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): May 8, 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.  ☐

Securities registered or to be registered pursuant to Section 12(b) of the Act.

 

Title of each class

 

Trading

Symbol(s)

 

Name of each exchange

on which registered

Common Stock, par value $0.0001   CNST   Nasdaq Global Select Market

 

 

 


Item 7.01

Regulation FD Disclosure.

On May 8, 2019, Constellation Pharmaceuticals, Inc. (the “Company”) issued a press release entitled “Constellation Pharmaceuticals Announces First-Quarter 2019 Financial Results.” A copy of the press release is attached hereto as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.

On May 8, 2019, the Company posted a Corporate Overview presentation on the “Investors & Media” section of the Company’s website (www.constellationpharma.com). The information contained in, or that can be accessed through, the Company’s website is not a part of this filing. 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 99.1 and 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

 

99.1    Press Release dated May 8, 2019 (furnished herewith)
99.2    Corporate Overview dated May 2019 (furnished herewith)


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: May 8, 2019                          By:  

/s/ Jigar Raythatha

    Name:   Jigar Raythatha
    Title:   Chief Executive Officer
EX-99.1

Exhibit 99.1

Constellation Pharmaceuticals Announces First-Quarter 2019 Financial Results

 

   

Company to present an interim update of data from the MANIFEST clinical trial of CPI-0610 at ASCO on June 3 and at EHA on June 15

 

   

Related investor event at ASCO to be held on June 4

CAMBRIDGE, Massachusetts, May 8, 2019 – Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, announced its first-quarter 2019 financial results today.

“2019 is a year of data for Constellation,” said Jigar Raythatha, President and Chief Executive Officer of Constellation Pharmaceuticals. “We look forward to an exciting year ahead, as we continue to see strong enrollment trends and expect multiple clinical readouts throughout the year for both CPI-0610 in myelofibrosis (MF) and CPI-1205 in prostate cancer.

“We look forward to presenting an interim update of data from the Phase 2 MANIFEST clinical trial for CPI-0610 in a poster presentation at ASCO and an oral presentation at EHA in June,” Mr. Raythatha continued. “We believe these data will support the view that CPI-0610 has the potential to be a disease-modifying agent in MF. Additionally, we expect to provide further data readouts on both CPI-0610 and CPI-1205 in the second half of 2019.

“Our vision is to become a late-stage oncology development company in 2020, with an exciting pipeline of development and discovery programs that have the potential to bring important new medicines to underserved cancer patients,” Mr. Raythatha concluded.

Medical Presentations

Constellation plans to present a poster providing an interim update of data from the MANIFEST clinical trial of CPI-0610 at the American Society for Clinical Oncology (ASCO) annual meeting at 9:00 AM EDT/8:00 CDT on June 3. In addition, Dr. Ronald Hoffman of Mt. Sinai Health System, an investigator in the MANIFEST trial, will make an oral presentation providing an interim


update of data at the European Hematology Association (EHA) annual meeting at 12:15 PM CEST/6:15 AM EDT on June 15. Data to be presented at these events were generated from 44 patients enrolled as of April 17, 2019. Twelve patients received 24-week assessments and 16 patients received 12-week assessments. The Company plans to report data for these patients based on the following parameters: spleen volume reduction; total symptom score improvement; hematologic parameters such as increased hemoglobin and conversion to transfusion independence; bone marrow fibrosis improvement; and safety.

Investor Event

The Company will also host an analyst/investor meeting, with an accompanying conference call and webcast, to discuss the interim update of data at Hyatt McCormick Place in Chicago at 8:00 AM EDT/7:00 AM CDT on June 4. The agenda of the meeting will include an overview of MF, the potential impact of CPI-0610 on MF, review of the interim update of data from MANIFEST, and a panel discussion with Dr. Srdan Verstovsek of MD Anderson Cancer Center, an investigator in the MANIFEST trial, and Dr. Raajit Rampal of Memorial Sloan Kettering Cancer Center. Additional details about this event will be announced at a later date.

Recent News

 

 

Provided data update of MANIFEST clinical trial at J.P. Morgan Healthcare Conference. In a press release on January 3 and a presentation at the J.P. Morgan Healthcare Conference on January 9, Constellation provided an interim update of data on the Phase 2 MANIFEST clinical trial of CPI-0610. As disclosed in that presentation, each of the first four ruxolitinib-resistant MF patients in MANIFEST remained on study as of December 10, 2018. Two patients were treated with a combination of CPI-0610 and ruxolitinib for over 16 months, and two patients were treated with CPI-0610 monotherapy for over 12 months. Each of these four patients showed a reduction in spleen volume, symptom improvement, and an increased hemoglobin level. One of the combination therapy patients, who was transfusion dependent before therapy, converted to being transfusion independent after CPI-0610 was added to the ongoing regimen. Additionally, bone marrow biopsies before and after treatment were analyzed for the two patients on monotherapy, and both demonstrated a one-grade improvement in bone marrow fibrosis score and associated improvements in hemoglobin and platelets. Taken together, these results suggest that CPI-0610 may be modifying the underlying course of the disease in these ruxolitinib-resistant MF patients.


 

Presented ProSTAR results at AACR. On April 1, Constellation presented results from the Phase 1b portion of the ProSTAR clinical trial of CPI-1205 at the American Association for Cancer Research annual meeting. These results showed clinical activity in subsets of a heterogeneous population of advanced mCRPC patients in combination with either abiraterone or enzalutamide. All PSA responses seen in the trial were ³80%, deeper than the ³50% reduction endpoint in the trial. The majority of patients with measurable lesions achieved durable disease control during the study. For more details, please review the poster on our website here.

The Company initiated the Phase 2 portion of the trial in late 2018 to better define the patient populations most likely to benefit from CPI-1205. The Company looks forward to reporting initial Phase 2 data in the second half of 2019.

 

 

Expanded Board of Directors. In February, Constellation announced the appointment of Dr. Scott Braunstein to its Board of Directors. Dr. Braunstein brings a track record of growing emerging and established biopharmaceutical companies as a board member, pharmaceutical executive, and investor.

 

 

Enhanced Management Team. Also in February, Constellation announced the appointment of Jessica Christo as Senior Vice President and Chief Product Development Officer. Ms. Christo has 25 years of product development experience in the biopharmaceutical industry. Most recently, she was Senior Vice President of Development Operations at Verastem Oncology, where she had broad clinical and regulatory responsibilities and contributed to the approval of COPIKTRATM.

First Quarter 2019 Financial Results

 

 

Cash, cash equivalents, and marketable securities as of March 31, 2019, increased 1.0% compared to December 31, 2018, to $115.8 million due to proceeds from a $20 million term loan led by Hercules Capital, which approximately offset operating expenses in the quarter.

 

 

Research and development (R&D) expenses increased 58.8% year over year to $15.7 million in the first quarter of 2019 mainly due to increased clinical trial expenses.


 

General and administrative (G&A) expenses grew 92.3% year over year to $4.4 million in the first quarter of 2019, primarily due to personnel-related and facility-related costs in connection with expanding the support functions of 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 60.5% year over year to $19.4 million mainly due to increases in G&A and R&D expenses. The net loss per share attributable to common stockholders decreased 94.0% to $0.75 per share for the first quarter of 2019 due to an increase in shares outstanding as a result of the initial public offering in 2018 and conversion of preferred stock to common stock.

Financial Guidance

The Company expects that cash, cash equivalents and marketable securities as of March 31, 2019, will fund operating expenses and capital expenditure requirements into the third quarter of 2020.

Anticipated Milestones

The Company anticipates achieving the following milestones during 2019:

First Half 2019

 

 

Provide an interim update of data from the MANIFEST Phase 2 trial of CPI-0610 at ASCO and EHA

 

 

Complete an investigational new drug (IND) filing 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

 

     Three months ended
March 31,
 

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

   2019     2018  

Revenue

   $ —       $ —    

Operating expenses:

    

Research and development

     15,677       9,874  

General and administrative

     4,429       2,303  
  

 

 

   

 

 

 

Total operating expenses

     20,106       12,177  
  

 

 

   

 

 

 

Loss from operations

     (20,106     (12,177

Other income (expense):

    

Interest income

     755       109  

Interest expense

     (75     (34
  

 

 

   

 

 

 

Total other income (expense), net

     680       75  
  

 

 

   

 

 

 

Net loss attributable to common stockholders

     (19,426     (12,102
  

 

 

   

 

 

 

Other comprehensive gain:

    

Unrealized gain on marketable securities

     9       —    
  

 

 

   

 

 

 

Other comprehensive gain

     9       —    
  

 

 

   

 

 

 

Comprehensive loss

     (19,417     (12,102
  

 

 

   

 

 

 

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

   $ (0.75   $ (12.44

Weighted average common shares outstanding, basic and diluted

     25,804,595       972,981  

Constellation Pharmaceuticals, Inc.

Consolidated Balance Sheets

 

(In $ thousands)    March 31,
2019
     December 31,
2018
 

Cash and cash equivalents

   $ 52,447      $ 114,592  

Marketable securities

     63,344        —    

Other current assets

     2,695        2,711  

Total assets

     124,923        118,938  

Current liabilities

     17,121        14,660  

Total liabilities

     38,848        14,780  

Total stockholders’ equity

   $ 86,075      $ 104,158  

Note: Abbreviated financial statements; please refer to Form 10-Q for the first quarter of 2019 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, 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

May 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 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


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 2L patients at ASCO/EHA 2019 EZH2 Franchise CPI-1205 2L mCRPC* Phase 1b data at AACR 2019 Initial Phase 2 data in 2H 2019 CPI-0209 (2nd Generation) Solid Tumors File IND 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


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 potentially differentiated safety profile Phase 1 data suggest that thrombocytopenia (DLT) is dose dependent, reversible and non-cumulative Activity seen at range of doses below the MTD CPI-0610 is a Potential Best-in-Class BET Inhibitor *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

Reduce Inflammation and Suppress Cells in the Bone Marrow That Drive MF (Megakaryocytes) Mechanism of Potential Disease Modification in Myelofibrosis 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

Unmet Need for a Disease-Modifying Therapy That Impacts All Four Hallmarks of MF * Based on preliminary data Hallmarks of Myelofibrosis Spleen Volume Constitutional Symptoms Anemia & Transfusion Dependence Bone Marrow Fibrosis JAKi’s CPI-0610*


Slide 13

Potential Value Proposition for CPI-0610 in Various Patient Segments of MF 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 Aimed at Addressing Unmet Needs MANIFEST: 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 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 Durable 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 stains; 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 Potential Rapid Path to First Approval for CPI-0610 Lack of disease-modifying agents Inadequate response in majority of 1L patients No approved therapy in 2L disease Increased anemia and transfusion dependence Spleen Volume Constitutional Symptoms Anemia & Transfusion Dependence Bone Marrow Fibrosis Hallmarks of Myelofibrosis Significant Unmet Needs Goal for CPI-0610 in MF


Slide 20

Interim update from MANIFEST ASCO poster presentation, June 3, 8:00 AM CDT EHA oral presentation, June 15, 12:15PM CEST Investor meeting/conference call at ASCO, June 4, 7:00 AM CDT Enrollment: 44 patients (as of April 17, 2019) 24-week assessment: 12 patients 12-week assessment: 16 patients Update to include: spleen volume reduction, total symptom score, transfusion dependence, bone marrow fibrosis, safety Next Catalyst – MANIFEST Update


Slide 21

CPI-1205 and CPI-0209 EZH2 Franchise


Slide 22

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 23

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


Slide 24

*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


Slide 25

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


Slide 26

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 *ASCO 2018 Poster Khalaf, et al. (Kim Chi lab)


Slide 27

Note: In ProSTAR, abiraterone is dosed in combination with prednisone Phase 2 Initiated ProSTAR Trial Design Enzalutamide + CPI-1205 (Progressed on Abiraterone) n ~ 35 Enzalutamide Alone (Progressed on Abiraterone) n ~ 35 vs. Primary endpoint: Response rate PSA reduction, CTC reduction, ORR Enzalutamide + CPI-1205 (Prior Abiraterone Progression) Abiraterone + CPI-1205 (Prior Enzalutamide Progression) Phase 1b – Advanced mCRPC Phase 2 – 2L mCRPC Patients Only CPI-1205 + Abiraterone (Progressed on Enzalutamide) n ~ 30 Initiated Initiated Initiated Primary endpoints: MTD, RP2D Results presented at AACR Testing Biomarkers for Patient Enrichment


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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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CPI-1205 observed to be well-tolerated and clinically active Recommended Phase 2 dose of 800 mg three times daily Patients’ PSA responses tended to be deeper (e.g., PSA80) and more durable than expected with ARSi alone Activity observed in combo with abiraterone, which has poor 2L responses, or enzalutamide and in AR-V7-negative patients CPI-1205 + abiraterone: PSA80: 2/18 (11%) of all patients PSA80: 2/10 (20%) of AR-V7-negative patients ORR: **DCR = 6/8 (75%) or **DCR ≥ 3 months = 4/8 (50%) CPI-1205 + enzalutamide: PSA80: 3/16 (19%) of all patients PSA80: 3/11 (27%) of AR-V7 negative patients ORR: PR = 1/5 (20%) **DCR = 3/5 (60%) or **DCR ≥ 3 months = 3/5 (60%) ProSTAR Phase 1b Conclusions* *Please see poster CT094/18, which was presented at AACR on April 1, 2019, in the Investors & Media/Presentations section of http://www.constellationpharma.com **Disease Control Rate (DCR): Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) Cycle 1 Day 1 Cycle 4 Day 1 Initial update for Phase 2 data in 2H 2019 medical meeting Resolution of bone metastases in patient on CPI-1205 + enzalutamide for one month followed by CPI-1205 monotherapy for two months


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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 IND filing 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 Activate additional sites in US, Canada / EU for CPI-0610 in myelofibrosis Initiate Phase 2 portion of ProSTAR trial 1H 2019 CPI-1205 – Determine ORIOn-E safety and recommended Phase 2 dose (RP2D) CPI-1205 – Provide update from Phase 1b portion of ProSTAR trial at AACR on April 1 CPI-0610 – Provide interim update from MANIFEST Phase 2 trial CPI-0209 – File IND for CPI-0209 2H 2019 CPI-1205 – Provide interim update from Phase 2 portion of ProSTAR CPI-0610 – Provide additional update from MANIFEST trial


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Cash and cash equivalents and marketable securities as of March 31, 2019, of $115.8 million Current cash expected to fund operations into Q3 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 Support for robust discovery/preclinical pipeline Crossover financing round in April 2018 and IPO in July 2018 raised $160 million from high-quality investors Venture debt of $20 million raised in March 2019; $20 million more available in part upon achievement of milestones Strong Cash Position $ Millions, Except Per-Share Amounts 1Q19 1Q18 R&D Expenses $15.7 $9.9 G&A Expenses $4.4 $2.3 Other Income, Net $0.7 $0.1 Net Loss Attributable to Common Stockholders ($19.4) ($12.1) Net Loss Per Share Attributable to Common Stockholders ($0.75) ($12.44)


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Management Team Jigar Raythatha President and CEO Emma Reeve SVP & Chief Financial Officer Adrian Senderowicz, M.D. SVP & Chief Medical Officer Patrick Trojer, PhD SVP & Chief Scientific Officer Karen Valentine SVP, Chief Legal Officer & General Counsel Jessica Christo SVP & Chief Product Development Officer Brad Prosek SVP, Corporate Development 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 Medicine Board of Directors Founders & Scientific Advisory Board Mark Goldsmith, M.D., Ph.D. (Chairman), Revolution Medicines Jigar Raythatha Jim Audia, Ph.D., Chicago Biomedical Consortium Scott Braunstein, M.D., BOD – Esperion, Trevena, Ziopharm, Marinus Tony Evnin, Ph.D., Venrock Steven Hoerter, Deciphera Pharmaceuticals Peter Svennilson, The Column Group Bob Tepper, M.D., Third Rock Ventures Elizabeth Tréhu, M.D., Jounce Therapeutics