On October 7, 2021 -Forma Therapeutics Holdings, Inc. (Nasdaq: FMTX), a clinical-stage biopharmaceutical company focused on sickle cell disease, prostate cancer and other rare hematologic diseases and cancers, reported positive initial results from a Phase 1 trial of its novel CBP/p300 inhibitor, the oral small molecule FT-7051, in men with metastatic castration-resistant prostate cancer (mCRPC) (Press release, Forma Therapeutics, OCT 7, 2021, View Source [SID1234590945]). Initial clinical data from the Courage Study, an ongoing first-in-human Phase 1 trial presented at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), showed an encouraging safety profile of FT-7051, as well as high specificity to the CBP/p300 pathway.
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"Preliminary data from the Courage Study are promising," said Andrew J. Armstrong, M.D., principal investigator of the Courage Study, and Professor of Medicine, Pharmacology and Cancer Biology, and Director of Research at the Duke Cancer Institute Center for Prostate and Urologic Cancers. "Managing the balance between safety, tolerability and efficacy is a key element of targeting this pathway, and thus far the doses studied are achieving pharmacodynamic target engagement with acceptable tolerability."
Preliminary results reported today include data as of Sept. 1, 2021, from eight men enrolled in the trial. FT-7051 was administered in 28-day cycles, with 21 days of dosing followed by seven days of no dosing. Three patients remain on study; five patients left the study (four due to disease progression and one withdrawal of consent). The adaptive trial design is intended to efficiently explore safe and efficacious doses of FT-7051. Prior to enrollment, all of the men had received diagnoses of mCRPC, castration-levels of serum testosterone and rising levels of the biomarker prostate specific antigen (PSA) after the failure of at least two lines of therapy with an approved androgen-receptor pathway inhibitor.
The initial pharmacokinetic (PK) analysis of FT-7051 documented rapid absorption, which produced maximum blood concentrations within two hours. The 150 mg dose achieved drug concentrations that approached the predicted efficacious dose based on modeling with preclinical results. Skin biopsies of the men participating in the study demonstrated a reduction in H3K27AC, a marker of activity in the CBP/p300 pathway, the target of FT-7051.
The majority of the treatment-emergent adverse events (TEAEs) were mild or moderate, at Grade 2 or lower, with no events leading to treatment discontinuation. One patient experienced Grade 3 hyperglycemia, which was medically managed. Following a dose reduction, this patient remained on treatment and experienced an ongoing PSA decline of greater than 50% at 12 weeks and greater than 80% at 16 weeks. Based upon these safety results, dose escalation is ongoing. The trial is continuing according to its adaptive design to further understand the safety and tolerability of FT-7051, gather data on clinical response including PSA and radiographic tumor response, as well as the assessment of secondary endpoints of clinical response.
"There is substantial need for new therapies to treat those with mCRPC as they progress while on existing lines of anti-androgen or chemotherapy," said David N. Cook, Ph.D., senior vice president, Forma Therapeutics’ chief scientific officer. "Thanks to the eight patients who participated in the Courage Study to date, we have made progress in understanding the potential of CBP/p300 inhibition in prostate cancer and look forward to continuing our dose escalation study."
Presentation Details
Abstract P202: Initial Findings from an Ongoing First-in-human Phase 1 Study of the CBP/p300 Inhibitor FT-7051 in Men with Metastatic Castration-Resistant Prostate Cancer (Link)
Abstract P204: Targeting the p300/CBP Epigenetic Pathway to Overcome Hormone Therapy Resistance in Advanced Prostate Cancer
Forma continues to enroll men into the Courage Study. For more information, please visit View Source or View Source
About CBP/p300
Tumor resistance to anti-androgen therapies can arise due to mutations and other changes within the androgen receptor (AR). Androgen binds to two paired proteins in ARs, CBP and p300, in a location that is highly resistant to mutations known as the bromodomain. FT-7051 is designed to attach to the CBP/p300 bromodomain potently and selectively, which then blocks androgen binding and reduces AR activation. In preclinical studies, FT-7501 demonstrated activity in both prostate cancer models that were sensitive or resistant to the approved androgen-inhibitor medicine enzalutamide.
About Prostate Cancer
Prostate cancer is the second most frequent cancer in men globally, accounting for more than 1.4 million new diagnoses and 6.8 percent of all male cancer deaths in 2020.1 In the United States, more than 248,000 men will be diagnosed with prostate cancer in 2021, and the disease will account for more than 34,000 deaths.2 When cancer has spread beyond the prostate and surgery or radiation are not an option, first-line treatment suppresses the male hormone androgen because it can stimulate prostate cancer cell growth.3,4 This treatment, called medical castration, slows progression for about two years, but most men will develop resistance and their cancer will progress.5,6 The five-year survival rate of men with metastatic prostate cancer is 30 percent.7