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 14, 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 2.02

Results of Operations and Financial Condition.

On August 14, 2018, Constellation Pharmaceuticals, Inc. (the “Company”) announced its financial results for the quarter ended June 30, 2018. The full text of the press release issued in connection with the announcement is being furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.

The information in this Item 2.02, including Exhibit 99.1 attached hereto, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934 (the “Exchange Act”) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933 or the Exchange Act, except as expressly set forth by specific reference in such a filing.

 

Item 7.01

Regulation FD Disclosure.

On August 14, 2018, the Company posted a Corporate Overview presentation on its website. A copy of the presentation is attached as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated herein by reference.

The information in this Item 7.01, including Exhibit 99.2 attached hereto, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934 (the “Exchange Act”) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933 or the Exchange Act, except as expressly set forth by specific reference in such a filing.

 

Item 9.01

Financial Statements and Exhibits.

(d) Exhibits

The following exhibits are furnished herewith:

 

99.1   

Press Release dated August 14, 2018

99.2   

Corporate Overview dated August 2018


 

 

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 14, 2018     By:   /s/ Emma Reeve
      Name: Emma Reeve
      Title: Chief Financial Officer
EX-99.1

Exhibit 99.1

Constellation Pharmaceuticals Announces Second-Quarter and Six-Month 2018 Financial Results

 

   

Company raises an aggregate of $160 million in crossover financing in April and initial public offering (IPO) in July

 

   

Company progressing its pipeline, including clinical programs CPI-1205 and CPI-0610

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

“We at Constellation are pleased to report our financial results for the first time as a public company,” said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals. “We are focusing our efforts and investing the capital that we raised in our recent crossover round and IPO with the goal of building a broad portfolio of important epigenetics-based medicines to serve inadequately treated cancer patients.

“We have many things to be excited about in the months ahead,” Mr. Raythatha continued. “Our robust epigenetics platform has delivered multiple programs into the clinic that are testing differentiated approaches to treating cancer. These programs have provided encouraging preliminary clinical data, details of which we disclosed in our IPO prospectus. We look forward to providing further updates on the progress of our two lead programs in metastatic castration-resistant prostate cancer and myelofibrosis, including evaluation of proof of concept in mid-2019. We aim to expand on this clinical pipeline with new drug candidates generated by our epigenetics platform.”

In conjunction with the Company’s IPO, Constellation is expanding its leadership team. To that end, in July the Company appointed Karen Valentine as Chief Legal Officer and General Counsel. “We are thrilled to have someone with Karen’s extensive legal and business experience in the biotech space join Constellation,” Mr. Raythatha concluded. “We welcome her and will benefit considerably from her leadership.”


News

 

 

On July 18, the Company priced its IPO of 4,000,000 shares at a price of $15.00 per share, for gross proceeds of $60 million, before underwriting discounts and commissions and offering expenses payable by the Company. On July 19, the Company’s common stock began trading on the Nasdaq Global Select Market under the symbol “CNST.” The IPO closed on July 23.

 

 

On July 16, the Company appointed Karen Valentine as Chief Legal Officer and General Counsel. Ms. Valentine joins Constellation after serving as Chief Legal Officer and General Counsel of Agenus Inc.

 

 

In June, two scientific publications preclinically validated the role of the EZH2 inhibitor CPI-1205 in cancer immunotherapy. CPI-1205’s potential effect as an immunotherapy was first established through the Company’s collaboration with the laboratory of Dr. Padmanee Sharma at MD Anderson Cancer Center. The work is documented in “Modulation of EZH2 Expression in T Cells Improves Efficacy of anti-CTLA-4 Therapy,” which was published in the Journal of Clinical Investigation. Constellation also contributed CPI-1205 product to a study by the laboratories of Dr. Jeffrey Bluestone at UCSF and Dr. Michel DuPage at UC Berkeley discussed in the article “Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity,” published in Cell Reports. These studies support the rationale for the Company’s ORIOn-E trial.

 

 

On April 9, the Company announced completion of a $100 million financing, with funds provided by both existing and new investors. The Company plans to utilize the proceeds of this financing and of its IPO to advance its multiple clinical trials, including the ongoing ProSTAR and ORIOn-E trials for CPI-1205 and the ongoing MANIFEST trial for CPI-0610, to continue development of CPI-0209, and to advance its preclinical pipeline.

Second Quarter 2018 Financial Results

 

 

Cash and cash equivalents as of June 30, 2018 grew 24% to $88.5 million compared to March 31, 2018, primarily due to capital raised in a preferred stock offering in April, partially offset by operating expenses. This cash balance did not reflect proceeds from the IPO, which occurred in July.


 

Research and development (R&D) expenses increased 19% year over year to $9.5 million in the second quarter of 2018 mainly due to increased CPI-1205 clinical trial expenses.

 

 

General and administrative (G&A) expenses grew 67% year over year to $2.5 million in the second quarter of 2018, primarily due to increased personnel costs related to building out the organization as the Company evolves from a preclinical-stage company to a multi-candidate clinical-stage company, as well as costs associated with the IPO.

 

 

The net loss attributable to common stockholders decreased 3% year over year to $11.9 million and decreased 22% to $9.96 per share for the second quarter of 2018.

Financial Guidance

The Company expects that its cash and cash equivalents as of June 30, 2018, together with the proceeds of the IPO, will fund planned operations into the first quarter of 2020.

Overview of Key Programs

ProSTAR: CPI-1205 is a small molecule designed to promote anti-tumor activity by specifically inhibiting EZH2, an enzyme that suppresses target gene expression. The ProSTAR trial is an open-label Phase 1b/2 clinical trial of CPI-1205 in combination with either abiraterone acetate or enzalutamide, which are androgen receptor signaling (ARS) inhibitors, in patients with metastatic castration-resistant prostate cancer (mCRPC) who previously progressed on treatment with one of these ARS inhibitors. In the Phase 1b portion of this trial, the Company is aiming to establish safety, pharmacokinetics, pharmacodynamics, maximum tolerated dose and a recommended Phase 2 dose of CPI-1205 in combination with these agents. The Company has observed preliminary evidence of clinical activity in the Phase 1b portion of this trial. In the randomized Phase 2 portion, the Company will aim to assess the response rate of a selected combination of CPI-1205 and one of these ARS inhibitors compared to that of the ARS inhibitor alone.

ORIOn-E: In accordance with the Company’s franchise approach to targeting EZH2, the Company has initiated the ORIOn-E trial, a Phase 1b/2 clinical trial of CPI-1205 in combination with ipilimumab or pembrolizumab for the treatment of patients with solid tumors who have previously progressed on treatment with an immune checkpoint inhibitor that inhibits PD-L1 or PD-1. In the Phase 1b portion of the trial, the Company seeks to establish the safety, pharmacokinetics, maximum tolerated dose, and recommended Phase 2 dose of the combination.


MANIFEST: CPI-0610 is a potent and selective small molecule designed to promote anti-tumor activity by selectively inhibiting the function of BET proteins to decrease the expression of abnormally expressed genes in cancer. In MANIFEST, an open-label Phase 2 clinical trial, the Company is evaluating CPI-0610 as a second-line treatment for patients with myelofibrosis (MF), a progressive hematological cancer. The Company is studying CPI-0610 in combination with ongoing ruxolitinib treatment in MF patients who have experienced disease progression, and as a monotherapy in MF patients not eligible for, or no longer on, ruxolitinib. The Company aims to evaluate safety, pharmacokinetics, reduction in spleen volume, patient-reported symptom improvement and improvements in red-blood-cell transfusion independence rate in patients who were transfusion dependent at baseline.

CPI-0209: Also in accordance with our franchise approach to targeting EZH2, the Company has developed a second-generation EZH2 inhibitor, CPI-0209, and is currently conducting IND-enabling studies. The Company expects to provide additional updates on the development of CPI-0209 in the context of its EZH2 franchise approach in 2019.

In all of the above referenced clinical trials, the Company plans to collect and analyze biomarkers to assess the biology of the EZH2 or BET proteins, which may allow the Company to enrich for patients who are most likely to respond to treatment.

Anticipated Milestones

The Company anticipates the following upcoming milestones:

Late 2018

Initiate Phase 2 portion of ProSTAR trial for CPI-1205

Early 2019

Determine safety and recommended Phase 2 dose (RP2D) in ORIOn-E trial for CPI-1205

Mid 2019

Evaluate proof of concept for CPI-1205 in the ProSTAR trial

Evaluate proof of concept for CPI-0610 in the MANIFEST trial


Select Financial Information

Statements of operations and comprehensive loss (unaudited)

 

      Six months ended
June 30,
    Three months ended
June 30,
 
($ in thousands, except share and per-share amounts)    2018     2017     2018     2017  

Revenue

   $     $     $     $  

Operating expenses:

                                

Research and development

     19,410       14,874       9,536       8,022  

General and administrative

     4,789       2,655       2,486       1,490  

Total operating expenses

     24,199       17,529       12,022       9,512  

Loss from operations

     (24,199     (17,529     (12,022     (9,512

Other income (expense):

                                

Interest income

     377       66       268       32  

Interest expense

     (221     (553     (187     (255

Change in fair value of preferred stock tranche liability

           4,353             1,743  

Total other income, net

     156       3,866       81       1,520  

Net loss and comprehensive loss

     (24,043     (13,663     (11,941     (7,992

Cumulative dividends on convertible preferred stock

           (8,524           (4,327

Net loss attributable to common stockholders

   $ (24,043   $ (22,187   $ (11,941   $ (12,319

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

   $ (22.12   $ (23.24   $ (9.96   $ (12.81

Weighted average common shares outstanding, basic and diluted

     1,086,697       954,750       1,199,164       961,431  

Balance sheets (unaudited)

 

(In $ thousands)    June 30,
2018
    December 31,
2017
 

Cash and cash equivalents

   $ 88,540     $ 16,404  

Other current assets

     2,065       1,318  

Total assets

     94,622       19,103  

Current liabilities

     9,413       11,131  

Total liabilities

     10,003       11,708  

Convertible preferred stock

     272,834       173,228  

Total stockholders’ deficit

   $ (188,215   $ (165,833

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. With a decade of experience in the field, the Company has a deep understanding of how epigenetic regulators modulate gene expression in cancer cells and in the tumor and immune microenvironment. Constellation is translating these insights to advance the company’s two lead clinical programs, the EZH2 inhibitor CPI-1205 for metastatic castration-resistant prostate cancer and solid tumors and the BET inhibitor CPI-0610 for myelofibrosis, and to explore other novel targets for which cancer epigenetics may enhance outcomes over currently available treatment options.


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, its anticipated achievement of milestones and its ability to fund its operations with cash on hand. 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 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, and other important factors, 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.

Contact

Ronald Aldridge

Investor Relations

Constellation Pharmaceuticals

+1 617-714-0539

ron.aldridge@constellationpharma.com

EX-99.2

Slide 1

Corporate Overview Developing Treatments Targeting Epigenetic Mechanisms in Tumor and Immune Cells for Cancer Patients August 2018 Exhibit 99.2


Slide 2

This presentation contains forward-looking statements that involve substantial risks and uncertainties, including the factors described under the Risk Factors section of our most recent filings with the Securities and Exchange Commission. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans, and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “target,” “should,” “would,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements. In addition, the forward-looking statements included in this presentation represent our views as of the date of this presentation. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this presentation. Forward-Looking Statements


Slide 3

Multiple Lead Clinical Programs CPI-1205 (EZH2) and CPI-0610 (BET) Encouraging Preliminary Clinical Data Prostate Cancer, Solid Tumors (Checkpoint Inhibitor Combos) 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

Epigenetics – Instructions for Genetic Code Master Regulator of Cell Fate Driving Discovery of Novel Therapeutics 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

EZH2 Franchise


Slide 7

EZH2 Inhibition Offers Broad Therapeutic Potential EZH2 “Writer” Activity Suppresses Gene Transcription EZH2 Polycomb Repressor 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: A mutation in the EZH2 gene alters EZH2 activity, which cancer cells depend on for growth Acquired Drug Resistance: EZH2 mediates gene silencing that leads to drug resistance


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 tumor 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 Yu et al., Cancer Research 2007 EZH2 gene signature* predicts outcomes in prostate cancer Pro-tumor signaling Enhances AR signaling K27 OFF EZH2 Coregulators AR AR Prostate tumor growth Chromatin EZH2 potentially enhances androgen signaling and promotes prostate tumor growth Combining EZH2 inhibition with androgen inhibitors could lead to synergistic effects *Signature of H3K27me3-occupied EZH2 target genes repressed in metastatic relative to clinically localized prostate cancer and benign prostate tissue


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 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 10-30% PSA Response* < 3 Months PSA PFS No Objective Responses EZH2 inhibition may enhance the activity of ARS inhibitors in 2nd Line mCRPC *% of patients achieving 50% PSA reduction; PSA: Prostate-Specific Antigen; PFS: Progression Free Survival


Slide 12

ProSTAR Trial Design Second-Line Trial After Ineffective Treatment on 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 RP2D vs. Primary endpoints: MTD, RP2D Primary endpoint: Response rate PSA reduction; CTC reduction; or Objective response Selected CPI-1205 + ARSi combo


Slide 13

Resolution of Bone Metastases Baseline Cycle 4 Day 1 CPI-1205 + Enzalutamide


Slide 14

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


Slide 15

ProSTAR Trial: Treatment Duration Data Cutoff May 25, 2018 Discontinued Treatment *Continued on CPI-1205 monotherapy after cycle 1 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 *


Slide 16

Summary of ProSTAR Efficacy Data Patients with > 1 Cycle of Therapy as of May 25, 2018 CPI-1205 + … Prognostic Factor at Baseline* Best PSA Response Best CTC Response Response on Metastatic Disease 1 Enzalutamide Not Applicable ↓85% Not Applicable Bone Mets Resolution 2 Enzalutamide CTC ↓83% ↓40% Complete Response 3 Abiraterone Not Applicable ↓10% Not Applicable TBD 4 Abiraterone CTC Not Evaluable TBD TBD 5 Enzalutamide CTC, ARV7 Stable ↑13% TBD 6 Enzalutamide CTC, ARV7 ↑120% ↓54% TBD 7 Enzalutamide CTC Stable ↑41% TBD * CTCs unfavorable at baseline or ARV7-positive at baseline Stable PSA = % PSA change < 50% Stable CTC = % CTC change < 30%


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 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

RP2D 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 CPI-0209 may provide more comprehensive EZH2 coverage, expanding addressable populations Vehicle Tazemetostat, 160 mg/kg oral, twice daily Lymphoma Xenograft Mouse Model


Slide 21

CPI-1205: Significant unmet medical need in second-line mCRPC Preclinical evidence of synergy with ARS inhibitors and immune checkpoint inhibitors Early clinical responses in combination studies as of May 25, 2018: objective responses, PSA reductions, CTC reductions We expect to evaluate ProSTAR proof of concept in mid-2019 CPI-0209: More comprehensive coverage of EZH2, with potentially broader use in oncology EZH2 Franchise: Summary


Slide 22

BET Inhibitor CPI-0610


Slide 23

BET – Epigenetic “Reader” Control of Key Oncogenic, Immune, Fibrotic Pathways Leads to Opportunity in Myelofibrosis Enhancer TSS BRD4 Transcription Factor … … Fibrosis TGF-b target genes Cancer Genetics MYC, BCL2 Immune Signaling NF-kB target genes


Slide 24

Treated 138 patients in Phase 1 trials of hematologic malignancies Favorable PK/PD profile Multiple objective responses at a range of doses below the maximum tolerated dose Activity established in the context of NF-κB-driven diseases ABC-DLBCL (Phase 1) 7 patients: 1 CR, 2 PR, 1 SD (16+ months) Myelofibrosis (Phase 2) 4 patients: 2 combo with ruxolitinib, 2 monotherapy Evidence of reduction in spleen size and symptom improvement; transfusion independence achieved in one patient CPI-0610 Background


Slide 25

Myelofibrosis Background Source: MPN Research Foundation Only approved treatment is ruxolitinib (Jakafi) based on spleen volume reduction and symptom improvement ~75% of ruxolitinib patients discontinued after five years in COMFORT-I and -II* 57% of ruxolitinib patients required dose reductions due to adverse events in COMFORT-I** Transfusion dependence increases on ruxolitinib in SIMPLIFY-1*** SIMPLIFY-1, Gilead (momelotinib) *Verstovsek S, Mesa RA, Gotlib J, et al. ; COMFORT-I Investigators. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015;100(4):479-488. Harrison CN, Vannucchi AM, Kiladjian JJ, et al.; Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis [published correction appears inLeukemia. 2017;31(3):775]. Leukemia. 2016;30(8):1701-1707. **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. ***Mesa, R, et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor–Naıve Patients With Myelofibrosis J Clin Oncol 2017; 35(34):3844-3850.


Slide 26

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


Slide 27

Inflammatory Cytokines Associated with Clinical Outcomes and CPI-0610 Target Engagement Barabanshikova (2017) Oncol Res Treat Reduced Survival in Patients with High Levels of IL-8 Reduction of IL-8 in NHL Patient Blood (PD Assay in Clinic) IL8 expression Concentration of CPI-0610 mM


Slide 28

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 Rationale for BET’s Role in Myelofibrosis


Slide 29

MANIFEST: CPI-0610 Phase 2 Trial in Myelofibrosis Objectives: Evaluate spleen size reduction after 24 weeks of treatment Evaluate patient-reported symptom improvement Evaluate transfusion independence rate, if applicable CPI-0610 + ruxolitinib n=35 CPI-0610 n=35 CPI-0610 dosing of 125mg up to 225mg once daily in both arms 2L MF patients on ruxolitinib despite disease progression on therapy 2L MF patients not eligible for, or no longer on, ruxolitinib


Slide 30

CPI-0610 Myelofibrosis Phase 2 Trial Status Update Data Cutoff May 25, 2018 Significantly reduced spleen size in all four evaluable patients by MRI Reduced spleen size Symptom improvement 1 patient with thrombocytosis and 1 patient transfusion dependent at baseline – both resolved Ongoing > 10 months Ongoing > 5 months


Slide 31

CPI-0160 Improving Hemoglobin Levels and Transfusion Dependence Data Cutoff May 25, 2018 Patient treated with CPI-0610 + ruxolitinib combination therapy Example: Transfusion independence and improved hemoglobin levels CPI-0610 Improved Hemoglobin Levels in Each Patient Treated


Slide 32

Significant unmet medical need: most patients are ineligible for, or have inadequate long-term response to, ruxolitinib Positive preliminary clinical data in each MANIFEST patient as of May 25, 2018 (spleen reduction, improvement in hematological parameters) Preliminary evidence suggests disease-modifying properties Key goals: enroll additional patients, demonstrate proof of concept by mid-2019, and determine subsets of patients most likely to benefit in order to drive optimal design of pivotal study CPI-0610 Summary


Slide 33

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


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Financial Strength


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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 Successful IPO in July raised $60 million in gross proceeds, excluding underwriting fees Post-IPO cash expected to fund operations through 1Q20, 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 and preclinical operations Financial Strength


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Summary of Financial Results $ millions, except per-share amounts 1H18 1H17 2Q18 2Q17 R&D Expenses $19.4 $14.9 $9.5 $8.0 G&A Expenses $4.8 $2.7 $2.5 $1.5 Other Income (Expense), Net $0.2 $3.8 $0.1 $1.5 Cumulative Dividends on Convertible Preferred Stock -- ($8.5) -- ($4.3) Net Loss Attributable to Common Stockholders ($24.0) ($22.2) ($11.9) ($12.3) Net Loss Per Share Attributable to Common Stockholders ($22.12) ($23.24) ($9.96) ($12.81) R&D expenses increased due to higher CPI-1205 clinical expenses G&A expenses increased due to building organization for multi-candidate clinical company and IPO costs


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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


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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


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Appendix


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Preclinical Results Activity at picomolar concentrations Excellent in vivo PK/PD relationship Highly selective for EZH2 Effective tumor regression Phase 1 Clinical Results Initial exploration in lymphoma Single agent activity observed PK/PD relationship established Well tolerated Screening Cycle 4 Follicular Lymphoma Compelling Preclinical and Phase 1 Data for CPI-1205 Tumor Reduction and Safety Established in Phase 1 Testing Screening Cycle 4 CPI-1205 100 mg/kg twice/day Lymphoma Xenograft Mouse Model


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