Form 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): December 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 December 10, 2018, the Company issued a press release entitled “Constellation Pharmaceuticals Initiates Phase 2 Portion of ProSTAR Clinical Trial in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC)” announcing that the Phase 1b portion of the ProSTAR trial had met its endpoints and the first dosing of patients in Phase 2 has begun. 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 December 10, 2018, 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 December 10, 2018 (furnished herewith)

99.2   

Corporate Overview dated December 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: December 10, 2018     By:   /s/ Emma Reeve
     

Name: Emma Reeve

Title: Chief Financial Officer

     
EX-99.1

Exhibit 99.1

 

Constellation Pharmaceuticals Initiates Phase 2 Portion of ProSTAR Clinical Trial in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC)

 

   

Dosing has begun in a randomized study of CPI-1205 / enzalutamide combination versus enzalutamide alone in second-line mCRPC

 

   

Single-arm CPI-1205 / abiraterone / prednisone combination added to potentially address low response rates and short duration of response in second-line mCRPC with abiraterone alone

 

   

Preliminary Phase 1b results suggest CPI-1205 is well-tolerated, with a robust PK/PD profile and clinical activity in both arms in second-line mCRPC

CAMBRIDGE, Massachusetts, December 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 an update of the ProSTAR study, its ongoing Phase 1b/2 clinical trial of CPI-1205 in patients with metastatic castration-resistant prostate cancer (mCRPC).

The ProSTAR study is evaluating CPI-1205, Constellation’s potent and highly selective small-molecule EZH2 inhibitor, in combination with either enzalutamide or abiraterone / prednisone (“abiraterone”), in mCRPC patients who experienced disease progression while receiving the other ARS inhibitor. Based on encouraging results from the Phase 1b portion of ProSTAR, the Company has initiated dosing in the randomized Phase 2 portion studying CPI-1205 in combination with enzalutamide versus enzalutamide alone. Constellation has also decided to expand the Phase 2 portion of the study by adding an arm evaluating CPI-1205 in combination with abiraterone in the second-line setting.

“We are pleased that CPI-1205 achieved its Phase 1b endpoints in ProSTAR, demonstrating an encouraging safety profile and evidence of clinical activity in both arms,” said Adrian Senderowicz, Chief Medical Officer of Constellation


Pharmaceuticals. “As we advance into the Phase 2 portion of the study, we believe combination therapy with CPI-1205 may provide a meaningful second-line treatment option to patients with metastatic castration-resistant prostate cancer, an area of significant unmet medical need. We are excited about expanding our opportunity to include an arm evaluating CPI-1205 in combination with abiraterone in the second-line setting, given that very few patients experience a 50% reduction in PSAs on second-line treatment with abiraterone and that time to progression in this setting is typically short.”

Initiation and Expansion of Phase 2 Portion of ProSTAR

As planned, Constellation has already begun dosing patients in the Phase 2 portion of the study, evaluating CPI-1205 in combination with enzalutamide versus enzalutamide alone. The Company continues to expect enrollment of up to 35 patients in both the treatment and the control arms.

Additionally, Constellation is expanding the trial to include a separate Phase 2 arm evaluating CPI-1205 in combination with abiraterone in up to 30 mCRPC patients who progressed on prior enzalutamide therapy. This arm, which will soon begin dosing patients, will not be randomized against a control arm due to the low response rate and lack of durability seen with abiraterone in the second-line setting.

In a recent randomized cross-over trial, only 4% of patients taking abiraterone after disease progression on enzalutamide, and only 31% of patients taking enzalutamide after disease progression on abiraterone, achieved a 50% reduction in PSA levels. Time to PSA progression was only 1.3 months and 2.7 months, respectively. Time to disease progression was only 1.6 months and 2.7 months, respectively.1

Constellation continues to expect to determine proof of concept for CPI-1205 in mid-2019.

1 D. Khalaf et al, Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mCRPC): results for 2nd-line therapy, poster presented at 2018 American Society of Clinical Oncology meeting.

About mCRPC

mCRPC is an advanced form of prostate cancer and is defined by disease progression despite treatment with androgen depletion therapy (ADT). mCRPC may present as one or any combination of the following: a continuous rise in serum levels of PSA, progression of known metastases, or appearance of new metastases. Prognosis is associated with several factors, including the


ability to perform certain daily activities and the presence of bone pain. Additional symptoms commonly include anemia (low healthy red blood cell levels), weight loss, fatigue, hypercoagulability (abnormal blood coagulation), and increased susceptibility to infection. mCRPC presents as a spectrum of disease ranging from patients without symptoms but rising PSA levels despite ADT, to patients with metastases and significant debilitation.

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; 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 is investigational in nature and has 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 December 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 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 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 for Pembro Arm Early 2019* CPI-0209 (2nd Gen) Solid Tumors / Heme Malignancies Initiate Phase 1 Mid 2019 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 Trial * Further development not anticipated due to other corporate priorities


Slide 6

CPI-1205 and CPI-0209 EZH2 Franchise


Slide 7

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 which create a functional dependency on EZH2 Regulation of Immune Cells: EZH2 reprograms T cells to suppress an anti-tumor immune response


Slide 8

*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 Yu et al., Cancer Research 2007 Pro-tumor Signaling Enhances AR Signaling K27 OFF EZH2 Coregulators Prostate Tumor Growth Chromatin AR AR 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


Slide 9

Evidence of EZH2 Synergy with Androgen Receptor Signaling (ARS) CPI-1205 Enhances the Gene Signature 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


Slide 10

2L mCRPC Patients Suffer Poor and Short Responses to Abiraterone and Enzalutamide *ASCO 2018 Poster Khalaf, et al (Kim Chi Lab) PSA 80 > PSA30 = 6% > PSA50 = 4% > PSA80 = 0% PSA PFS = 1.3 months TTP = 1.6 months > PSA30 = 43% > PSA50 = 31% > PSA80 = 10% PSA PFS = 2.7 months TTP = 2.7 months Goal: Treat with CPI-1205 combination therapy to achieve deeper and more durable responses


Slide 11

Current Treatment Paradigm in mCRPC mCRPC 1st Line Abiraterone or Enzalutamide 2nd Line Enzalutamide or Abiraterone (Poor Activity) 3rd Line Chemotherapy or Palliative Care EZH2 inhibition may enhance the activity of ARS inhibitors and reduce need for chemotherapy Pre-Metastatic Prostate Cancer May Expand Future CPI-1205 Opportunity ARSi Moving Upstream


Slide 12

Phase 2 Expanded to Include Enzalutamide and Abiraterone ProSTAR Trial Design Testing Biomarkers for Patient Enrichment Enzalutamide + CPI-1205 (Progressed on Abiraterone) n = ~ 35 Enzalutamide Alone (Progressed on Abiraterone) n = ~ 35 vs. Primary endpoints: MTD, RP2D Primary endpoint: Response rate PSA reduction, CTC Reduction, ORR Enzalutamide + CPI-1205 (Prior Abiraterone Progression) Abiraterone + CPI-1205 (Prior Enzalutamide Progression) Phase 1b Phase 2 CPI+1205 Abiraterone (Progressed on Enzalutamide) n = ~ 30 Initiated Note: In ProSTAR, abiraterone is dosed in combination with prednisone


Slide 13

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


Slide 14

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


Slide 15

Data cutoff May 25, 2018 *Continued on CPI-1205 monotherapy after cycle 1 Discontinued treatment ProSTAR Trial: Treatment Duration 2 of 6 evaluable patients achieved PSA reduction of >80% 2 of 4 evaluable patients with CTCs achieved CTC reduction of > 30% 2 of 2 evaluable patients had resolution of metastatic disease C1D1 C2D1C3D1 C4D1C5D1C6D1 C7D1 Cycles of Treatment (One Cycle = One Month) Patient # 1 2 3 4 5 6 7 8 9 10 CPI-1205 + Abiraterone CPI-1205 + Enzalutamide *


Slide 16

Phase 1b Endpoints achieved Well-tolerated Robust PK/PD profile Clinical activity across all three parameters (objective responses, PSA reductions, CTC reductions) In combination with either abiraterone or enzalutamide Phase 2 Expansion Portion of ProSTAR Initiated Expanding original plan in order to study combos with either enzalutamide or abiraterone Randomized arm with CPI-1205 800 mg TID (RP2D) + enzalutamide versus enzalutamide alone Single arm with CPI-1205 800 mg TID + abiraterone Not randomized against control arm due to low response rate and durability in abiraterone in 2L 4% of patients on 2L abiraterone experience PSA50 response (Khalaf, et al ASCO 2018) Time to disease progression in 2L abiraterone is only about 1.6 months ProSTAR Phase 2 Initiated


Slide 17

Significant PSA Reduction in Heavily Pre-Treated and Refractory Patient Experience with a Compassionate-Use Patient 3,000 2,500 2,000 1,500 1,000 500 12 agents prior to CPI-1205, including second-generation androgen inhibitors, chemotherapy, PARP inhibitors, tyrosine kinase inhibitors, checkpoint inhibitors, radium 223, and radiotherapy Start CPI-1205 + Enzalutamide (PSA ~ 2900) PSA Score (ng/mL) 80% reduction in PSA levels Evidence of tumor size reduction in the neck 6/1/2016 9/1/2016 12/1/2016 3/1/2017 6/1/2017 9/1/2017 12/1/2017 3/1/2018 PSA levels escalated significantly in final year of treatment prior to CPI-1205 + enzalutamide Treatment interrupted due to non-treatment-related pneumonia Subsequent progression in liver led to discontinuation. Patient later died. Expansion cohort in advanced prostate cancer initiated to evaluate potential anti-tumor activity


Slide 18

Tazemetostat CPI-0209 Once-Daily Treatment Resulted in Rapid, Complete, and Durable Tumor Regression CPI-0209: Second-Generation EZH2 Inhibitor CPI-0209 May Provide More Comprehensive EZH2 Coverage, Expanding Addressable Populations Lymphoma Xenograft Mouse Model Vehicle Tazemetostat, 160 mg/kg oral, twice daily Vehicle CPI-0209, 25 mg/kg oral, once daily Cessation of treatment


Slide 19

CPI-0610 BET Inhibitor


Slide 20

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 Concentration of CPI-0610 mM Correlation Between IL-8 (NF-kB Target Gene) Expression and CPI-0610 Exposure (Constellation Data)


Slide 21

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 22

BET Inhibition May Block Proliferation of Inflammatory Bone Marrow Cells and Synergize with JAK Inhibition BET Role in Myelofibrosis 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 23

Constellation Pharmaceuticals Data Rationale for Targeting BET Inhibition in Myelofibrosis CPI-0610 vs DMSO 25 nM 100 nM 400 nM Vehicle 1–2+ JQ1 (BETi) 1+ Ruxolitinib 1+ Combo 0 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


Slide 24

Myeloproliferative neoplasm characterized by scarring (fibrosis) of the bone marrow caused by impaired hematopoiesis 17,000–20,000 diagnosed 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 25

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-1** 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 26

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 Need for New Disease-Modifying Treatments in MF *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 35% Decrease Individual Patients Ruxolitinib Spleen Response – SIMPLIFY-1* Change in Spleen Volume from Baseline (%) 150% 100% 50% 0% -50% -100% MMB (n = 184) RUX (n = 204) Change in TSS from Baseline (%) 150% 100% 50% 0% -50% -100% Ruxolitinib TSS Response – SIMPLIFY-1* Individual Patients 50% Decrease MMB (n = 174) RUX (n = 190) 28.4% TSS50 42.2% TSS50 Transfusion Dependence – SIMPLIFY-1*


Slide 27

First-line arm in combination with ruxolitinib aims to address inadequate response to ruxolitinib alone in spleen volume reduction, patient-reported symptom improvement, and other factors, including lack of disease-modifying effects of ruxolitinib Second-line arm aims to provide a treatment option, as a monotherapy and in combination with ruxolitinib, for patients with disease progression after ruxolitinib, looking for: Spleen volume reduction and patient-reported symptom improvement Improvement in transfusion independence rate in patients who are transfusion dependent Evidence of disease modification/improved hematopoietic function Rationale for MANIFEST Design


Slide 28

* Cohort 3 will enroll anemic patients, pivotal trial plans would include all comers Robust Development Plan to Expand the CPI-0610 Opportunity MANIFEST: Expanded Phase 2 Trial in MF Cohort 1A: 2L Transfusion Dependent (TD) n = ~ 16 Cohort 1B: 2L Non-TD n = ~ 25 Cohort 2A: 2L Transfusion Dependent n = ~ 16 Cohort 2B: 2L Non-TD n = ~ 25 Cohort 3: 1L* n = ~ 43 CPI-0610 Mono CPI-0610 + Rux CPI-0610 + Rux 2L MF patients no longer on ruxolitinib 2L MF patients on ruxolitinib despite disease progression on therapy 1L MF patients 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 29

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


Slide 30

Data cutoff May 25, 2018 Patient Achieved Transfusion Independence and Improved Platelet Count Improved Hematopoiesis on CPI-0610 Patient treated with CPI-0610 + ruxolitinib combination therapy Transfusions No Transfusions for >24 Weeks 4 wks 4 wks 4 wks 6 wks


Slide 31

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


Slide 32

CPI-0610 has demonstrated clinical activity in early clinical trials with NF-κB-driven cancers, including myelofibrosis, suggesting CPI-0610 may be differentiated among BET inhibitors Preliminary 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 33

Discovery Platform Fueling the Pipeline Innate Adaptive Normalize 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


Slide 34

Financial Strength


Slide 35

Potential Value Creation Catalysts 2019 2018 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 Early 2019 ORIOn-E safety and recommended Phase 2 dose (RP2D) Mid 2019 ProSTAR (CPI-1205) proof of concept MANIFEST (CPI-0610) proof of concept Initiate Phase 1 for CPI-0209


Slide 36

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 September 30, 2018, of $128.5 million Strong Cash Position $ Millions, Except Per-share Amounts 9M18 3Q18 R&D Expenses $32.1 $12.7 G&A Expenses $8.5 $3.7 Other Income (Expense), Net $0.6 $0.5 Net Loss Attributable to Common Stockholders ($40.0) ($15.9) Net Loss Per Share Attributable to Common Stockholders ($5.45) ($0.81)


Slide 37

Management Team 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 Chief Scientific Officer Karen Valentine Chief Legal Officer, General Counsel 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 Med. Board of Directors Founders & Scientific Advisory Board Mark Goldsmith, M.D., Ph.D. (Chairman), CEO, Revolution Medicines Jigar Raythatha Jim Audia, Ph.D., Chicago Biomedical Consortium Tony Evnin, Ph.D., Venrock Steven Hoerter, Agios Pharmaceuticals Peter Svennilson, The Column Group Bob Tepper, M.D., Third Rock Ventures Elizabeth Tréhu, M.D., Jounce Therapeutics