Rare Daily Staff

Cogent Biosciences reported positive initial data from its ongoing phase 2 APEX clinical trial evaluating the selective KIT D816V inhibitor bezuclastinib in patients with advanced systemic mastocytosis, a rare hematologic disorder.

Despite a broad market sell-off, shares of Cogent rose nearly 4 percent on the news and the company announced plans for a $125 million public market offering. The data are being presented today in a poster presentation at the 2022 European Hematology Association Congress in Vienna, Austria.

Systemic mastocytosis occurs when mast cells inappropriately accumulate in various internal organs in the body. About 90 percent of people with systemic mastocytosis have nonadvanced systemic mastocytosis (NonAdvSM), a life-long illness with chronic symptoms including headaches, urticaria pigmentosa, skin lesions, skin redness and warmth, abdominal pain, bloating, vomiting, diarrhea, and gastroesophageal reflux that significantly impact the patient’s quality of life. Many patients are also at high risk for severe, life-threatening anaphylactic reactions to various triggers such as insect bites. Advanced systemic mastocytosis (AdvSM) is a rare, very aggressive form of systemic mastocytosis. Patients with AdvSM may suffer from a multitude of debilitating symptoms such as anemia, thrombocytopenia, ascites, bone fractures, gastrointestinal abnormalities, and enlargement of the liver, spleen, and lymph nodes, which ultimately lead to organ failure and early death. The median life expectancy for AdvSM is less than 3.5 years.

Bezuclastinib is designed to target exon 17 mutations found within the KIT receptor tyrosine kinase, including KIT D816V. KIT D816V remains in a perpetual ‘on’ state causing mast cells, a type of white blood cell, to accumulate in various internal organs including the bone marrow. Bezuclastinib is a highly selective and potent KIT inhibitor with the potential to provide a powerful new treatment option for patients with both these diseases.

APEX is a global, open-label, multi-center, two-part phase 2 clinical trial in patients with AdvSM evaluating the safety, efficacy, pharmacokinetic, and pharmacodynamic profiles of bezuclastinib. As of the data cutoff date of May 24, 2022, 11 patients had been treated in Part 1 at one of four dose levels. The median age of patients at study entry was 70 years (ranging from 48-87 years). Patients were enrolled with the following sub-types: two patients with aggressive systemic mastocytosis (ASM), eight patients with systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and one patient with mast cell leukemia (MCL). Two patients had received prior avapritinib and midostaurin treatment.

As of the data cutoff date of May 24, 2022, all 11 patients treated were evaluated for signs of clinical activity. Eight of 11 patients, who had been treated for at least two cycles, had available data from bone marrow biopsy, and were evaluated for additional endpoints Cycle 3 Day 1 (C3D1) evaluable. All the patients achieved ≥50 percent reduction in serum tryptase levels by central assessment and 89 percent median reduction in serum tryptase, and six of these patients achieved reduction to <20 ng/mL.

Of the eight patients who were (C3D1 evaluable), all achieved ≥50 percent reduction in bone marrow mast cells by central review. Six of these patients achieved complete clearance of bone marrow mast cell aggregates. All demonstrated decreases in KIT D816V variant allele fraction by droplet digital polymerase chain reaction. All patients remained on treatment with treatment duration ranging from 0.5 to 4.8 months.

Two patients enrolled had previously received and discontinued avapritinib for toxicity reasons (intracranial hemorrhage, thrombocytopenia). Both patients have demonstrated clinical outcomes consistent with the avapritinib-naïve patients, including similar magnitude reductions in serum tryptase.

As of the cutoff date, May 24, 2022, bezuclastinib was generally well-tolerated at all doses. The majority of adverse events were Grade 1/2 and seen in no more than one patient with one serious adverse event and no Grade 4 events reported. Grade 3 events reported as at least possibly related were anemia (1 patient), neutropenia (1 patient) and hypersensitivity/mediator flare (1 patient). There were no reported cases of periorbital/peripheral edema, cognitive effects, or intracranial bleeding events, which have been associated with other KIT inhibitors. As of the cutoff date, all patients remained on study. Subsequently, one SM-AHN patient with chronic myelomonocytic leukemia transformed to acute myeloid leukemia and discontinued participation in the trial.

“These results reinforce the hypothesis that a potent, selective KIT D816V inhibitor with limited CNS penetration has the potential to provide meaningful clinical activity to all systemic mastocytosis patients, without the tolerability challenges seen with other available treatment options,” said Andrew Robbins, CEO at Cogent Biosciences. “Based on these results, we expect to accelerate our timelines and investment and look forward to providing another APEX clinical update by the end of 2022, and to presenting SUMMIT clinical data in non-advanced systemic mastocytosis (NonAdvSM) patients in the first half of 2023.”

Photo: Andrew Robbins, CEO at Cogent Biosciences

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