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): August 7, 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

Symbol(s)

 

Name of each exchange

on which registered

Common Stock, $0.0001 par value per share   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 August 7, 2019, Constellation Pharmaceuticals, Inc. (the “Company”) issued a press release entitled “Constellation Pharmaceuticals Announces Second-Quarter and Six-Month 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 August 7, 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 August 7, 2019 (furnished herewith)
99.2    Corporate Overview dated August 7, 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: August 7, 2019     By:  

/s/ Jigar Raythatha

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

Exhibit 99.1

Constellation Pharmaceuticals Announces Second-Quarter and Six-Month 2019 Financial Results

 

   

Data presented at ASCO and EHA suggest potential disease-modifying activity of CPI-0610 across the spectrum of myelofibrosis (MF) parameters, with multiple potential pathways for approval

 

   

The EZH2 franchise continues to advance: the ProSTAR study of CPI-1205 remains on track, and the IND for CPI-0209 was filed and cleared by the FDA

CAMBRIDGE, Massachusetts, August 7, 2019 – Constellation Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, today announced its second-quarter and six-month 2019 financial results.

“2019 is a year of data for Constellation,” said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals. “We made multiple important data presentations in the second quarter that help to advance our vision of becoming a late-stage oncology development company, with an exciting pipeline of development and discovery programs.

“We look forward to providing further data updates in the second half of 2019 across our pipeline,” Mr. Raythatha continued. “We remain deeply committed to delivering important new medicines to cancer patients around the world in order to reduce their suffering and improve their lives.”

Program Updates

CPI-0610

 

   

Data presented at ASCO and EHA from the MANIFEST study suggest that CPI-0610 may have disease-modifying effects.

 

   

In addition to improvements in spleen volume and constitutional symptoms, the interim data suggest improvements in anemia, transfusion dependence, and bone marrow fibrosis.


   

Our vision for CPI-0610 is to create a differentiated treatment for MF in ruxolitinib-resistant patients and to transform standard of care as a first-line therapy. We have begun planning for pivotal trials.

EZH2 Franchise

 

   

Enrollment for the ProSTAR clinical trial for CPI-1205 continues on track.

 

   

We are enrolling patients in three cohorts:

 

   

CPI-1205 + abiraterone in second-line mCRPC;

 

   

CPI-1205 + enzalutamide in second-line mCRPC, randomized against enzalutamide alone; and

 

   

CPI-1205 + enzalutamide in heavily pre-treated patients who have progressed after treatment with each of enzalutamide, abiraterone, and chemotherapy.

 

   

We plan to provide an update for ProSTAR in the fourth quarter and additional data in early 2020.

 

   

The IND for CPI-0209, our second-generation and potentially best-in-class EZH2 inhibitor, was filed and cleared by the FDA.

 

   

CPI-0209 could address additional patient populations beyond those targeted by first-generation EZH2 inhibitors.

Milestones

The Company anticipates achieving the following milestones during the second half of 2019:

CPI-0610 MANIFEST Study

 

   

Update spleen volume, symptom, and anemia data from about 40 ruxolitinib-resistant patients and bone-marrow-fibrosis changes from a subset of patients.

 

   

Update status of conversion from transfusion dependence to transfusion independence from about 16 ruxolitinib-resistant patients.

 

   

Disclose spleen volume and symptom data for 10-15 JAK-inhibitor-naïve (first-line) patients.


EZH2 Franchise

 

   

Dose the first patients in a Phase 1 clinical trial of CPI-0209.

 

   

Provide an update from the ProSTAR clinical trial of CPI-1205 across various patient contexts.

Second Quarter 2019 Financial Results

 

   

Cash, cash equivalents, and marketable securities as of June 30, 2019, were $98.1 million, a decline of 14.4% compared to December 31, 2018, primarily due to operating expenses.

 

   

Research and development (R&D) expenses increased 67.3% year over year to $16.0 million in the second quarter of 2019 mainly due to increased clinical trial expenses.

 

   

General and administrative (G&A) expenses grew 96.5% year over year to $4.9 million in the second quarter of 2019, primarily due to building out the organization of the company.

 

   

The net loss increased 73.9% year over year to $20.8 million for the second quarter of 2019, mainly due to increased R&D and G&A expenses. The net loss per share attributable to common shareholders decreased 92.0% to $0.80 per share 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.

First Half 2019 Financial Results

 

   

Research and development (R&D) expenses increased 63.0% year over year to $31.6 million in the first half of 2019, mainly due to increased clinical trial expenses.

 

   

General and administrative (G&A) expenses grew 94.5% year over year to $9.3 million in the first half of 2019, primarily due to building out the organization of the company.

 

   

The net loss increased 67.2% year over year to $40.2 million for the first half of 2019, mainly due to increased R&D and G&A expenses. The net loss per share attributable to common shareholders decreased 92.9% to $1.56 per share 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

Constellation expects that cash, cash equivalents, and marketable securities as of June 30, 2019, will enable the Company to fund planned operating expenses and capital expenditure requirements until late third-quarter 2020.

Constellation Pharmaceuticals, Inc.

Consolidated Statements of Operations and Comprehensive Loss

 

     Six months ended June 30,     Three months ended June 30,  

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

   2019     2018     2019     2018  

Revenue

   $ —       $ —       $ —       $ —    

Operating expenses:

        

Research and development

     31,632       19,410       15,955       9,536  

General and administrative

     9,315       4,789       4,886       2,486  
  

 

 

   

 

 

   

 

 

   

 

 

 

Total operating expenses

     40,947       24,199       20,841       12,022  
  

 

 

   

 

 

   

 

 

   

 

 

 

Loss from operations

     (40,947     (24,199     (20,841     (12,022

Other income (expense):

        

Interest income

     1,407       377       652       268  

Interest expense

     (653     (221     (578     (187
  

 

 

   

 

 

   

 

 

   

 

 

 

Total other income (expense), net

     754       156       74       81  
  

 

 

   

 

 

   

 

 

   

 

 

 

Net loss attributable to common stockholders

     (40,193     (24,043     (20,767     (11,941
  

 

 

   

 

 

   

 

 

   

 

 

 

Other comprehensive gain

        

Unrealized gain on marketable securities

     11       —         2       —    
  

 

 

   

 

 

   

 

 

   

 

 

 

Total other comprehensive gain

     11       —         2       —    
  

 

 

   

 

 

   

 

 

   

 

 

 

Comprehensive loss

     (40,182     (24,043     (20,765     (11,941
  

 

 

   

 

 

   

 

 

   

 

 

 

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

   $ (1.56   $ (22.12   $ (0.80   $ (9.96

Weighted average common shares outstanding, basic and diluted

     25,807,132       1,086,697       25,809,556       1,199,164  

Constellation Pharmaceuticals, Inc.

Consolidated Balance Sheets

 

(In $ thousands)    June 30,
2019
     December 31,
2018
 

Cash and cash equivalents

   $ 55,043      $ 114,592  

Marketable securities

     43,057        —    

Total current assets

     100,666        117,303  

Total assets

     114,253        118,938  

Current liabilities

     17,201        14,660  

Long-term debt, net of current portion and discount

     19,568        —    

Total liabilities

     47,069        14,780  

Total stockholders’ equity

   $ 67,184      $ 104,158  


About Constellation Pharmaceuticals

Constellation Pharmaceuticals is a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics that address serious unmet medical needs in patients with cancers associated with abnormal gene expression or drug resistance. Constellation’s integrated epigenetics platform enables the Company to validate targets and generate small molecules against these targets that selectively modulate gene expression in tumor and immune cells to drive anti-tumor activity. Platform insights and clinical experience guide development of wholly owned lead product candidates: CPI-0610, which inhibits bromodomain and extra-terminal domain, or BET, proteins, and CPI-1205, which inhibits enhancer of zeste homolog 2, or EZH2, proteins. The Company believes that its approach to targeting these central gene regulatory mechanisms associated with cancer proliferation may enable it to provide therapeutic benefits to cancer patients.

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 or interim clinical data, the development status of the Company’s product candidates, and the Company’s plans for future data presentations. 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; determine whether preliminary or interim data 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-0610, CPI-1205, 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-0610, CPI-1205, CPI-0209, and other product candidates are investigational in nature and have not yet been approved by the FDA or other regulatory authorities.

Contacts

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

August 7, 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

Constellation Highlights Two wholly owned clinical programs: CPI-0610 (BET) and CPI-1205 (EZH2) 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 CPI-0209 expands the potential of our EZH2 franchise Robust discovery platform fuels the pipeline Data updates in 2H 2019 for both clinical programs


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 Ph 2 data at ASCO/EHA Additional update in 4Q19 EZH2 Franchise CPI-1205 2L mCRPC* Phase 1b data at AACR Additional update in 4Q19 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

2L: Discontinue ruxolitinib Symptomatic MF 1L: Treatment with ruxolitinib 2L: Continue on ruxolitinib Myelofibrosis Patient Journey CPI-0610 + Rux Combo Diseased Bone Marrow Diseased Bone Marrow Diseased Bone Marrow Diseased Bone Marrow Multiple Positioning Options for CPI-0610 Disease Progression CPI-0610 Add-On CPI-0610 Monotherapy Vision for CPI-0610 Provide Differentiated Treatment for 2L Ruxolitinib-Resistant Patients Transform Standard of Care in 1L JAK-Inhibitor-Naïve Patients


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

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 48mg QD capsule **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 Doses Lowest Active Dose*


Slide 13

* Based on preliminary data ** Full-year 2018 earnings releases of Incyte and Novartis *** Constellation estimate Working to Meet Unmet Needs for a Disease-Modifying Therapy That Impacts All Four Hallmarks of MF Hallmarks of Myelofibrosis JAKi’s CPI-0610* Spleen Volume Constitutional Symptoms Anemia & Transfusion Dependence Bone Marrow Fibrosis 2018 Rux WW Sales: ~$2.4B** 2018 Rux WW MF Sales: ~$1.4B***


Slide 14

Data cutoff April 17, 2019 TD = Transfusion Dependent; TI = Transfusion Independent; SVR = Spleen Volume Response Cohorts 1A/1B and Cohorts 2A/2B will apply a Simon-2 stage design MANIFEST Study Design Overview Cohort 1A: TD n = up to 16 Cohort 1B: Non-TD n = up to 25 CPI-0610 Mono No longer on ruxolitinib Refractory or intolerant or ineligible Cohort 2A: TD n = up to 16 Cohort 2B: Non-TD n = up to 25 CPI-0610 + Ruxolitinib “Add on” to ruxolitinib Sub-optimal response or MF progression Study Population Treatment Arm / Cohort Cohort 3: JAKi Naive n = up to 43 No prior JAK inhibitor use Anemic (Hgb < 10 g/dL) CPI-0610 + Ruxolitinib Data Cut as of April 17, 2019 44 patients enrolled No patient experienced disease progression Poor prognostic factors 16 patients for at least 12 weeks


Slide 15

Baseline Demographics and Disease Characteristics Parameter Cohort 1A 0610 Mono TD (n=2) Cohort 1B 0610 Mono Non-TD (n=8) Cohort 2A 0610 + Rux TD (n=16) Cohort 2B 0610 + Rux Non-TD (n=15) Cohort 3 0610 + Rux JAKi Naïve (n=3) TOTAL (n=44) Age Median (range) 68 (67, 69) 70 (46, 80) 72.5 (41, 83) 66 (49, 75) 71 (67, 76) 69 (41, 83) Sex Female (n, %) 1 (50.0) 5 (62.5) 6 (37.5) 6 (40.0) 0 (0.0) 18 (40.9) Male (n, %) 1 (50.0) 3 (37.5) 10 (62.5) 9 (60.0) 3 (100.0) 26 (59.1) ECOG ≤1 (n, %) 2 (100.0) 7 (87.5) 14 (87.5) 14 (93.3) 2 (66.7) 39 (88.6) 2 (n, %) 0 (0.0) 1 (12.5) 1 (6.3) 1 (6.7) 1 (33.3) 4 (9.1) Unknown (n, %) 0 (0.0) 0 (0.0) 1 (6.3) 0 (0.0) 0 (0.0) 1 (2.3) DIPSS Intermediate 1-2 2 (100.0) 5 (62.5) 13 (81.2) 12 (80.0) 3 (100.0) 35 (79.6) High 0 (0.0) 3 (37.5) 3 (18.8) 3 (20.0) 0 (0.0) 9 (20.4) MF Subtype Primary MF (n, %) 1 (50.0) 6 (75.0) 10 (62.5) 9 (60.0) 3 (100.0) 29 (65.9) Post PV MF (n, %) 0 (0.0) 1 (12.5) 3 (18,8) 3 (20.0) 0 (0.0) 7 (15.9) Post ET MF (n, %) 1 (50.0) 0 (0.0) 2 (12.5) 3 (20.0) 0 (0.0) 6 (13.6) Unknown (n, %) 0 (0.0) 1 (12.5) 1 (6.3) 0 (0.0) 0 (0.0) 2 (4.5) Mutation Status n 2 7 16 15 2 42 ≥3 mutations (n, %) 1 (50.0) 3 (42.9) 9 (56.3 ) 10 (66.7) 1 (50.0) 24 (57.1) ASXL1 (n, %) 1 (50.0) 4 (57.1) 8 (50.0) 12 (80.0) 1 (50.0) 26 (61.9) Prior Ruxolitinib Tx Duration <6 months 0 (0.0) 1 (12.5) 3 (18.8) 2 (13.3) 0 (0.0) 6 (13.6) ≥6 months 0 (0.0) 6 (75.0) 12 (75.0) 13 (86.7) 0 (0.0) 31 (70.5) Unknown 1 (50.0) 1 (12.5) 1 (6.3) 0 (0.0) 0 (0.0) 3 (6.8) Not Applicable 1 (50.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (100.0) 4 (9.1) Platelets Median (range) 292.5 (157, 428) 548.0 (89, 895) 188.5 (77, 631) 224.0 (108, 673) 165 (112, 174) 211.5 (89, 895) <450 x 109/L 2 (100.0) 3 (37.5) 14 (87.5) 14 (93.3) 3 (100.0) 36 (81.8) ≥450 x 109/L 0 (0.0) 5 (62.5) 2 (12.5) 1 (6.7) 0 (0.0) 8 (18.2) Hemoglobin Median (range) 7.55 (7.0, 8.1) 9.25 (7.9, 11.8) 8.35 (6.4, 9.4) 10.3 (8.1, 13.0) 8.7 (7.9, 8.9) 8.9 (6.4, 13.0) <10g/dL 2 (100.0) 6 (75.0) 16 (100.0) 6 (40.0) 3 (100.0) 33 (75.0) ≥10g/dL 0 (0.0) 2 (25.0) 0 (0.0) 9 (60.0) 0 (0.0) 11 (25.0) Spleen Volume n 2 8 11 13 3 37 Median (range) 1514.5 (452, 2577) 2114.5 (635, 3997) 1179.0 (167.9, 4007) 2409.0 (123, 4941) 1810.0 (1379, 2409) 2164.0 (123, 4941) Total Symptoms Score (TSS) n 0 6 13 13 3 35 Median (range) NA 22.2 (9.2, 42.6) 13.0 (1.4, 37.3) 28.0 (5.0, 56.0) 14.6 (9.1, 16.7) 17.0 (1.4, 56.0) Data cutoff April 17, 2019


Slide 16

Treatment Duration Total 44 patients enrolled 39 patients active on treatment; 5 patients discontinued Evaluable patients population Safety: Received C1D1 treatment – n=44 SVR: Baseline and one post-baseline data available – n=16 @ 12 weeks; n=12 @ 24 weeks TSS: Baseline TSS data available – n=11 @ 12 weeks Bone marrow morphology: Baseline and one post-baseline data available – n=10 @ 24 weeks Reasons for treatment discontinuation 11-250 – Depression Grade 4 and alcohol intoxication Grade 2 14-262 – Squamous cell carcinoma Grade 3 (due to prior ruxolitinib therapy) 40-270 – Acute renal failure Grade 5 (unlikely related) 39-282 – Diarrhea Grade 2 (withdrew consent) 43-291 – Diarrhea Grade 2 (pre-existent condition IBD, withdrew consent) Data cutoff April 17, 2019


Slide 17

Data cutoff April 17, 2019 *Please see poster A Phase 2 Study of CPI-0610…, which was presented at ASCO on June 3, 2019, in the Investors & Media/Presentations section of http://www.constellationpharma.com Summary of CPI-0610 Data Update from ASCO/EHA 2019 14 of 16 (88%) patients achieve spleen reduction 6 of 11 (55%) of patients achieve >50% improvement in TSS 15 of 16 (94%) achieve improvement in Patient Global Impression of Change (PGIC) Trend of rising HgB due to CPI-0610 treatment 2 of 3 combo patients converted from TD to TI 6 of 10 (60%) patients achieved improvement in bone marrow morphology Hallmarks of Myelofibrosis Spleen Volume Constitutional Symptoms Anemia & Transfusion Dependence Bone Marrow Fibrosis


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Data cutoff April 17, 2019 *Patient ineligible for ruxolitinib due to very low hemoglobin Best Spleen Volume Reduction (n=16) 14 of 16 evaluable patients had spleen volume reductions Median change of -19.2% Spleen volume reduction observed in 4 of 4 evaluable non-TD monotherapy MF patients (depicted in blue) * *


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Data cutoff April 17, 2019 Improvements in Symptoms Best % Total Symptom Score (TSS) Improvement (n=11) Best Patient Global Impression of Change (PGIC) Observed (n=16) Improvement in TSS observed in 100% of patients 6 of 11 (55%) patients achieve > 50% improvement in TSS Improvement in PGIC observed in 15 of 16 (94%) patients No patient worsened


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Data cutoff April 17, 2019 HMR = High Molecular Risk; Patients with one of these mutations: ASXL1, EZH2, IDH1/2 and SRSF2 Bone marrow evaluable population: Baseline reading available and at least one reading at or after 24 weeks – 10 of 44 patients Fibrosis Score Improvements Observed in Monotherapy and Combination Contexts Improvement in Bone Marrow Morphology 4 of 6 patients improved within first 6 months of treatment Baseline Cycle 17 MF Grade 2 MF Grade 1 Patient 11-248 Heavily Pre-Treated, ASXL1 and JAK2 Mutation Evidence of Reduced Fibrosis


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Data cutoff April 17, 2019 Two Transfusion-Dependent Patients Converted to Transfusion Independence Patient 11-246: CPI-0610 + Ruxolitinib, CALR Mutation Patient 11-252: CPI-0610 + Ruxolitinib, JAK2, TET2, SRSF2 and U2AF1 Mutations Patients no longer anemic Hemoglobin increase sustained for >69 weeks and >24 weeks Weeks on study Weeks on study 3 15 30 3 15 30 45 60 75 90


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Data cutoff April 17, 2019 Improvement in Hemoglobin Mean Hemoglobin Levels by Treatment Regimen Substantial increase in hemoglobin is observed in CPI-0610 monotherapy patients With CPI-0610 + ruxolitinib combination, observed improvement in hemoglobin is delayed Patients potentially need to overcome effect of ruxolitinib in JAK-2 signaling, a critical component of EPO pathway Weeks on study 12 24 36 48 60 72 84 96


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Patient 11-247, Non-TD, CPI-0610 Monotherapy, ASXL1 and CALR mutations Hematologic Improvements with CPI-0610 Monotherapy H&E Reticulin Baseline: MF Gr 3 C17: MF Gr 2 Patient Global Impression Change (PGIC) Bone Marrow Effects Platelets Normalization, Hb Improvement Resistant to Ruxolitinib; increase in spleen and worsening symptoms while on Rux Prior treatment: Imetelstat, HU, Pembrolizumab Monotherapy (225 mg) Spleen volume reduction by MRI (Best: 25.4%) Normalization of platelet levels over 1 year >1.5 g/dl Hgb increase over >12 weeks Improvement in PGIC Resolution of headache, less frequent night sweats Bone marrow improvement History CPI-0610 Therapy Observations Data cutoff April 17, 2019


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Reduction in Pro-inflammatory Cytokine Levels Cytokine reductions observed in MF patients with CPI-0610 monotherapy or combo with ruxolitinib Data cutoff April 17, 2019


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Treatment Emergent Adverse Events (TEAE) Treatment Emergent Adverse Event All Grade n=44 (n, %) ≥3 Grade* n=44 (n, %) Blood and Lymphatic System Disorders Anemia 2 (4.5) 2 (4.5) Thrombocytopenia 3 (6.8) 2 (4.5) Neutropenia 1 (2.3) 1 (2.3) Investigations Platelet Count Decreased 3 (6.8) 2 (4.5) Blood Creatinine Increased 1 (2.3) 1 ( 2.3) Gastrointestinal Disorders Diarrhea 10 (22.7) 1 (2.3) Vomiting 6 (13.6) 1 (2.3) Nausea 4 (9.1) 1 (2.3) Metabolism and Nutrition Disorders Decreased appetite 3 (6.8) 0 (0.0) Dehydration 1 (2.3) 1 (2.3) Hyponatremia 1 (2.3) 1 (2.3) Renal and Urinary Disorders Acute Kidney Injury 1 (2.3) 1 (2.3) Proteinuria 1 (2.3) 1 (2.3) General Disorders and Administration Site Conditions Fatigue 5 (11.4) 1 (2.3) Infections and Infestations Upper respiratory tract infection 6 (13.6) 0 (0.0) Pneumonia 1 (2.3) 1 (2.3) Respiratory, Thoracic and Mediastinal Disorders Epistaxis 6 (13.6) 0 (0.0) Cough 5 (11.4) 0 (0.0) Skin and Subcutaneous Tissue Disorder Pruritis 5 (11.4) 0 (0.0) Rash 3 (6.8) 0 (0.0) Psychiatric Disorder Depression 0 (0.0) 1 ( 2.3) Alcohol With 1 ( 2.3) 0 (0.0) Nervous System Disorders Headache 6 (13.6) 0 (0.0) Dysgeusia 5 (11.4) 0 (0.0) Summary of TEAE by ≥10% Frequency and AESI All ≥3 grade TEAE were observed in patients treated with CPI-0610 + ruxolitinib therapy; no ≥3 grade TEAE was observed with CPI-0610 monotherapy Data cutoff April 17, 2019


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Data cutoff April 17, 2019 Effects on Platelet Levels CPI-0610 Monotherapy (n=10) No Patients with Grade 3 Thrombocytopenia CPI-0610 + Ruxolitinib (n=34) 4 of 34 Patients with Grade 3 Thrombocytopenia CPI-0610 monotherapy demonstrated minimal, non-cumulative, and manageable thrombocytopenia Combination therapy of CPI-0610 and ruxolitinib showed non-cumulative, manageable, and generally reversible asymptomatic Grade 3 thrombocytopenia


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Key Takeaways from ASCO/EHA 2019 Update Activity across all four hallmarks of myelofibrosis: spleen, symptoms, hematologic function, and bone marrow fibrosis CPI-0610-driven activity in ruxolitinib-resistant patients as monotherapy and as an add-on to ruxolitinib Substantial symptom and spleen improvement observed Evidence of early effects on bone marrow fibrosis and trend of increasing hemoglobin over time suggest potential disease-modifying effects CPI-0610 generally well-tolerated as a monotherapy and in combination with ruxolitinib


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*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. ^COMFORT-1: A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis Verstovsek, S., et al; N Engl J Med 2012;366:799-807. † 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. Potential Paths to Registration for CPI-0610 2L Transfusion-Dependent Patients† 1L JAKi-Naïve Patients*^ Convert to Transfusion Independence Increase Rate of SVR35 Response Rate of Transfusion Dependence (%) Spleen Volume Change from Baseline (%) 29% SVR35 41.9% SVR35 Goal: áSVR35 due to CPI-0610/rux synergy and improved tolerability of rux Anticipated Data By End of 2019 Results from approximately 40 ruxolitinib-resistant patients Transfusion dependence to independence conversion results from approx. 16 patients treated w/ CPI-0610 + ruxolitinib Spleen Volume Reduction and Total Symptom Score results from 10-15 JAK-inhibitor-naïve patients Planning has begun for potential pivotal trials Ruxolitinib Spleen Volume Response (SVR%) SIMPLIFY-1 COMFORT-1


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CPI-1205 and CPI-0209 EZH2 Franchise


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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


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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 CPI-1205 may enhance the activity of ARS inhibitors and reduce need for chemotherapy Pre-Metastatic Prostate Cancer


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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)


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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 of CPI-1205 + enzalutamide initiated in heavily pre-treated patients who have progressed after treatment with each of enzalutamide, abiraterone, and chemotherapy.


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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 filed and cleared by FDA in 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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CPI-0209 Preclinical Activity in Bladder Cancer Tumor volume (mm3) Relative tumor volume (% change) Days Post Grouping Days Post Grouping CPI-0209 Causes Tumor Regression in ARID1A Mutant Bladder Cancer Xenografts CPI-0209 Is More Efficacious Than Cisplatin Single Agent Treatment


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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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2019 –Year of Data Potential Value Creation Catalysts 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, cash equivalents and marketable securities as of June 30, 2019, of $98.1 million Current cash, cash equivalents and marketable securities expected to fund operations until late 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 2Q19 2Q18 R&D Expenses $16.0 $9.5 G&A Expenses $4.9 $2.5 Other Income, Net $0.1 $0.1 Net Loss Attributable to Common Stockholders ($20.8) ($11.9) Net Loss Per Share Attributable to Common Stockholders ($0.80) ($9.96)


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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 Bob Tepper, M.D., Third Rock Ventures Elizabeth Tréhu, M.D., Jounce Therapeutics