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 16, 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))

Securities registered pursuant to Section 12(b) of the Act:

 

Title of each class

 

Trading

Symbols(s)

 

Name of each exchange

on which registered

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

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 7.01

Regulation FD Disclosure.

On May 16, 2019, Constellation Pharmaceuticals, Inc. (the “Company”) issued a press release entitled “Constellation Pharmaceuticals Provides Interim Update of Data for CPI-0610 in ASCO and EHA Abstracts.” 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 16, 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.

On May 16, 2019, an abstract titled CPI-0610, a Bromodomain and Extraterminal Domain (BET) Inhibitor, Reduces Pro-Inflammatory Cytokines, Bone Marrow Fibrosis and the Number of Transfusions in Myelofibrosis Patients, which had been submitted by Constellation Pharmaceuticals, Inc. to the European Hematology Association (EHA) in connection with the 2019 EHA Annual Meeting on June 13-16, 2019 in Amsterdam, was published by EHA. A copy of the abstract is attached hereto as Exhibit 99.3 to this Current Report on Form 8-K and is incorporated herein by reference.

The information in this Item 7.01, including Exhibits 99.1, 99.2, and 99.3 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 16, 2019
99.2    Corporate Overview Dated May 16, 2019 (furnished herewith)
99.3    Abstract published by EHA titled CPI-0610, a BromoDomain and Extraterminal Domain (BET) Inhibitor, Reduces Pro-Inflammatory Cytokines, Bone Marrow Fibrosis and the Number of Transfusions in Myelofibrosis Patients (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 16, 2019     By:  

/s/ Jigar Raythatha

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

Exhibit 99.1

Constellation Pharmaceuticals Provides Interim Update of Data for CPI-0610 in ASCO and EHA Abstracts

 

   

Data published in two abstracts suggest that CPI-0610 may have potential disease-modifying effects in treating myelofibrosis

 

   

All ten evaluable patients experienced spleen volume reductions

 

   

Improvements in symptom scores, bone marrow fibrosis, and hemoglobin levels also seen

 

   

Two transfusion dependent patients became transfusion independent

 

   

Additional data based on a more recent data cut will be presented at ASCO on June 3 and EHA on June 15

CAMBRIDGE, Massachusetts, May 16, 2019 – Constellation Pharmaceuticals, Inc. (Nasdaq: CNST) today announced that two abstracts relating to the MANIFEST clinical trial of CPI-0610 for myelofibrosis – one in association with the American Society for Clinical Oncology (ASCO) annual meeting and the other in association with the European Hematology Association (EHA) annual meeting – published online. The abstracts include an analysis based on a data cutoff of January 17, 2019, from 18 enrolled patients. Upcoming presentations at ASCO and EHA will reflect an analysis of a larger patient population based on a data cutoff of April 17, 2019.

MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating CPI-0610, either as a monotherapy or in combination with ruxolitinib, in a second-line setting in patients with MF who are refractory to or intolerant of or have relapsed or lost response to ruxolitinib. Patients in the two second-line arms are being stratified based on transfusion dependent status. The primary endpoint for the cohorts with transfusion-dependent patients is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for the patients who were non-transfusion dependent at baseline is spleen volume reduction. In addition, the Company added a third arm designed to evaluate treatment with CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK 1/2-inhibitor-naïve MF patients.


Data Highlights From Abstracts

Below are highlights of data on second-line patients in the ASCO and EHA abstracts, which published on May 15 and May 16, respectively.

 

   

Spleen volume reductions as measured by MRI occurred in all ten evaluable patients and ranged from 6% to 44%.

 

   

Symptom improvements were observed.

 

   

Out of the four patients who received bone marrow assessments, three had a one-grade improvement in bone marrow fibrosis and had hemoglobin increases of ³1.5 g/dL for ³12 weeks without transfusions. The fourth patient had a one-grade improvement in the bone marrow reticulin score. All of these score improvements were based on a scale of 0-3.

 

   

Two of the four patients with bone marrow assessments were transfusion dependent at baseline, and both of these patients became transfusion independent.

 

   

Hemoglobin increases of ³1.5 g/dL occurred in both of two evaluable patients on monotherapy and three of nine patients on the combination with ruxolitinib.

 

   

CPI-0610, both as monotherapy and in combination with ruxolitinib, was generally well tolerated. The most common side effects were Grade 1 / 2 diarrhea, nausea / vomiting, and reversible and non-cumulative thrombocytopenia.

“Interim data from the MANIFEST trial indicate that CPI-0610 has been generally well-tolerated, with promising therapeutic activity for the treatment of myelofibrosis,” said Adrian Senderowicz, Chief Medical Officer at Constellation Pharmaceuticals. “In addition to spleen and symptom improvement in these refractory patients, we are pleased to see an array of clinical data suggesting the potential for disease-modifying effects, such as improved hematopoietic function, conversion to transfusion independence, and improvement in bone marrow fibrosis. We look forward to providing further updates of the MANIFEST trial at both ASCO and EHA.”

ASCO Poster Presentation

TITLE: A Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Protein Inhibitor (BETi) alone or with Ruxolitinib (RUX), in Patients with Myelofibrosis (MF)

Poster Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant


Date and Time: Monday, June 3, 2019, 8:00 AM CDT (9:00 AM EDT)

Dr. Marina Kremyanskaya of the Mount Sinai School of Medicine, an investigator in the MANIFEST clinical trial, will present a poster with updated details of interim data at the American Society for Clinical Oncology (ASCO) annual meeting. The data to be presented in the poster were gathered from 44 patients enrolled as of April 17, 2019. Twelve patients received 24-week assessments and 16 patients received 12-week assessments. Among the parameters being assessed were spleen volume reduction, total symptom scores, transfusion dependence, bone marrow fibrosis, and safety.

EHA Oral Presentation

TITLE: CPI-0610, A Bromodomain and Extraterminal Domain (BET) Inhibitor, Reduces Proinflammatory Cytokines, Bone Marrow Fibrosis and the Number of Transfusions in Myelofibrosis Patients

Session: New Agents in MPN

Date and Time: June 15, 12:15 PM CEST (6:15 AM EDT)

Dr. Ronald Hoffman of Mt. Sinai Health System, an investigator in MANIFEST, will make an oral presentation on these updated interim data at the European Hematology Association (EHA) annual meeting on June 15 at 12:15 PM CEST.

Investor Event. Constellation will also host an investor meeting and conference call to discuss these interim data on June 4 at 7:00 AM CDT. This event will include participation by Dr. Srdan Verstovsek, a medical oncologist at the University of Texas MD Anderson Cancer Center who is an investigator in the MANIFEST trial, and Dr. Raajit Rampal, hematologic oncologist at Memorial Sloan Kettering Cancer Center. Details will be announced later.

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

May 16, 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 EZH2 Franchise CPI-1205 2L mCRPC* Phase 1b data at AACR Initial Phase 2 data in 2H 2019 CPI-0209 (2nd Generation) Solid Tumors File IND in mid-2019 Preclinical Tumor Targeted (Undisclosed) Solid Tumors / Heme Malignancies Tumor Microenvironment Targeted (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: 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 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

Best spleen volume reductions as measured by MRI occurred in all ten evaluable patients and ranged from 6% to 44% Symptom improvements were also observed Out of the four patients who received bone marrow assessments, three had a one-grade improvement in bone marrow fibrosis and had hemoglobin increases of ≥1.5 g/dL for ≥12 weeks without transfusions. The fourth patient had a one-grade improvement in the bone marrow reticulin score. Two of the four patients with bone marrow assessments were transfusion dependent at baseline, and both of these patients became transfusion independent. Hemoglobin increases of ≥1.5 g/dL occurred in both of two evaluable patients on monotherapy and three of nine patients on the combination with ruxolitinib CPI-0610, both as monotherapy and in combination with ruxolitinib, was generally well tolerated Summary of Data Update in ASCO/EHA Abstracts


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

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 22

CPI-1205 and CPI-0209 EZH2 Franchise


Slide 23

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 24

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 25

*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 26

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 27

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 28

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


Slide 29

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


Slide 30

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


Slide 31

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


Slide 32

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

EX-99.3

Exhibit 99.3

Abstract Submission

16. Myeloproliferative neoplasms - Clinical

EHA-1821

CPI-0610, A BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) INHIBITOR, REDUCES PRO- INFLAMMATORY CYTOKINES, BONE MARROW FIBROSIS AND THE NUMBER OF TRANSFUSIONS IN MYELOFIBROSIS PATIENTS

Ronald Hoffman* 1, 2, John Mascarenhas1, 2, Marina Kremyanskaya1, 2, Prithviraj Bose3, Vikas Gupta4, Gary Schiller5, Elena Liew6, Anna Godfrey7, Jennifer Mertz8, Jessica Piel8, Patrick Trojer8, Claudia Lebedinsky8, Adrian Senderowicz8, Sujan Kabir8, Jeffrey Supko9, Srdan Verstovsek3

1Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 2 Myeloproliferative Neoplasm Research Consortium (MPN-RC), New York, 3Department of Leukemia, MD Anderson Cancer Center, Houston, United States, 4Princess Margaret Hospital, Toronto, Canada, 5University of California, Los Angeles, United States, 6University of Alberta, Alberta, Canada, 7Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom, 8Constellation Pharmaceuticals, Cambridge, 9Massachusetts General Hospital, Boston, United States

Does the study abide by applicable national and international regulations and guidelines, including but not limited to ethical committees, data protection and privacy regulations, informed consent and off-label use of drugs?: Yes Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with a cytokine (CK) milieu that leads to bone marrow (BM) fibrosis. Ruxolitinib (RUX) is the only approved therapy for MF, but patients (pts) can eventually relapse/have inadequate response. RUX can also worsen anemia and pts may require transfusions. BET proteins are transcriptional regulators that control key oncogenic pathways, including NF-kB, MYC, and BCL2 and TGFß signaling, an important driver of fibrosis. Preclinical studies suggest that a combination of a BET inhibitor (BETi) and RUX results in a synergistic reduction of the hallmarks of MF: splenomegaly, BM fibrosis and the mutant (MUT) allele burden (Kleppe 2018). CPI-0610 is a selective and potent BETi that impacts megakaryocyte differentiation (unpublished data), cells responsible for pro-inflammatory CK production and is currently being evaluated in MF, alone or in combination with RUX in a clinical trial with 3 arms: CPI-0610 alone (Arm 1), CPI-0610+RUX in pts exposed to RUX/with an inadequate response to RUX (Arm 2), or CPI-0610+RUX in JAKi naïve pts with anemia (Arm 3). Arm 1 and 2 are stratified between transfusion dependence (TD) and splenomegaly at baseline.

Aims: Phase 2 study to assess CPI-0610 alone or “add-on” to RUX in MF pts. Primary endpoints: conversion of TD to transfusion independence (TI), spleen volume response, patient reported outcomes, safety and PK. Additional endpoints include: changes in pro-inflammatory CK levels, BM fibrosis and MUT profiling.

Methods: Pt samples were used to analyze CK levels, MUT profiles and BM fibrosis. CK analyses utilized Myriad-RBM InflammationMAP and CustomMAP and MUT analysis utilized the Rapid Heme Panel (Kluk, 2016).

Results: 23 pts were accrued to this multi-center study, with 18 pts analyzed: MUT profiles which revealed the following MUT: 11 ASXL1(61%), 10 JAK2(56%), 6 CALR (33%) and 2 MPL(11%). 10 pts (56%) had at least 3 MUTs and 17 pts (94%) had at least one driver MUT (JAK2, CALR or MPL). 1 pt (6%) was triple negative and 12 pts (67%) had a high MUT profile (HMR). Baseline CK levels were elevated, in pts who failed/inadequate response to RUX. CPI-0610 at a starting dose of 125 mg QD (days 1-14 of 21-day cycle) reduced CK levels in both monotherapy and combination arms. Suppression of IL-18 was observed in all pts analyzed (n=8) with >50% decrease in 4/8 pts. Trends were also observed for a number of other CK, including IL-8 and CRP. CK inhibition was sustained over multiple cycles of CPI-0610 (combination/monotherapy). Best spleen volume reduction ranged from 6-44% in 10 pts. Out of the 4 pts with BM assessments (pre and at least 1 post), 2 were TD at baseline. Three pts had one grade improvement in BM fibrosis (1 at 6 mth, 2 at 1 yr) and had Hgb increases of ³1.5 g/dL for ³12 weeks without transfusions. The other pt had a 1 grade improvement in the BM reticulin score (at 6 mth). Moreover, both of the TD pts became TI. Hepcidin levels and PK will be presented. The most common adverse events were Grade 1/2 diarrhea, nausea/vomiting and reversible and non-cumulative thrombocytopenia.


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Summary/Conclusion: CPI-0610 alone or in combination with Rux demonstrates encouraging clinical activity (spleen responses, conversion to TI and improvement in BM fibrosis) with good tolerability. Assessment of CK levels suggest that CPI-0610 therapy durably reduces pro-inflammatory CK. Notably, levels of individual CK were reduced to levels observed in normal healthy donors and were maintained during treatment. Genomic profiling data shows that majority of pts had HMR MUT at baseline. Updated data will be presented.

Keywords: Bone Marrow Fibrosis, Cytokine, Epigenetic, Myelofibrosis