Treating Genetically Defined Diseases
Cogent’s lead drug candidate, PLX9486, 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. The result is an orphan disease called Systemic Mastocytosis. Exon 17 mutations have also been found in advanced Gastrointestinal Stromal Tumors (GIST), which have a strong dependence on oncogenic KIT signaling. PLX9486 is a highly selective and potent KIT inhibitor with the potential to provide a powerful new treatment option for patients with both of these diseases.
About Systemic Mastocytosis
Systemic Mastocytosis occurs when mast cells inappropriately accumulate in various internal organs in the body. About 90% of people with Systemic Mastocytosis have Indolent Systemic Mastocytosis (ISM), a life-long illness with chronic symptoms including headaches, urticaria pigmentosa, skin lesions, skin redness and warmth (flushing), abdominal pain, bloating, vomiting, diarrhea, and gastroesophageal reflux (GERD), 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 (ASM) is a rare, very aggressive form of Systemic Mastocytosis. Patients with ASM 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 ASM is less than 3.5 years.
Cogent expects to begin clinical trials in ASM in the first half of 2021 with clinical trials in ISM to follow in the second half of 2021, pending FDA interactions.
Gastrointestinal Stromal Tumors (GIST) are categorized by uncontrolled cell growth in the tissues of the gastrointestinal (GI) tract. At diagnosis, about 80% of GIST patients’ tumors are the result of primary KIT mutations. Approved therapies currently inhibit a subset of these mutations, but most patients develop resistance due to additional secondary KIT mutations, including mutations in Exon 17. PLX9486 is designed to be a potent and selective inhibitor of KIT Exon 17 mutations, and by combining PLX9486 with drugs that inhibit additional KIT mutations, Cogent is addressing a clear unmet medical need for patients with GIST.
The safety profile of PLX9486 has been clinically evaluated in 50+ patients both as a single agent and as part of a combination therapy. In a Phase 1/2 trial testing the combination of PLX9486 with sunitinib in 18 patients with advanced GIST, median progression free survival (PFS) reached 11 months. Most of these patients were heavily treated previously, having received sunitinib or other kinase inhibitors prior to treatment with PLX9486.
Cogent plans to initiate a late-stage clinical trial for GIST patients during the second half of 2021 pending FDA interactions.