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): October 10, 2018

 

 

Constellation Pharmaceuticals, Inc.

(Exact Name of Registrant as Specified in Charter)

 

 

 

Delaware   001-38584   26-1741721

(State or Other Jurisdiction

of Incorporation)

 

(Commission

File Number)

 

(IRS Employer

Identification No.)

215 First Street, Suite 200

Cambridge, Massachusetts

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

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

Not applicable

(Former Name or Former Address, if Changed Since Last Report)

 

 

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):

 

Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

 

Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

 

Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

 

Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).

Emerging growth company  ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.  ☐

 

 

 


Item 7.01.

Regulation FD Disclosure.

On October 10, 2018, the Company issued a press release entitled “Constellation Pharmaceuticals Enhances and Expands Phase 2 MANIFEST Study of CPI-0610 in Myelofibrosis” announcing amendments to the trial design of its MANIFEST trial. 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 October 10, 2018, Constellation Pharmaceuticals, Inc. (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, is furnished under Item 7.01 of Form 8-K, and 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 October 10, 2018 (furnished herewith)
99.2    Corporate Overview dated October 2018 (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: October 10, 2018     By:  

/s/ Jigar Raythatha

    Name:  

Jigar Raythatha

    Title:   Chief Executive Officer
EX-99.1

Exhibit 99.1

Constellation Pharmaceuticals Enhances and Expands Phase 2 MANIFEST Study of CPI-0610 in Myelofibrosis

– Amends second-line trial design to stratify for transfusion dependence based on positive preliminary data –

– Expands study to include an additional arm evaluating CPI-0610 as first-line therapy in combination with ruxolitinib in JAK-inhibitor-naïve myelofibrosis (MF) patients –

– Maintains prior guidance for determining proof of concept by mid-2019

– Company to host conference call at 8:30 AM EDT on Thursday, October 11 –

CAMBRIDGE, Massachusetts, October 10, 2018 – Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, today announced several planned updates to the Phase 2 portion of its ongoing MANIFEST study, an open-label Phase 1/2 clinical trial of its BET inhibitor CPI-0610 in MF.

MANIFEST is evaluating CPI-0610, either as a monotherapy or in combination with ruxolitinib, in patients with MF who are refractory or intolerant or have relapsed or lost response to the standard of care. Based on encouraging preliminary data in this trial, Constellation is amending the design of each second-line cohort to stratify all patients enrolled in the study based on transfusion dependence status. In addition, the Company is amending the design of MANIFEST to include a third cohort designed to evaluate treatment with CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK 1/2-inhibitor-naïve MF patients.

The Company made these updates based on the unmet medical need for disease-modifying therapies in myelofibrosis, especially among patients requiring red-blood-cell transfusions. The changes are intended to enhance the clinical trial design by providing additional measures of potential clinical benefit and to expand the potential addressable patient population for CPI-0610.

“We are encouraged by the preliminary data from MANIFEST, which may indicate synergistic and disease-modifying effects of CPI-0610 in myelofibrosis,” said Adrian Senderowicz, Senior Vice President and Chief Medical Officer of Constellation Pharmaceuticals. “We are enhancing the study’s design to better measure these potential effects. Among the key goals of MANIFEST are identifying the most appropriate endpoints and patient populations for future pivotal studies. We continue to look forward to determining proof of concept for CPI-0610 in MF by mid-2019.”

MANIFEST Enhancements

The Phase 2 proof-of-concept portion of MANIFEST in a second-line setting is designed to study the anti-tumor activity and safety of the BET inhibitor CPI-0610 in treatment of patients with MF as a monotherapy and in combination with the JAK-1/2 inhibitor


ruxolitinib. This portion of the study had been expected to enroll 70 patients (35 on monotherapy and 35 on combination therapy) to evaluate safety, pharmacokinetics, reduction in spleen volume, and patient-reported symptom improvement in all enrolled patients, as well as improvements in red-blood-cell transfusion independence rate in patients who were transfusion-dependent at baseline. Preliminary data from this trial demonstrated spleen volume reduction, symptom improvement, and positive hemoglobin effects, which Constellation believes may be the result of improved hematopoiesis. In addition, as Constellation reported previously, one of four patients treated with CPI-0610 was transfusion-dependent at baseline and later converted to transfusion independence.

As a result of this positive preliminary hematological data, all enrolled patients in both the combination and monotherapy arms will now be stratified by transfusion dependence status, with each cohort expected to enroll up to 16 transfusion-dependent patients and up to 25 non-transfusion-dependent patients. Proof of concept in these cohorts will be based on conversion to transfusion independence and other factors in transfusion-dependent patients; and by reduction in spleen volume, patient-reported symptom improvement, and other factors in non-transfusion-dependent patients.

In addition, Constellation is adding a third cohort to this trial, which will evaluate treatment with CPI-0610 in combination with ruxolitinib as first-line therapy in up to 43 JAK 1/2-inhibitor-naïve MF patients. This cohort will only enroll anemic patients. Constellation’s current plan for a potential pivotal trial of CPI-0610 as a first-line treatment would be to enroll all-comers. Proof of concept for this cohort will be measured by reduction in spleen volume, patient-reported symptom improvement, and other factors.

The Company expects to update this protocol change at https://clinicaltrials.gov under study ID NCT02158858 in the near future.

Conference Call/Corporate Presentation

Constellation’s CEO Jigar Raythatha and CMO Adrian Senderowicz will host a conference call to discuss this protocol change in greater detail at 8:30 AM EDT on Thursday, October 11. To participate in the conference call, please dial (877) 473-2077 (US) or +1(661) 378-9662 (international) and refer to conference ID 4165317. A live webcast will be available in the investor section of the company’s website. The webcast will be archived for 60 days following the call. Constellation has posted an updated version of its corporate presentation in the investor section of the company’s website.

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 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.


Contact

Ronald Aldridge

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

Developing Treatments Targeting Epigenetic Mechanisms in Tumor and Immune Cells for Cancer Patients Corporate Overview October 2018 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

Multiple Lead Clinical Programs CPI-1205 (EZH2) and CPI-0610 (BET) Encouraging Preliminary Clinical Data Prostate cancer, solid tumors and myelofibrosis Near-Term Milestones Proof-of-concept determination for each lead program expected in mid-2019 Expanding the EZH2 Opportunity Second-generation EZH2 inhibitor (CPI-0209) Robust Discovery Platform Novel chromatin-modifying proteins targeting tumor cells and innate immune cells Constellation Highlights


Slide 4

Instructions for Genetic Code Transcriptional control to turn genes on or off Tumor Cells MDSC Tumor microenvironment NK Cell T Cell Target transcriptional networks that result in cell death Re-program immune cells to overcome resistance to cancer immunotherapies Focused on three distinct classes that chemically modify chromatin Writers Erasers Readers


Slide 5

Multiple Near-Term Opportunities for Success Product Candidates Indications Preclinical Phase 1 Phase 2 Phase 3 Next Milestone EZH2 Franchise CPI-1205 mCRPC Proof of Concept Mid 2019 CPI-1205 Solid Tumors Safety and RP2D Early 2019 CPI-0209 (2nd Gen) Solid Tumors / Heme Malignancies BET Inhibitor CPI-0610 Myelofibrosis Proof of Concept Mid 2019 Preclinical Tumor Microenvironment (Undisclosed) Solid Tumors / Heme Malignancies Immune Microenvironment (Undisclosed) Solid Tumors ProSTAR Trial ORIOn-E Trial MANIFEST


Slide 6

CPI-1205 and CPI-0209 EZH2 Franchise


Slide 7

EZH2 Inhibition Offers Broad Therapeutic Potential EZH2 “Writer” Activity Suppresses Gene Transcription EZH2 Polycomb Repressive Complex 2 (PRC2)… SUPPRESSED TRANSCRIPTION … methylates Histone H3 at Lysine 27 (K27) Regulation of Immune Cells: EZH2 reprograms T cells to suppress an anti-tumor immune response Cancer Genetics: Mutations in genes which create a functional dependency on EZH2 Acquired Drug Resistance: EZH2 mediates gene silencing that diminishes response to existing therapies


Slide 8

Expanding EZH2 Opportunity Mutant follicular lymphoma Solid tumors in combination with standard of care in both tumors and immune cells mCRPC Anti-PD-1 Progressors Solid tumors and/or heme malignancies Genetics that validate EZH2 Enhance effectiveness of standard of care Comprehensive target engagement Constellation Focus CPI-1205 CPI-0209


Slide 9

Model for EZH2 Role in Prostate Cancer *Signature of H3K27me3-occupied EZH2 target genes repressed in metastatic relative to clinically localized prostate cancer and benign prostate tissue Yu et al., Cancer Research 2007 EZH2 gene signature* predicts outcomes in prostate cancer Pro-tumor signaling Enhances AR signaling K27 OFF EZH2 Coregulators Prostate tumor growth Chromatin AR AR


Slide 10

Evidence of EZH2 Synergy With Androgen Receptor Signaling (ARS) CPI-1205 enhances the gene signature of enzalutamide in prostate cancer cells Enzalu- tamide CPI- 1205 Combo CPI-1205 is active as monotherapy and synergistic with enzalutamide in killing prostate cancer cells


Slide 11

Current Treatment Paradigm in mCRPC *ASCO 2018 Poster Khalaf, et al (Kim Chi Lab) Metastatic Castration-Resistant Prostate Cancer (30,000-50,000 Diagnosed Annually) 1st Line Abiraterone or Enzalutamide 2nd Line Enzalutamide or Abiraterone 3rd Line Chemotherapy or Palliative Care 60-80% PSA Response* 9-15 Months PSA PFS PSA50 = 4% (Abi) and 31% (Enza)* PSA PFS = 1.3 months (Abi) and 2.7 months (Enza)* No Objective Responses EZH2 inhibition may enhance the activity of ARS inhibitors


Slide 12

ProSTAR Trial Design Second-Line Trial After Ineffective Treatment with Androgen Receptor Signaling (ARS) Inhibitor Randomized Phase 2 Phase 1b Enzalutamide + CPI-1205 (Prior Abiraterone Progression) Abiraterone + CPI-1205 (Prior Enzalutamide Progression) Selected ARS Inhibitor + CPI-1205 (Progressed on Different ARS Inhibitor) n=35 Selected ARS Inhibitor Alone (Progressed on Different ARS Inhibitor) n=35 Testing Biomarkers for Patient Enrichment vs. Primary endpoints: MTD, RP2D Primary endpoint: Response rate PSA reduction; CTC reduction; or Objective response Selected CPI-1205 + ARSi combo RP2D


Slide 13

ProSTAR Trial: Treatment Duration Data cutoff May 25, 2018 *Continued on CPI-1205 monotherapy after cycle 1 Discontinued Treatment Cycles of treatment (one cycle = one month) Patient # 1 2 3 4 5 6 7 8 9 10 CPI-1205 + Abiraterone CPI-1205 + Enzalutamide C1D1 C2D1 C3D1 C4D1 C5D1 C6D1 C7D1 * 2 of 6 evaluable patients achieved PSA80 2 of 4 evaluable patients with CTCs achieved CTC reduction of > 30% 2 of 2 evaluable patients had resolution of metastatic disease


Slide 14

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


Slide 15

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


Slide 16

Experience with a Compassionate-Use Patient Significant PSA Reduction in Heavily Pre-Treated and Refractory 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.


Slide 17

CPI-1205 Improves Anti-Tumor Immune Activity Pam Sharma June 2018 Jeff Bluestone and Michel DuPage June 2018 Synergistic impact with checkpoint inhibitor in preclinical model MB49


Slide 18

CPI-1205 Checkpoint Combination Study Design Enrolling All Comers in Solid Tumors Phase 2 Phase 1b Ipilimumab + CPI-1205 (Prior Anti-PD-(L)1) Pembrolizumab + CPI-1205 (Prior Anti-PD-(L)1) RP2D Expansion Cohorts Checkpoint Inhibitor + CPI-1205 Testing Biomarkers for Patient Enrichment


Slide 19

Clinical Activity Observed in Anti-PD-1 Progressors ORIOn-E Summary as of May 25, 2018 Discontinued Treatment Stable Disease Partial Response Treatment Ongoing CPI-1205 +pembrolizumab CPI-1205 + ipilimumab 1 2 3 4 5 6 7 8 9 Baseline Cycle 4 42% Reduction in Tumor Volume from Baseline Phase 1b/2 All Comers Solid Tumors Progressed on Anti-PD-(L)1 1 PR + 3 SD out of 6 patients treated with CPI-1205 + ipilimumab


Slide 20

CPI-0209: Second-Generation EZH2 Inhibitor Once-Daily Treatment Resulted in Rapid, Complete, and Durable Tumor Regression Vehicle Tazemetostat, 160 mg/kg oral, twice daily Lymphoma Xenograft Mouse Model Expected to enter Phase 1 in 2019 CPI-0209 may provide more comprehensive EZH2 coverage, expanding addressable populations


Slide 21

CPI-0610 BET Inhibitor


Slide 22

BET “Reader” Proteins Control of Key Immune, Fibrotic, and Oncogenic Pathways Leads to Opportunity in Myelofibrosis (MF) Enhancer TSS BRD4 Transcription Factor … … Fibrosis TGF-β target genes Immune Signaling NF-κB target genes Cancer Genetics MYC, BCL2


Slide 23

Mechanism of Action BET Inhibition May Block Proliferation of Inflammatory Bone Marrow Cells and Synergize with JAK Inhibition BET Signaling Megakaryocyte Differentiation/Proliferation Pro-inflammatory Cytokines (e.g. IL-8) JAK/STAT Signaling STAT STAT Cytoplasm Nucleus NF-kB Target Genes BETs P P


Slide 24

Rationale for BET’s Role in Myelofibrosis CPI-0610 vs DMSO 25 nM 100 nM 400 nM Inhibition of Megakaryocyte Differentiation in vitro BET inhibitor + ruxolitinib led to synergistic reduction in spleen volume (left) and improved bone marrow fibrosis score (right) Kleppe et al 2018 Cancer Cell Vehicle 1-2+ JQ1 (BETi) 1+ Ruxolitinib 1+ Combo 0 Constellation Pharmaceuticals Data


Slide 25

Myeloproliferative neoplasm characterized by scarring (fibrosis) of the bone marrow caused by impaired hematopoiesis 17,000-20,000 patients in US* Three main features: Symptoms of organomegaly (spleen and liver) Symptoms of systemic inflammation Anemia and thrombocytopenia Only approved therapy is ruxolitinib, which has been shown to relieve symptoms but has limited evidence of disease modification Myelofibrosis (MF) Background *Internal market research


Slide 26

Standard of care and the only approved drug treatment is ruxolitinib (Jakafi) Significant improvement in splenomegaly and symptoms, but limited evidence of disease modifying effect 30-40% of patients respond adequately in clinical trials* Thrombocytopenia and/or anemia may lead to patients receiving sub-optimal dosing or discontinuation of treatment 57% of ruxolitinib patients required dose reductions due to adverse events in COMFORT-I** Patients may require blood transfusions, which become more frequent during ruxolitinib treatment or due to disease progression Underserved MF Patient Population *Mesa RA, Kiladian JJ, et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis. J Clin Oncol. 2017 Dec 1;35(34):3844-3850. doi: 10.1200/JCO.2017.73.4418. Epub 2017 Sep 20Haematologica. 2015;100(4):479-488. Verstovsek S., Mesa RA, Gotlib J, et al; COMFORT-I Investigators. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55. . **Verstovsek S,, Mesa RA, Gotlib J, et al; COMFORT-I Investigators. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55.


Slide 27

Need for New Disease-Modifying Treatments in MF Ruxolitinib Spleen Response – SIMPLIFY-1* Ruxolitinib TSS Response – SIMPLIFY-1* Inadequate response in 1L disease No approved therapy in 2L disease Patients burdened by increased reliance on transfusions Need for new disease-modifying therapies that increase response rate and improve hematopoietic function Transfusion Dependence – SIMPLIFY-1* * Source: Mesa, R., et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis J Clin Oncol 2017: 35(34):3844-3850 26.5% SVR35 29% SVR35 28.4% TSS50 42.2% TSS50


Slide 28

Treated 138 patients in Phase 1 trials of hematologic malignancies Multiple objective responses observed at a range of doses below the maximum tolerated dose Demonstrated favorable PK/PD profile Activity seen in the context of NF-κB-driven diseases ABC-DLBCL (Phase 1) 7 patients at relevant doses: 1 CR, 2 PR, 1 SD (16 months) Myelofibrosis (Phase 2) Evidence of transfusion independence in one patient, reduction in spleen size, and symptom improvement CPI-0610 Background Correlation between IL-8 (NF-kB target gene) expression and CPI-0610 exposure IL-8 expression Concentration of CPI-0610 mM % change from baseline Phase 1 data in 38 evaluable lymphoma patients = ABC-DLBCL


Slide 29

MANIFEST: CPI-0610 Phase 2 Trial Design in MF Prior to Amendment CPI-0610 n=35 CPI-0610 dosing of 125mg up to 225mg once daily in both arms 2L MF patients no longer on ruxolitinib 2L MF patients on ruxolitinib despite disease progression on therapy CPI-0610 + ruxolitinib n=35 Objectives: Evaluate spleen size reduction after 24 weeks of treatment Evaluate patient-reported symptom improvement Evaluate transfusion independence rate, if applicable


Slide 30

Spleen Size Reduced in All Patients as Measured by MRI MANIFEST: First Four Patients Treated Ongoing > 10 months Ongoing > 5 months Reduced spleen size Symptom improvement One patient with thrombocytosis and one patient transfusion-dependent at baseline—both resolved Data cutoff May 25, 2018


Slide 31

Improved Hematopoiesis on CPI-0610 Patient Achieved Transfusion Independence and Improved Platelet Count Patient treated with CPI-0610 + ruxolitinib combination therapy Data cutoff May 25, 2018


Slide 32

Improved Hematopoiesis on CPI-0610 Hemoglobin Levels Increased in First Four Patients Treated Data cutoff May 25, 2018


Slide 33

All patient data disclosed to date come from our first site We have made considerable progress in our 2018 goals of activating additional sites 7 sites in the US and 5 in Canada are active, with more to follow in US and Europe We have enrolled additional patients at these sites and look forward to providing updates at future medical meetings Clinical Trial Execution


Slide 34

Preliminary signs of clinical activity in each of the evaluable 2L patients in MANIFEST* SVR and symptom improvement Potential disease-modifying effects* Improved hematopoiesis, including hemoglobin level improvement, in each patient Resolution of transfusion dependence Modifying the 2L cohorts to stratify for transfusion dependence status to better measure hematopoietic effects Initiating a 1L cohort in combination with ruxolitinib Rationale for Protocol Amendment * Data cutoff May 25, 2018


Slide 35

MANIFEST: Expanded Phase 2 Trial in MF *Cohort 3 will enroll anemic patients, pivotal trial plans anticipated to include all comers Robust Development Plan to Expand the CPI-0610 Opportunity 2L MF patients no longer on ruxolitinib 2L MF patients on ruxolitinib despite disease progression on therapy Cohort 1A: 2L Transfusion Dependent (TD) n = up to 16 Cohort 1B: 2L Non-TD n = up to 25 Cohort 2A: 2L Transfusion Dependent n = up to 16 Cohort 2B: 2L Non-TD n = up to 25 Cohort 3: 1L* n = up to 43 1L MF patients CPI-0610 Mono CPI-0610 + Rux CPI-0610 + Rux Primary Endpoints: Transfusion independence rate in Cohorts 1A, 2A Spleen volume reduction and Total Symptom Score assessment at 24 weeks in Cohorts 1B, 2B, and 3 Note: Each cohort will implement adaptive Simon’s two-stage design


Slide 36

CPI-0610 has demonstrated clinical activity in early clinical trials with NF-κB-driven cancers, including MF, suggesting CPI-0610 may be differentiated among BET inhibitors Early clinical data in 2L myelofibrosis show improvements in spleen volume, symptom scores, hematopoiesis, and transfusion independence, which may indicate the potential for disease modification We have modified MANIFEST in 2L patients to stratify for transfusion dependent status and added a 1L arm, which increases the potential opportunity for CPI-0610 Multiple new clinical trial sites initiated in US and ex-US We continue to expect determination of proof of concept by mid-2019 CPI-0610 Summary


Slide 37

Discovery Platform Fueling the Pipeline Tumor Cells Innate Adaptive Discovery Programs Targeting Epigenetic Regulators on the Tumor and Immune Microenvironment Normalize aberrant gene expression within cancer cells Increase tumor immunogenicity Re-program immune cells to overcome resistance to cancer immunotherapies Immune Cells


Slide 38

Financial Strength


Slide 39

Potential Value Creation Catalysts Early 2018 Complete crossover financing Expand enrollment in ProSTAR Initiate ORIOn-E Select 2nd generation EZH2 inhibitor candidate (CPI-0209) Late 2018 Additional active sites in US, Canada / EU for CPI-0610 in myelofibrosis Initiate Phase 2 portion of ProSTAR Trial 2019 2018 Early 2019 Safety and recommended Phase 2 dose (RP2D) from ORIOn-E Mid 2019 ProSTAR (CPI-1205) proof of concept Myelofibrosis (CPI-0610) proof of concept


Slide 40

Post-IPO cash expected to fund operations into 2020, including: Ongoing clinical trials to determine proof of concept for CPI-1205 and CPI-0610 Continued advancement of CPI-0209 Ongoing support for robust discovery/preclinical Oversubscribed crossover financing round in April raised $100 million from high-quality investors Cash and cash equivalents as of June 30, 2018, of $88.5 million does not include $60 million in gross proceeds, excluding underwriting fees, from successful IPO in July Strong Cash Position $ millions, except per-share amounts 1H18 2Q18 R&D Expenses $19.4 $9.5 G&A Expenses $4.8 $2.5 Other Income (Expense), Net $0.2 $0.1 Cumulative Dividends on Convertible Preferred Stock -- -- Net Loss Attributable to Common Stockholders ($24.0) ($11.9) Net Loss Per Share Attributable to Common Stockholders ($22.12) ($9.96)


Slide 41

Experienced Management Team, Board, and Scientific Advisors Jigar Raythatha President and CEO Emma Reeve Chief Financial Officer Adrian Senderowicz, M.D. Chief Medical Officer Brad Prosek SVP, Corporate Development Robert Sims, PhD SVP, Research Patrick Trojer, PhD SVP, Translational Sciences Management Team Karen Valentine Chief Legal Officer, General Counsel Brenda Sousa SVP, HR and Operations Mark Goldsmith, M.D., Ph.D. (Chairman), CEO, Revolution Medicines Jigar Raythatha Jim Audia, Ph.D., Chicago Biomedical Consortium Board of Directors Tony Evnin, Ph.D., Venrock Peter Svennilson, The Column Group Bob Tepper, M.D., Third Rock Ventures Danny Reinberg, Ph.D., NYU, HHMI, NAS David Allis, Ph.D., Rockefeller Univ., NAS Yang Shi, Ph.D., Harvard Medical School David Livingston, M.D., Dana Farber Cancer Center Scott Lowe, Ph.D. Memorial Sloan-Kettering Robert Schreiber, Washington U. School of Med. Founders & Scientific Advisory Board Pam Sharma, M.D., Ph.D., MD Anderson Cancer Center