chemotherapy, PARP inhibitors, tyrosine kinase inhibitors, checkpoint inhibitors, radium 223, and radiotherapy Start CPI-1205 + Enzalutamide (PSA ~ 2900) PSA Score (ng/mL) 80% reduction in PSA levels Evidence of tumor size reduction in the neck 6/1/2016 9/1/2016 12/1/2016 3/1/2017 6/1/2017 9/1/2017 12/1/2017 3/1/2018 PSA levels escalated significantly in final year of treatment prior to CPI-1205 + enzalutamide Treatment interrupted due to non-treatment-related pneumonia Subsequent progression in liver led to discontinuation. Patient later died.
Tazemetostat CPI-0209 Once-Daily Treatment Resulted in Rapid, Complete, and Durable Tumor Regression CPI-0209: Second-Generation EZH2 Inhibitor CPI-0209 May Provide More Comprehensive EZH2 Coverage, Expanding Addressable Populations Lymphoma Xenograft Mouse Model Vehicle Tazemetostat, 160 mg/kg oral, twice daily Vehicle CPI-0209, 25 mg/kg oral, once daily Cessation of treatment
CPI-0610 BET Inhibitor
Control of Key Immune, Fibrotic, and Oncogenic Pathways Leads to Opportunity in Myelofibrosis (MF) BET Family of Proteins … Enhancer TSS BRD4 Transcription Factor … Fibrosis TGF-β target genes Immune Signaling NF-κB target genes Cancer Genetics MYC, BCL2
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 CPI-0610 Background Concentration of CPI-0610 mM Correlation Between IL-8 (NF-kB Target Gene) Expression and CPI-0610 Exposure (Constellation Data)
BET Inhibition May Block Proliferation of Inflammatory Bone Marrow Cells and Synergize with JAK Inhibition Rationale for BET Role in Myelofibrosis BET Signaling Megakaryocyte Differentiation/Proliferation Pro-Inflammatory Cytokines (e.g., IL-8) JAK/STAT Signaling STAT STAT Cytoplasm Nucleus NF-kB Target Genes BETs P P
Constellation Pharmaceuticals Data Rationale for BET’s Role in Myelofibrosis CPI-0610 vs DMSO 25 nM 100 nM 400 nM Vehicle 1–2+ JQ1 (BETi) 1+ Ruxolitinib 1+ Combo 0 Inhibition of Megakaryocyte Differentiation in vitro BET Inhibitor + Ruxolitinib Led to Synergistic Reduction in Spleen Volume (Left) and Improved Bone Marrow Fibrosis Score (Right) * * * Kleppe et al 2018 Cancer Cell
Myeloproliferative neoplasm characterized by scarring (fibrosis) of the bone marrow caused by impaired hematopoiesis 17,000–20,000 diagnosed 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 Myelofibrosis (MF) Background * Internal market research
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 Underserved MF Patient Population *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.
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 Need for New Disease-Modifying Treatments in MF *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 26.5% SVR35 29% SVR35 35% Decrease Individual Patients Ruxolitinib Spleen Response – SIMPLIFY-1* Change in Spleen Volume from Baseline (%) 150% 100% 50% 0% -50% -100% MMB (n = 184) RUX (n = 204) Change in TSS from Baseline (%) 150% 100% 50% 0% -50% -100% Ruxolitinib TSS Response – SIMPLIFY-1* Individual Patients 50% Decrease MMB (n = 174) RUX (n = 190) 28.4% TSS50 42.2% TSS50 Transfusion Dependence – SIMPLIFY-1*
First-line arm in combination with ruxolitinib aims to address inadequate response to ruxolitinib alone in spleen volume reduction, patient-reported symptom improvement, and other factors, including lack of disease-modifying effects of ruxolitinib Second-line arm aims to provide a treatment option, as a monotherapy and in combination with ruxolitinib, for patients with disease progression after ruxolitinib, looking for: Spleen volume reduction and patient-reported symptom improvement Improvement in transfusion independence rate in patients who are transfusion dependent Evidence of disease modification/improved hematopoietic function Rationale for MANIFEST Design
* Cohort 3 will enroll anemic patients, pivotal trial plans would include all comers Robust Development Plan to Expand the CPI-0610 Opportunity MANIFEST: Expanded Phase 2 Trial in MF 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 Cohort 3: 1L* n = up to 43 CPI-0610 Mono CPI-0610 + Rux CPI-0610 + Rux 2L MF patients no longer on ruxolitinib 2L MF patients on ruxolitinib despite disease progression on therapy 1L MF patients 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
Best Spleen Response Reduced spleen size Symptom improvement One patient with thrombocytosis and one patient transfusion-dependent at baseline—both resolved Spleen Size Reduced in All Patients as Measured by MRI MANIFEST: First Four Patients Treated Data cutoff May 25, 2018 Ongoing > 10 months Ongoing > 5 months COMBINATION MONOTHERAPY
Data cutoff May 25, 2018 Patient Achieved Transfusion Independence and Improved Platelet Count Improved Hematopoiesis on CPI-0610 Patient treated with CPI-0610 + ruxolitinib combination therapy Transfusions No Transfusions for >24 Weeks 4 wks 4 wks 4 wks 6 wks
Data cutoff May 25, 2018 Hemoglobin Levels Increased in First Four Patients Treated Improved Hematopoiesis on CPI-0610
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 CPI-0610 Summary
Discovery Platform Fueling the Pipeline Innate Adaptive Normalize aberrant gene expression within cancer cells Increase tumor immunogenicity Re-program immune cells to overcome resistance to cancer immunotherapies Tumor Cells Immune Cells Discovery Programs Targeting Epigenetic Regulators on the Tumor and Immune Microenvironment
Potential Value Creation Catalysts 2019 2018 Early 2018 Complete crossover financing Expand enrollment in ProSTAR Initiate ORIOn-E Select 2nd generation EZH2 inhibitor candidate (CPI-0209) Late 2018 Additional active sites in US, Canada / EU for CPI-0610 in myelofibrosis Initiate Phase 2 portion of ProSTAR Trial Early 2019 Safety and recommended Phase 2 dose (RP2D) from ORIOn-E Mid 2019 ProSTAR (CPI-1205) proof of concept MANIFEST (CPI-0610) proof of concept Initiate Phase 1 for CPI-0209
Post-IPO cash expected to fund operations into 2020, including: Ongoing clinical trials to determine proof of concept for CPI-1205 and CPI-0610 Continued advancement of CPI-0209 Ongoing support for robust discovery/preclinical Oversubscribed crossover financing round in April raised $100 million from high-quality investors Cash and cash equivalents as of September 30, 2018, of $128.5 million Strong Cash Position $ Millions, Except Per-share Amounts 9M18 3Q18 R&D Expenses $32.1 $12.7 G&A Expenses $8.5 $3.7 Other Income (Expenses), Net $0.6 $0.5 Net Loss Attributable to Common Stockholders ($40.0) ($15.9) Net Loss Per Share Attributable to Common Stockholders ($5.45) ($0.81)
Management Team Jigar Raythatha President and CEO Emma Reeve Chief Financial Officer Adrian Senderowicz, M.D. Chief Medical Officer Brad Prosek SVP, Corporate Development Robert Sims, PhD SVP, Research Patrick Trojer, PhD SVP, Translational Sciences Karen Valentine Chief Legal Officer, General Counsel Brenda Sousa SVP, HR and Operations Experienced Management Team, Board, and Scientific Advisors Danny Reinberg, Ph.D., NYU, HHMI, NAS David Allis, Ph.D., Rockefeller Univ., NAS Yang Shi, Ph.D., Harvard Medical School Pam Sharma, M.D., Ph.D., MD Anderson Cancer Center David Livingston, M.D., Dana Farber Cancer Center Scott Lowe, Ph.D. Memorial Sloan-Kettering Robert Schreiber, Washington U. School of Med. Board of Directors Founders & Scientific Advisory Board Mark Goldsmith, M.D., Ph.D. (Chairman), CEO, Revolution Medicines Jigar Raythatha Jim Audia, Ph.D., Chicago Biomedical Consortium Tony Evnin, Ph.D., Venrock Steven Hoerter, Agios Pharmaceuticals Peter Svennilson, The Column Group Bob Tepper, M.D., Third Rock Ventures Elizabeth Tréhu, M.D. Jounce Therapeutics
Expanding EZH2 Opportunity Mutant Follicular Lymphoma Solid Tumors in Combination with Standard of Care in Both Tumors and Immune Cells mCRPC Anti-PD-1 Progressors Solid Tumors and/or Heme Malignancies Genetics That Validate EZH2 Enhance Effectiveness of Standard of Care Comprehensive Target Engagement Constellation Focus CPI-1205 CPI-0209
CPI-1205 Improves Anti-Tumor Immune Activity Pam Sharma June 2018 Jeff Bluestone and Michel DuPage June 2018 Synergistic Impact with Checkpoint Inhibitor in Preclinical Model MB49
Enrolling All Comers in Solid Tumors CPI-1205 Checkpoint Combination Study Design Ipilimumab + CPI-1205 (Prior Anti-PD-(L)1) Pembrolizumab + CPI-1205 (Prior Anti-PD-(L)1) Expansion Cohorts Checkpoint Inhibitor + CPI-1205 Phase 1b Phase 2 Testing Biomarkers for Patient Enrichment RP2D
1 PR + 3 SD out of 6 patients treated with CPI-1205 + ipilimumab 42% Reduction in Tumor Volume from Baseline Phase 1b/2 All Comers Solid Tumors Progressed on Anti-PD-(L)1 ORIOn-E Summary as of May 25, 2018 Clinical Activity Observed in Anti-PD-1 Progressors Discontinued Treatment Stable Disease Partial Response Treatment Ongoing Baseline Cycle 4