Delivering Breakthrough Medicines for Rare Hematologic Diseases and Cancers

Delivering Breakthrough Medicines for Rare Hematologic Diseases and Cancers

July 01, 2020PAP-Q2-20-CL-003

FORMA Therapeutics recently completed its transformation from a research organization to an integrated biopharma company and is advancing exciting candidates through the clinic.

Emilie Branch, Managing Editor at Pharma's Almanac, sat down with FORMA Therapeutics CEO Frank D. Lee to discuss this transformation and the innovative compounds in the FORMA pipeline.

Transforming from an Early Discovery to an Integrated Biopharma Company

FORMA Therapeutics was founded as an early discovery company leveraging extensive chemistry expertise and capabilities in high-throughput screening and genetics and established numerous research partnerships and licensing deals. At the end of 2018, FORMA elected to transform itself from a research-focused company to a fully integrated biopharmaceutical organization with the capability to develop and commercialize products for patients.

A Focus on Rare Hematologic Disorders

Another key aspect of FORMA’s transformation into an integrated biopharma company was the decision to focus on the discovery, development, and commercialization of transformative medicines for patients with rare hematologic diseases and cancers. This decision was reached after reviewing FORMA’s scientific expertise and determining where the company had the greatest potential to develop breakthrough therapies that will have a measurable impact for patients.

FORMA’s sharpened focus on serving patients with rare hematologic diseases and cancers contributed to the successful closing in December 2019 of a $100 million Series D financing round led by a syndicate of venture funds.

The newly raised capital will enable FORMA Therapeutics to support ongoing clinical development of exciting pipeline candidates, including FT-4202, FORMA’s pyruvate kinase-R (PKR) activator for the treatment of sickle cell disease (SCD); FT-7051, a novel and potent selective inhibitor of CBP/p300 binding to DNA for androgen receptor–driven cancers; and various compounds at the preclinical stage.

Multimodal Therapy for Sickle Cell Disease

The lead candidate is FT-4202 for the treatment of SCD, which presents an opportunity to be a true breakthrough therapy for sickle cell patients.

SCD occurs when two defective hemoglobin genes are inherited, leading to the formation of sickle hemoglobin (HbS) that polymerizes upon deoxygenation. This polymerization leads to red blood cell (RBC) sickling, chronic hemolytic anemia, and vaso-occlusion, all of which contribute to acute painful crises, end organ damage, reduced quality of life, and early mortality.

SCD is the most common monogenic disorder, affecting approximately 100,000 people in the United States and millions globally. Despite recent advances in treatment, most patients with SCD still suffer from lifelong disability, significant morbidity, reduced quality of life, and life expectancy reduced by 25–30 years.

Marketed drugs for SCD are designed to either increase healthy hemoglobin levels or decrease 2,3-diphosphoglycerate (2,3-DPG, a metabolic intermediate that decreases Hb–oxygen affinity to promote oxygen offloading in tissues) levels. In vitro studies have shown FT-4202 to have a favorable impact on both. In addition, it is an easy-to-take, once-daily oral medication with an attractive safety profile.

By activating the natural PKR activity of RBCs through a multimodal approach, FORMA believes that FT-4202 may normalize ATP and 2,3-DPG levels, thereby improving overall RBC membrane health, increasing hemoglobin, and decreasing vaso-occlusive crises.

From the patient perspective, an easy-to-take oral pill would be a tremendous advantage. SCD patients have a high rate of noncompliance. One available medication requires monthly infusions, which many patients believe indicates that they have a more serious form of the disease. The conventional treatment — hydroxyurea — takes three to six months to work, requires many dose adjustments, and often causes side effects similar to chemotherapy agents. As a result, despite two recent new approvals, there is still a significant unmet medical need.

A multicenter, placebo-controlled phase I trial involving up to 100 patients is currently underway to assess the safety and tolerability of FT-4202 and obtain proof of concept, with final results anticipated later this year. Early results in healthy patients indicate that PKR activation by FT-4202 increases oxygen affinity and decreases sickle hemoglobin polymerization, with an attractive safety and tolerability profile. FORMA Therapeutics expects the data generated from this study to enable a pivotal trial in SCD.

Ultimately, the company believes that this drug could serve as a foundational therapy. With its safety profile, multimodal mechanism of action, and lack of drug– drug interactions, FT-4202 has the potential to be given to patients at a young age (SCD is generally detected shortly after birth), leading to early disease modification and thus potential avoidance of the effects of SCD that develop later in life. The U.S. FDA has granted Fast Track and Rare Pediatric Disease designations for FT-4202 in SCD.

Selective Inhibitor of Androgen Receptor Signaling

The second program that FORMA is excited about originated from their genetics research. FT-7051 is a novel potent and selective inhibitor of CBP/p300 binding to DNA with the potential to treat castration-resistant prostate cancer (CRPC) and other AR-expressing cancers. Suppression of CBP/p300 by FT-7051 has the potential to block androgen and estrogen receptor signaling and promote antitumor activity. By inhibiting CBP/p300, therefore, FT-7051 offers a potential therapy for patients whose cancers are dependent upon AR signaling, including those resistant to anti-androgen therapies.

The biology of the AR cascade has been associated with many types of cancers, but molecules developed to inhibit this pathway have failed to be sufficiently targeted, preventing dosing at a level that is both effective and tolerated by patients.

On the basis of preclinical research, FT-7051 appears to be highly targeted with little or no off-target effects. FORMA anticipates initiating a phase I study in castration-resistant prostate cancer in the second half of 2020. The company believes that FT-7051 may also have utility for the treatment of small cell lung cancer and some AR-driven breast cancers, two other cancer types with few therapy options available today.

Taking Care of Patients and Employees

To be truly successful at drug development, it is essential to focus on the patient journey and have a genuine interest in doing good for patients. FORMA ensures that their staff understands the experiences of patients suffering from the diseases they are hoping to treat by bringing patients to the campus.

In addition, FORMA’s leadership has been selected not only for their experience, but for their passion for the work. For instance, Chief Medical Officer Patrick Kelly, M.D., worked at sickle cell centers for most of his career, and as such is intimately familiar with treating sickle cell patients and understands the devastating impact that SCD can have.

As importantly, FORMA strives to create a positive work environment that offers employees opportunities for growth, enables appropriate work–life balance, and encourages everyone to perform at their best and focus on the mission of delivering for patients. By investing in their culture, values, and people, FORMA Therapeutics is setting the stage for great things to happen.

Executing on Vision to Deliver Breakthrough Medicines

Each pipeline candidate was developed in house and is protected by wholly owned intellectual property through at least 2038. With this exciting pipeline, extensive funding, and talented and committed workforce, FORMA Therapeutics has begun to execute on their vision to become a great company helping patients by delivering breakthrough medicines.

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