lirametostat (CPI-1205) / Novartis - LARVOL DELTA

ProSTAR: A Study Evaluating CPI-1205 in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=175 | Completed | Sponsor: Constellation Pharmaceuticals | Phase classification: P1b/2 ➔ P1/2 | Active, not recruiting ➔ Completed

Phase classification • Trial completion • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Enhancer of zeste homolog 2 inhibitors overcome glucocorticoid resistance in acute lymphoblastic leukemia by augmenting pro-apoptotic signaling (AACR 2024) - "Hypothesis EZH2 inhibitors may enhance GC efficacy by augmenting downstream effects of GCs.Methods We performed in-vitro studies of EZH2 inhibitors, EPZ-6438 and CPI-1205, at graded doses in GC resistance human-derived B-cell (SUPB15) and T-cell (SUPT1, KOPTK1, PEER) ALL cell lines followed by graded doses of dexamethasone (dex). Furthermore, in-vivo testing of EZH2 inhibitors in patient derived xenografts will be performed. Conclusion EZH2 inhibitors can overcome GC resistance in ALL posing as a potential novel therapeutic agent to treat relapsed/refractory ALL."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5 • BCL2L11 • NR3C1

EZH2 inhibitors increase the activity of carboplatin in aggressive variant prostate cancer by modulating DNA repair pathways (EACR-AACR 2024) - "We then determined the effects of clinically-tested EZH2 inhibitors (GSK-126, Tazemetostat, CPI-1205) on nuclear and cell-free H3K27me3 levels. Further analysis showed that EZH2 inhibitors reduce the expression of key DNA repair genes that are implicated in carboplatin resistance (e.g. ERCC1 , ERCC2, P53) . Conclusion The combination of EZH2 inhibitors and carboplatin is a promising treatment for AVPC."

Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • AR • ERCC1 • ERCC2 • EZH2

ProSTAR: A phase Ib/II study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2019) - P1b/2; "The co-primary endpoint includes PSA50 and composite response rate (either CTC 30% reduction or ORR per PCWG3). Patient accrual in US sites began in December 2017."

Clinical • P1/2 data

EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine. (PubMed, Sci Rep) - "The EZH2 inhibitor GSK126 also repressed proliferation of CNDT2.5 cells. Exposure of GOT1 three-dimensional cell spheroids to CPI-1205 or metformin arrested cell proliferation and decreased spheroid size. These novel findings support a possible role of EZH2 as a candidate oncogene in SI-NETs, and suggest that CPI-1205 and metformin should be further evaluated as therapeutic options for patients with SI-NETs."

Journal • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Small Intestinal Carcinoma • Solid Tumor • EZH2

ProSTAR: A phase Ib/II study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2019) - P1b/2; "The co-primary endpoint includes PSA50 and composite response rate (either CTC 30% reduction or ORR per PCWG3). Patient accrual in US sites began in December 2017."

Clinical • P1/2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A phase 1b/2 study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration resistant prostate cancer (mCRPC). (ASCO-GU 2018) - "Secondary objectives include safety, pharmacokinetic, pharmacodynamics profiles and activity (PSA, circulating tumor cells, imaging) in mCRPC. Once RP2D is established, we will start a Phase 2 trial of a 2nd generation androgen inhibitor combined with CPI-1205."

Clinical • P1/2 data • Non-Hodgkin’s Lymphoma • Prostate Cancer

Phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) (AACR 2019) - "Both CPI-1205 800 mg PO TID and 400 mg PO BID plus cobicistat, combined with full doses of either E or A/P, are well tolerated, with acceptable safety. Encouraging clinical activity has been observed. CPI-1205 800 mg PO TID + E or A/P has been selected for phase 2 expansion, and patient enrollment is ongoing"

Clinical • P1 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

ProSTAR: A Study Evaluating CPI-1205 in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1b/2; N=242; Active, not recruiting; Sponsor: Constellation Pharmaceuticals; Trial completion date: May 2021 ➔ Dec 2021; Trial primary completion date: May 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

ORIOn-E: A Study Evaluating CPI-1205 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: Constellation Pharmaceuticals; Active, not recruiting ➔ Completed; Phase classification: P1/2 ➔ P1

Clinical • Pan tumor • Phase classification • Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

ProSTAR: A Study Evaluating CPI-1205 in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1b/2; N=242; Active, not recruiting; Sponsor: Constellation Pharmaceuticals; Trial completion date: Dec 2020 ➔ May 2021; Trial primary completion date: Dec 2020 ➔ May 2021

Clinical • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

ProSTAR: A Study Evaluating CPI-1205 in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1b/2; N=242; Active, not recruiting; Sponsor: Constellation Pharmaceuticals; Trial completion date: Aug 2020 ➔ Dec 2020; Trial primary completion date: Aug 2020 ➔ Dec 2020

Clinical • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

CPI-1205 + Ipilimumab: “1 PR + 3 SD out of 6 patients 0 1 2 3 4 treated with CPI-1205 + ipilimumab”; Advanced solid tumors (Constellation Pharmaceuticals) - Investor Presentation: "42% Reduction in Tumor Volume from Baseline"

P1/2 data • Oncology • Solid Tumor

Constellation Pharmaceuticals highlights EZH2 inhibition program in prostate cancer at Biomedical Conference (GlobeNewswire) - "The presentation discusses preclinical evidence showing the effectiveness of the EZH2 inhibitor CPI-1205 in treating metastatic castration-resistant prostate cancer (mCRPC) dependent on androgen receptor signaling (ARS). CPI-1205 was shown to combine synergistically with ARS inhibitors, such as enzalutamide or abiraterone acetate, to inhibit the growth of prostate cancer cell models and also was effective in overcoming mechanisms of resistance to ARS inhibitors."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Urothelial Cancer

A phase 1 study of CPI-1205, a small molecule inhibitor of EZH2, preliminary safety in patients with Bcell lymphomas (TAT 2018) - P1; "Based upon the safety profile/PD of CPI-1205, an expansion phase in GCB-DLBCL or FL with/out EZH2 mutation was initiated at 800mg BID and subsequently TID. Additional trials using CPI-1205 in combination in solid tumors are ongoing."

Clinical • P1 data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

CPI-1205: “2 of 4 evaluable patients with CTCs achieved CTC reduction of > 30%”; Metastatic prostate cancer (Constellation Pharmaceuticals) - Investor Presentation: "2 of 2 evaluable patients had resolution of metastatic disease"

P1/2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Urothelial Cancer

ProSTAR: A Study Evaluating CPI-1205 in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1b/2; N=242; Active, not recruiting; Sponsor: Constellation Pharmaceuticals; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

CPI-1205: Mid-year data update from P1/2 ProSTAR trial (NCT03480646) for mCRPC in H1 2020 (Constellation Pharmaceuticals) - Corporate Presentation

P1/2 data

Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. (PubMed, J Clin Invest) - "We hypothesized that inhibition of EZH2 expression in T cells would increase the effectiveness of anti-CTLA-4 therapy, which we tested in murine models. Collectively, our data demonstrated that modulating EZH2 expression in T cells can improve anti-tumor responses elicited by anti-CTLA-4 therapy, which provides a strong rationale for a combination trial of CPI-1205 plus ipilimumab."

Clinical • IO Biomarker • Journal

A Study Evaluating CPI-1205 in Patients With B-Cell Lymphomas (clinicaltrials.gov) - P1; N=41; Completed; Sponsor: Constellation Pharmaceuticals; Active, not recruiting ➔ Completed

Clinical • Trial completion

Constellation Pharmaceuticals announces second-quarter and six-month 2019 financial results (Constellation Pharma Press Release) - "The Company anticipates achieving the following milestones during the second half of 2019: Dose the first patients in a Phase 1 clinical trial of CPI-0209. Provide an update from the ProSTAR clinical trial of CPI-1205 across various patient contexts."

Enrollment status • P1/2 data

Constellation Pharmaceuticals Presentation Highlights Enhanced EZH2 Target Engagement, Leading to Second-Generation EZH2 Inhibitor CPI-0209 (GlobeNewswire, Constellation Pharmaceuticals , Inc.) - The culmination of the Company’s second-generation EZH2 inhibitor program was the identification of CPI-0209, which reversibly binds to the PRC2 complex with sub-pM binding affinity and a residence time of >3 months. Constellation expects to file an Investigational New Drug (IND) application for CPI-0209 in June 2019. 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

Preclinical • Regulatory

CPI-1205: “The combination of CPI-1205 800 mg TID or 400 mg BID with C administered with E or A/P were generally well tolerated”; Metastatic castration-resistant prostate cancer (Constellation Pharmaceuticals) - AACR 2019: “The CPI-1205 TID dosing regimen was suf­ficient to elicit a substantial PD response with similar results observed when combined with either E or A/P”

P1 data

Constellation Pharmaceuticals Announces First-Quarter 2019 Financial Results (GlobeNewswire, Constellation Pharmaceuticals , Inc.) - Company to present an interim update of data from the MANIFEST clinical trial of CPI-0610 at ASCO on June 3 and at EHA on June 15...Additionally, we expect to provide...an interim update of data from the Phase 2 portion of the ProSTAR trial for CPI-1205 [and] additional data update from the MANIFEST trial for CPI-0610...in the second half of 2019.

Clinical data

Constellation Pharmaceuticals Presents Results from Phase 1b Portion of ProSTAR Clinical Trial of CPI-1205 at AACR Meeting (GlobeNewswire, Constellation Pharmaceuticals , Inc.) - P1/2, N=242; ProSTAR (NCT03480646); Sponsor: Constellation Pharmaceuticals; "All PSA responses seen in the trial were ≥80%, deeper than the ≥50% reduction endpoint in the trial. All PSA responses were found in AR-V7-negative patients. Two out of 18 patients in the abiraterone arm achieved PSA reductions of more than 80%. Patients being treated with abiraterone after enzalutamide historically have been shown to achieve poor PSA responses and rapid time to disease progression...The Company expects to provide an initial update from the Phase 2 portion of ProSTAR in the second half of 2019."

P1/2 data