8-K

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

 

 

FORM 8-K

 

 

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of report (Date of earliest event reported): March 14, 2019

 

 

Constellation Pharmaceuticals, Inc.

(Exact Name of Registrant as Specified in Charter)

 

 

 

Delaware   001-38584   26-1741721

(State or Other Jurisdiction

of Incorporation)

 

(Commission

File Number)

 

(IRS Employer

Identification No.)

 

215 First Street, Suite 200

Cambridge, Massachusetts

  02142
(Address of Principal Executive Offices)   (Zip Code)

Registrant’s telephone number, including area code: (617) 714-0555

Not applicable

(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 March 14, 2019, Constellation Pharmaceuticals, Inc. (the “Company”) announced its financial results for the quarter and year ended December 31, 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 March 14, 2019, 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.

(d) Exhibits

The following exhibits are furnished herewith:

 

99.1    Press Release dated March 14, 2019
99.2    Corporate Overview dated March 2019


SIGNATURES

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: March 14, 2019     By:   /s/ Jigar Raythatha
      Name: Jigar Raythatha
      Title: Chief Executive Officer
EX-99.1

Exhibit 99.1

Constellation Pharmaceuticals Announces Fourth-Quarter and Full-Year 2018 Financial Results

CAMBRIDGE, Massachusetts, March 14, 2019 – Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, today announced its fourth-quarter and full-year 2018 financial results.

“2019 is a year of data for Constellation, and our clinical programs are making significant progress and approaching important readouts,” said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals.

“We are excited by preliminary data from our first four patients from the MANIFEST clinical trial, each showing one or more of the following: conversion from transfusion dependence to transfusion independence, hemoglobin increases, improvements in bone marrow fibrosis scores, spleen reductions, and symptom improvements. These results taken together suggest that CPI-0610 may have disease-modifying effects in myelofibrosis patients. We plan to present an interim update of data from MANIFEST from approximately 18-20 evaluable patients at a medical meeting in the second quarter of 2019.

“We also plan to present Phase 1b data from the ProSTAR clinical trial of CPI-1205 in metastatic castration-resistant prostate cancer in a poster at the American Association for Cancer Research annual meeting on April 1. Enrollment is on track in the Phase 2 portion of the ProSTAR trial, and we expect to provide an interim update of data of the Phase 2 portion at a medical meeting in the second half of 2019,” Mr. Raythatha continued.

“The Constellation team continues to work diligently toward becoming a late-stage oncology development company and bringing important new medicines to underserved cancer patients,” Mr. Raythatha concluded.

Recent News

MANIFEST


   

Enrollment is on track in the MANIFEST clinical trial in myelofibrosis patients. The Company has now opened approximately 20 clinical trial sites in the U.S., Canada, and Europe. As of February 28, 2019, 28 patients had been enrolled in the second-line arms of MANIFEST. The Company plans to provide an update on approximately 18-20 evaluable patients with at least three months of data at a second quarter medical meeting.

 

   

Each of the first four patients in MANIFEST remains on study. As of the last data cutoff on December 10, 2018, the first two patients treated with a combination of CPI-0610 and ruxolitinib had been treated for over 16 months. The first two patients treated with CPI-0610 monotherapy had been treated for over 12 months. As previously reported, each of these four patients has shown a reduction in spleen volume and improved hemoglobin levels. One of the combination therapy patients was transfusion dependent before therapy and converted to being transfusion independent after CPI-0610 was added to the patient’s regimen. As of December 10, 2018, this patient had been free of transfusions for over 52 weeks. Additionally, bone marrow biopsies before and after treatment were analyzed for the first two evaluable patients on monotherapy, and both demonstrated a one-grade improvement in bone marrow fibrosis score as well as associated improvements in hemoglobin. Taken together, these results suggest that CPI-0610 may be improving bone marrow function in these ruxolitinib-resistant MF patients.

 

   

We believe CPI-0610 has the potential for a differentiated toxicity profile compared with other BET inhibitors. In a Phase 1 clinical trial, the Company showed that the dose-limiting toxicity for BET inhibitors of thrombocytopenia was reversible and non-cumulative for CPI-0610. In addition, preliminary data suggest that CPI-0610 may have a wider therapeutic window relative to some other BET inhibitors, based on their published data. The recommended Phase 2 dose of CPI-0610 in the MANIFEST study is 125 mg once daily, with titration allowed up to 225 mg once daily, which is the maximum tolerated dose.

ProSTAR

 

   

Constellation plans to provide an update of Phase 1b data for ProSTAR in a poster at the Annual Meeting of the American Association for Cancer Research in Atlanta on April 1.


   

The Phase 2 portion of the ProSTAR clinical trial continues to enroll patients in line with the Company’s plans. Constellation plans to present an interim update of data of the Phase 2 portion of ProSTAR at a medical meeting in the second half of 2019.

 

   

Constellation recently began dosing in heavily pretreated patients in a new arm of ProSTAR. Previously, a compassionate-use patient, who had experienced disease progression despite treatment with 12 agents (including abiraterone, enzalutamide, and chemotherapy) prior to CPI-1205, experienced an 80% reduction in PSA levels and evidence of tumor size reduction in the neck lymph nodes when treated with CPI-1205 in combination with enzalutamide. The new treatment arm will enroll up to 30 patients in a single arm of CPI-1205 in combination with enzalutamide in heavily pretreated patients.

Corporate

 

   

On February 20, Constellation announced that Dr. Scott Braunstein was appointed to the Board of Directors. Dr. Braunstein is also a member of the Audit Committee. Dr Braunstein has an impressive track record of helping emerging and established biopharmaceutical companies as an investor and a pharmaceutical executive.

 

   

On March 1, Jessica Christo was appointed Chief Product Development Officer. Ms. Christo brings to Constellation 25 years of product development experience in the biopharmaceutical industry in clinical operations, data management, program management, biostatistics, and related fields.

Fourth Quarter 2018 Financial Results

 

   

Cash and cash equivalents as of December 31, 2018 decreased 10.8% to $114.6 million compared to September 30, 2018, primarily due to operating expenses.

 

   

Research and development (R&D) expenses increased 65.4% year over year to $16.6 million in the fourth quarter of 2018 mainly due to increased clinical trial expenses.

 

   

General and administrative (G&A) expenses grew 118.3% year over year to $4.0 million in the fourth 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 17.5% year over year to $19.9 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 95.6% to $0.77 per share for the fourth 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.

Full-Year 2018 Financial Results

 

   

Research and development (R&D) expenses increased 49.5% year over year to $48.8 million in 2018 mainly due to increased clinical trial expenses.

 

   

General and administrative (G&A) expenses grew 92.8% year over year to $12.5 million in 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 11.5% year over year to $59.9 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 91.1% to $5.00 per share for 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.

Financial Guidance

We expect that our cash and cash equivalents as of December 31, 2018, will fund operating expenses and capital expenditure requirements into the second quarter of 2020.

Anticipated Milestones

The Company anticipates achieving the following milestones during 2019:

First Half 2019

 

   

Provide a data update from the Phase 1b portion of the ProSTAR trial for CPI-1205 at the American Association for Cancer Research meeting on April 1


   

Provide an interim update of data from the MANIFEST Phase 2 trial of CPI-0610 at a second-quarter 2019 medical meeting

 

   

Initiate a Phase 1 trial for CPI-0209

Second Half 2019

 

   

Provide an interim update of data from the Phase 2 portion of the ProSTAR trial for CPI-1205

 

   

Provide an additional data update from the MANIFEST trial for CPI-0610

Financial Results (Unaudited)

Constellation Pharmaceuticals, Inc.

Consolidated Statements of Operations and Comprehensive Loss

 

     Years ended
December 31,
    Three months ended
December 31,
 

(In thousands, except share and per-share amounts)

   2018     2017     2018     2017  

Revenue

   $ —       $ —       $ —       $ —    

Operating expenses:

        

Research and development

     48,769       32,617       16,626       10,053  

General and administrative

     12,475       6,471       4,006       1,835  
  

 

 

   

 

 

   

 

 

   

 

 

 

Total operating expenses

     61,244       39,088       20,632       11,888  
  

 

 

   

 

 

   

 

 

   

 

 

 

Loss from operations

     (61,244     (39,088     (20,632     (11,888
  

 

 

   

 

 

   

 

 

   

 

 

 

Other income (expense):

        

Interest income

     1,547       169       688       58  

Interest expense

     (228     (901     —         (102

Change in fair value of preferred stock tranche liability

     —         4,443       —         —    
  

 

 

   

 

 

   

 

 

   

 

 

 

Total other income (expense), net

     1,319       3,711       688       (44
  

 

 

   

 

 

   

 

 

   

 

 

 

Net loss and comprehensive loss

     (59,925     (35,377     (19,944     (11,932

Cumulative dividends on convertible preferred stock

     —         (18,390     —         (5,048
  

 

 

   

 

 

   

 

 

   

 

 

 

Net loss attributable to common stockholders

     (59,925     (53,767     (19,944     (16,980

Net loss per share attributable to common stockholders, basic and diluted

   $ (5.00   $ (56.10   $ (0.77   $ (17.64

Weighted average common shares outstanding, basic and diluted

     11,984,293       958,447       25,789,305       962,330  


Constellation Pharmaceuticals, Inc.

Consolidated Balance Sheets

 

(In $ thousands)    December 31,
2018
     December 31,
2017
 

Cash and cash equivalents

     114,592        16,404  

Other current assets

     2,711        1,318  

Total assets

     118,938        19,103  

Current liabilities

     14,660        11,131  

Total liabilities

     14,780        11,708  

Convertible preferred stock

     —          173,228  

Total stockholders’ equity (deficit)

     104,158        (165,833

Note: Abbreviated financial statements; please refer to Form 10-K 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.

Forward-Looking Statements

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 implications of preliminary clinical data, the development status of the Company’s product candidates, the Company’s plans for future data presentations, its anticipated achievement of milestones, including determination of proof of concept and its financial guidance regarding the period in which it will have capital available to fund its operations. 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; whether preliminary or interim results from a clinical trial will be predictive of the final results of the trial; 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.

Contact

Ronald Aldridge

Senior Director, Investor Relations

Constellation Pharmaceuticals

+1 617-714-0539

ron.aldridge@constellationpharma.com

 


Lauren Arnold

Media Relations

MacDougall Biomedical Communications

+1 781-235-3060

larnold@macbiocom.com

EX-99.2

Slide 1

March 2019 Developing Next-Generation Epigenetic Treatments for Cancer Patients Corporate Overview Exhibit 99.2


Slide 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 implications of preliminary clinical data, the development status of the Company’s product candidates, the Company’s plans for future data presentations, its anticipated achievement of milestones, including determination of proof of concept and its financial guidance regarding the period in which it will have capital available to fund its operations. All statements, other than statements of historical facts, contained in this presentation, 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; whether preliminary or interim results from a clinical trial will be predictive of the final results of the trial; 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 presentation 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


Slide 3

Two wholly owned clinical programs: CPI-0610 (BET) and CPI-1205 (EZH2) Constellation Highlights CPI-0610 has possible disease-modifying effects in myelofibrosis CPI-1205 has been well tolerated and active in clinical studies in combination with ARS inhibitors in prostate cancer Data updates in Q2 2019 for both programs with additional updates in 2H 2019 CPI-0209 expands the potential of our EZH2 franchise Robust discovery platform fuels the pipeline


Slide 4

* Metastatic castration-resistant prostate cancer Multiple Near-Term Opportunities for Success Product Candidates Indications Preclinical Phase 1 Phase 2 Phase 3 Milestones BET Inhibitor CPI-0610 2L Myelofibrosis 1L Myelofibrosis Interim data update on 18-20 2L patients in Q2 2019 EZH2 Franchise CPI-1205 2L mCRPC* Ph 2 in combo with abi or enza Phase 1b data at AACR CPI-0209 (2nd Generation) Solid Tumors Initiate Phase 1 in mid-2019 Preclinical Tumor Microenvironment (Undisclosed) Solid Tumors / Heme Malignancies Innate Immunity (Undisclosed) Solid Tumors ProSTAR Trial MANIFEST Trial


Slide 5

Vision for 2019: A Year of Data 2019 Transition into a Late-Stage Oncology Development Company with an Exciting Pipeline of Development and Discovery Programs Generate positive POC and begin planning for pivotal registration studies with CPI-0610 and CPI-1205 Expand our EZH2 franchise by advancing CPI-0209 into clinical trials targeting solid tumors Deliver novel candidates into discovery and development portfolio


Slide 6

Epigenetics: 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


Slide 7

CPI-0610 BET Inhibitor


Slide 8

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


Slide 9

Kleppe et al., 2018 Cancer Cell In Vivo Support for BET Inhibition Enhancing JAK Inhibition in MF BET Inhibitor + Ruxolitinib Led to Synergistic Reduction in Spleen Improved Bone Marrow Fibrosis Score Vehicle 1–2+ JQ1 (BETi) 1+ Ruxolitinib 1+ Combo 0 * * * * Bar graph showing spleen weights (mg) of animals treated for 21 days (vehicle and JQ1) or 28 days (ruxolitinib and combo). n=4–5. *p value <0.05. Data is representative of three independent experiments. 


Slide 10

Potent and selective inhibitor of BET proteins Treated 138 patients in Phase 1 trials of various hematologic malignancies Preliminary clinical activity observed: Potentially disease-modifying in MF (Phase 2) Lymphoma – e.g., ABC-DLBCL (Phase 1) Signals of potential differentiated safety profile Phase 1 data suggest that thrombocytopenia (DLT) may be reversible and non-cumulative Activity seen at range of doses below the MTD CPI-0610 Overview *CR also achieved at lower dose of 40mg QD with a different formulation **Ability to titrate up to 225 mg #Source – Forero-Torres et al. (2017) - Poster at American Society for Hematology 2017 Annual Meeting ^Sources – Amorin et al. (2016) Lancet Haematology, Volume 3, Issue 4 196-204 Selected BET Inhibitors with Published Phase 1 Lymphoma Data 300 200 100 0 Dose – mg (once daily) MTD CPI-0610 INCB057643# OTX-015^ MK-8628^ Active Lymphoma Dose*/MF Ph2 Dose** Active Dose


Slide 11

Suppress Bone Marrow Cells (Megakaryocytes) Driving MF and Reduce Inflammation Mechanism for Potential Disease Modification BET Signaling Differentiation of Myeloid Cells into Megakaryocytes Pro-Inflammatory Cytokines (e.g., IL-8) JAK/STAT Signaling STAT STAT Cytoplasm Nucleus NF-kB Target Genes BETs P P CPI-0610 = Pathway Blocked by CPI-0610


Slide 12

* Constellation Pharmaceuticals estimates; Europe 5 = UK, France, Germany, Italy, Spain Myeloproliferative Neoplasm Leading to Bone Marrow Fibrosis and Impaired Hematopoiesis Myelofibrosis (MF) Background Ruxolitinib (Jakafi®**) Only Approved Therapy Ruxolitinib primarily provides symptomatic relief (spleen and systemic symptoms) No approved therapy in 2L disease Increased anemia and transfusion dependence Inadequate response in the majority of 1L patients Lack of disease-modifying effects Spleen Volume Systemic Symptoms Anemia & Transfusion Dependence Bone Marrow Fibrosis Market Size Treatment Paradigm Hallmarks of Myelofibrosis Significant Unmet Need 17 to 20K* Patients US 16 to 18K* Patients Europe 5 Preliminary Data Suggest Improvements with CPI-0610 Treatment ** Registered trademark of Incyte Corporation


Slide 13

Unmet Needs of MF Patients and Potential Value Proposition for CPI-0610 Increased Rate of Transfusion Dependence* Low Response Rate in 2L Patients** Majority of 1L Patients Do Not Respond* Convert to Transfusion Independence 2L Transfusion-Dependent Patients 2L Non-Transfusion-Dependent Patients Decrease Spleen Volume, Symptoms and Other Disease-Modifying Parameters 1L Patients Increase Rate of Spleen/Symptom Score Improvement (Combo with Ruxolitinib) Rate of Transfusion Dependence (%) Momelotinib Group (n=70) BAT Group (n=39) 7% Spleen Response 6% Spleen Response Spleen Volume from Baseline (%) Spleen Volume from Baseline (%) 26.5% Spleen Response 29% Spleen Response Momelotinib (n = 184) Ruxolitinib (n = 204) Non-responders * SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis. Mesa, R., et al. J Clin Oncol 2017: 35(34):3844-3850. ** Momelotinib Versus Best Available Therapy in Patients with Myelofibrosis Previously Treated with Ruxolitinib (Simplify 2): A Randomised, Open-Label, Phase 3 Trial. Harrison, C., et al. Lancet Haematol. 2018 Feb;5(2):e73-e81.


Slide 14

* 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 = ~ 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 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


Slide 15

Data cutoff December 10, 2018 MANIFEST: Data Update on First Four 2L MF Patients Treated Spleen Size Reduced in All Patients as Measured by MRI Best Spleen Response Reduced spleen size Symptom improvement One patient with thrombocytosis and one patient transfusion-dependent at baseline – both resolved for > 1 year Ongoing >16 months Ongoing >12 months CPI-0610 + Ruxolitinib COMBINATION CPI-0610 MONOTHERAPY


Slide 16

Data cutoff December 10, 2018 Transfusion Independence and Improved Anemia and Platelet Count in Rux-Resistant Patient Potential Improvement in Hematopoiesis After CPI-0610 Treatment Patient treated with CPI-0610 + ruxolitinib combination therapy No Transfusions for ≥ 52 Weeks Transfusions 4 wks 4 wks 4 wks 6 wks 2 1 2 1 1 Units of Blood Transfused


Slide 17

Data cutoff December 10, 2018 Increasing Trends in Hemoglobin Levels in First Four Patients Treated Potential for Improved Hematopoietic Function


Slide 18

Baseline Baseline Cycle 17 Cycle 17 CPI-0610 as a Monotherapy Correlates with Improved Bone Marrow Fibrosis* *Reticulin stain; Not yet confirmed by central review MF Grade 3 MF Grade 2 MF Grade 2 MF Grade 1 Patient #3 Heavily Pre-Treated, ASXL1 and CALR Mutation Patient #4 Heavily Pre-Treated, ASXL1 and JAK2 Mutation Evidence of Reduced Fibrosis Evidence of Reduced Fibrosis


Slide 19

Deliver a therapy that can achieve disease modification as a monotherapy or in combination with JAK inhibitors Conversion of TD to TI Spleen volume reduction Symptom improvement Additional support: Reduced anemia Improvement in fibrosis grade Biomarkers: Cytokine levels and allelic burden MF as Rapid Path to First Approval for CPI-0610 ** Registered trademark of Incyte Corporation Ruxolitinib (Jakafi®**) primarily provides symptomatic relief (spleen and systemic symptoms) Inadequate response in majority of 1L patients No approved therapy in 2L disease Increased anemia and transfusion dependence Spleen Volume Systemic Symptoms Anemia & Transfusion Dependence Bone Marrow Fibrosis Hallmarks of Myelofibrosis Significant Unmet Needs Goal for CPI-0610 in MF On Track for Discussion with Regulatory Authorities in 2019 on Potential Path Forward


Slide 20

CPI-1205 and CPI-0209 EZH2 Franchise


Slide 21

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 that create a functional dependency on EZH2 Regulation of Immune Cells: EZH2 reprograms T cells to suppress an anti-tumor immune response


Slide 22

Yu et al., Cancer Research 2007 *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 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 Pro-Tumor Signaling Coregulators Prostate Tumor Growth AR AR Synergistically Enhances AR Signaling EZH2


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*Bradley, WD, et al., ”EZH2 Inhibition as an Effective Treatment for Metastatic Castration-Resistant Prostate Cancer,” presentation at 2018 EORTC/NCI/AACR meeting EZH2 Synergy with Androgen Receptor Signaling (ARS) CPI-1205 Intensifies Gene Expression Effects 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 Synergy


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Current Treatment Paradigm in mCRPC mCRPC 1st Line Abiraterone or Enzalutamide 2nd Line Enzalutamide or Abiraterone (Poor Activity) 3rd Line Chemotherapy or Palliative Care EZH2 inhibition may enhance the activity of ARS inhibitors and reduce need for chemotherapy Pre-Metastatic Prostate Cancer May Expand Future CPI-1205 Opportunity ARSi Moving Upstream


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*ASCO 2018 Poster Khalaf, et al. (Kim Chi lab) 2L mCRPC Patients Treated with Abiraterone or Enzalutamide Suffer Poor Response Rate and Short Time to Progression* GOAL Treat with CPI-1205 combination therapy to achieve deeper and more durable responses > PSA30 = 6% > PSA50 = 4% > PSA80 = 0% TTP = 1.6 months > PSA30 = 43% > PSA50 = 31% > PSA80 = 10% TTP = 2.7 months Abiraterone + prednisone Enzalutamide


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Note: In ProSTAR, abiraterone is dosed in combination with prednisone Phase 2 Expanded to Include Enzalutamide and Abiraterone ProSTAR Trial Design Testing Biomarkers for Patient Enrichment Enzalutamide + CPI-1205 (Progressed on Abiraterone) n = ~ 35 Enzalutamide Alone (Progressed on Abiraterone) n = ~ 35 vs. Primary endpoints: MTD, RP2D Primary endpoint: Response rate PSA reduction, CTC reduction, ORR Enzalutamide + CPI-1205 (Prior Abiraterone Progression) Abiraterone + CPI-1205 (Prior Enzalutamide Progression) Phase 1b Phase 2 CPI-1205 + Abiraterone (Progressed on Enzalutamide) n = ~ 30 Initiated


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*Expansion cohort in advanced prostate cancer initiated to evaluate potential anti-tumor activity ProSTAR Update May 25, 2018 Data Recap 2 of 6 evaluable patients achieved PSA reduction of >80% 2 of 4 evaluable patients with CTCs achieved CTC reduction of >30% 2 of 2 evaluable patients had metastatic disease improve Compassionate use patient*: PSA80 and reduction in tumor size Current Enrollment Status 36 patients enrolled in ProSTAR Phase 1b across both arms PSA80, improvement in metastatic disease, and CTC reduction seen Phase 2 portion of trial initiated Next Steps Targeting presentation of Phase 1b data at AACR Initial update for Phase 2 data in 2H 2019 C1D1 C4D1


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*Continued on CPI-1205 monotherapy after cycle 1 Resolution of Bone Metastases Baseline Cycle 4 Day 1 CPI-1205 + Enzalutamide* Example Patient 1


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Objective Response by CT Scan February 2018 Baseline: December 2017 CPI-1205 + Enzalutamide Example Patient 2


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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. Expansion cohort in advanced prostate cancer initiated to evaluate potential anti-tumor activity


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CPI-1205 EZH2 Franchise Summary Preclinical synergy with androgen receptor signaling (ARS) inhibitors ProSTAR Phase 1b demonstrates well-tolerated combinations and evidence of activity with either enzalutamide or abiraterone ProSTAR Phase 2 started Best-in-class potential with more comprehensive coverage of EZH2 Broad application, including large patient populations across several solid tumors Single-agent and combination activity preclinically First-in-human studies planned for mid-2019 CPI-0209


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Lymphoma Xenograft – Mutated EZH2 Model Once-Daily Treatment Resulted in Rapid and Durable Tumor Regression CPI-0209: Second-Generation EZH2 Inhibitor CPI-0209 May Provide More Comprehensive EZH2 Coverage, Expanding Addressable Populations Cessation of treatment Prostate Cancer Xenograft – ARV7+ Model Vehicle CPI-0209, 25 mg/kg oral, once daily


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Discovery Platform Fueling the Pipeline Innate Adaptive Alter 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


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Financial/Operational Strength


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Potential Value Creation Catalysts 2019 –Year of Data 2018 –Year of Execution 1H 2018 Complete crossover financing Expand enrollment in ProSTAR Initiate ORIOn-E Select 2nd generation EZH2 inhibitor candidate (CPI-0209) 2H 2018 Complete IPO Additional active sites in US, Canada / EU for CPI-0610 in myelofibrosis Initiate Phase 2 portion of ProSTAR trial 1H 2019 ORIOn-E safety and recommended Phase 2 dose (RP2D) CPI-1205 – Update from Phase 1b portion of ProSTAR trial at AACR on April 1 CPI-0610 – Interim update from MANIFEST Phase 2 trial at Q2 2019 medical meeting Initiate Phase 1 for CPI-0209 2H 2019 CPI-1205 - Interim update from Phase 2 portion of ProSTAR CPI-0610 – Additional update from MANIFEST trial


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Cash and cash equivalents as of December 31, 2018, of $114.6 million Post-IPO cash expected to fund operations into Q2 2020, including: Ongoing clinical trials to determine efficacy and safety of CPI-1205 and CPI-0610 necessary to begin pivotal trials Continued advancement of CPI-0209 Ongoing support for robust discovery/preclinical pipeline Crossover financing round in April 2018 and IPO in July 2018 raised $160 million from high-quality investors Strong Cash Position $ Millions, Except Per-share Amounts FY18 FY17 R&D Expenses $48.8 $32.6 G&A Expenses $12.5 $6.5 Other Income, Net $1.3 $3.7 Net Loss Attributable to Common Stockholders ($59.9) ($53.8) Net Loss Per Share Attributable to Common Stockholders ($5.00) ($56.10)


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Management Team Jigar Raythatha President and CEO Emma Reeve Chief Financial Officer Adrian Senderowicz, M.D. Chief Medical Officer Patrick Trojer, PhD Chief Scientific Officer Brad Prosek SVP, Corporate Development 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 Scott Braunstein, M.D., Aisling Capital 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