FDA Approves Ayvakit (avapritinib) for the Treatment of Adults with Unresectable or Metastatic PDGFRA Exon 18 Mutant Gastrointestinal Stromal Tumor

Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy,  announced that the U.S. Food and Drug Administration (FDA) has approved Ayvakit (avapritinib) for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. Ayvakit is the first precision therapy approved to treat a genomically defined population of patients with GIST.

The FDA granted a full approval to Ayvakit based on efficacy results from the Phase 1 NAVIGATOR clinical trial, as well as combined safety results from multiple clinical trials for avapritinib. In patients with PDGFRA exon 18 mutant GIST, Ayvakit had an overall response rate (ORR) of 84 percent (95% CI: 69%, 93%), and a median duration of response (DOR) was not reached. The most common adverse reactions (≥20 percent) were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash and dizziness. Blueprint Medicines plans to make Ayvakit available in the U.S. within a week.

GIST is a rare, genomically driven sarcoma of the gastrointestinal (GI) tract. Approximately 6 percent of patients with newly diagnosed GIST have PDGFRA exon 18 mutations. The most common PDGFRA exon 18 mutation is the D842V mutation, which is resistant to all other approved therapies. A retrospective study showed that when these patients were treated with imatinib, they had an ORR of 0 percent.2

"Today's approval of Ayvakit brings forward a new standard of care for patients with PDGFRA exon 18 mutant GIST, a genomically defined population that previously had very limited treatment options. For the first time, we can offer these patients a highly effective treatment that targets the underlying genetic cause of their disease," said Michael Heinrich, M.D., Professor of Medicine at Oregon Health & Science University and an investigator on the NAVIGATOR trial. "Building on our growing understanding of the molecular basis of GIST, this milestone ushers in a new era of precision medicine in this disease. The FDA approval represents a call to action to conduct mutational testing in all patients with GIST before initiating kinase inhibitor therapy, as recommended by clinical guidelines, so appropriate patients may realize the benefits of this promising new medicine."

"The full approval of Ayvakit based on robust data from our Phase 1 NAVIGATOR clinical trial is an incredibly exciting milestone for our company and, more importantly, for GIST patients with a PDGFRA exon 18 mutation, who have been waiting for a new treatment option," said Jeff Albers, Chief Executive Officer at Blueprint Medicines. "Ayvakit is the first of what we hope will be many approved medicines enabled by our research platform. Now, as we begin to deliver Ayvakit to patients and their healthcare providers, we aim to fortify our leadership in the field of precision medicine and build a foundation for our broader portfolio by pairing our strong research and development capabilities with an equally talented commercial organization focused on addressing patient needs, accelerating diagnostic testing and enabling access."

Blueprint Medicines is dedicated to helping patients with PDGFRA exon 18 mutant GIST access treatment with Ayvakit and providing robust support throughout their treatment journey. As part of this commitment, Blueprint Medicines is introducing YourBlueprint™, a patient support program that offers access and affordability solutions for individuals receiving Ayvakit. For more information, visit YourBlueprint.com or call 1-888-BLUPRNT (1-888-258-7768), Monday to Friday, 8:00 a.m. to 8:00 p.m. ET. Healthcare providers who prescribe Ayvakit can fill out an enrollment form at YourBlueprint.com/HCP to help patients access Blueprint Medicines' support services.

https://en.wikipedia.org/wiki/Avapritinib

Fourth-line bosutinib ‘appropriate’ after prior CML treatment failure, intolerance

In continuation of my update on bosutinib

A Spanish study suggests that bosutinib can help improve or maintain response in patients with chronic myeloid leukaemia (CML) after treatment failure of three previous tyrosine kinase inhibitors (TKI).

Researcher Juan Luís Steegmann (Hospital Universitario de la Princesa, Madrid, Spain) and colleagues analysed medical records of 30 chronic phase CML patients with Philadelphia chromosome-positive disease given bosutinib under the Spanish Compassionate Use programme after discontinuing imatinib, dasatinib and nilotinib as a result of resistance or intolerance.

Of the 15 patients without a complete cytogenetic response at baseline, defined as after TKI use but before bosutinib initiation, two (13.3%) achieved it following bosutinib treatment.

Fourth-line bosutinib ‘appropriate’ after prior CML treatment failure, intolerance

Gleevec could be novel therapeutic agent for type 2 diabetes

The cancer treatment drug Imatinib, otherwise known as Gleevec is approved to treat various forms of cancer, mostly notably chronic myeloid leukemia (CML). However, researchers have stumbled onto another possible use for it, curing type 2 diabetes.

The team--made up of scientists from the Scripps Research Institute in United States, South Korea-based company Hyndai Pharm Co., Ltd., the Seoul National University, and Ulsan National Institute of Science and Technology (UNIST)--has identified for the first time that, through control of PPARγ, Gleevec lowers the level of insulin resistance, thereby reducing the risk of both hyperglycemia and obesity.

Acording to the team, led by Prof. Jang Hyun Choi (School of Life Sciences) of UNIST, "Although TZD-based medicines work effectively at improving glucose uptake by skeletal muscle and other peripheral tissues, due to increased risk of adverse effects they have been withdrawn from the market ." He continues, "In order to develop new type of medication that have fewer side effects, we have have discovered a new compound that can maintain stable blood sugar levels."

Among insulin-sensitizing drugs, TZDs are a therapeutic class that are selective agonists for PPARγ, which plays a central role in how the body metabolizes glucose, stores fat, and controls immune and inflammatory responses.

In the study, the team observed that the phosphorylation of PPARγ is closely related to developing diabetes. They also discovered that the removal of phosphoric acid from PPARγ shows anti-diabetic effects. To determine whether phosphoric acid is bound to PPARγ, the team developed a new chemical screening procedure. Using high throughput phosphorylation screening, the team discovered that Gleevec blocks CDK5-mediated PPARγ phosphorylation devoid of classical agonism as a PPARγ antagonist ligand.

Prof. Choi states, "Although studies have shown that Gleevec treatment may show improved insulin sensitivity and decrease blood glucose in patients with known diabetes, the exact cause hasn't been proven yet." He continues, "Through this research, we discovered Gleevec, which is used in leukemia medications, can inhibit the phosphorylation of PPARγ."

Gleevec could be novel therapeutic agent for type 2 diabetes