FDA Approves Cambridge Biotech’s First-Ever Drug for Cancer

Blueprint Medicines Corporation, a precision therapy company from Cambridge, Massachusetts, focused on genomically defined cancers, rare diseases and cancer immunotherapy, announced  on January 9th that the U.S. Food and Drug Administration (FDA) has approved AYVAKIT™ (avapritinib). This is the company’s first-ever FDA approval. The drug will be sold commercially under the name Ayvakit; it is a treatment for a rare, genetically linked form of gastrointestinal cancer.

Genomic therapy for GIST

Genomic studies have been increasingly used in clinical practices, leading to the discovery and use of ever more targeted therapies.

AYVAKIT is the first precision therapy approved to treat a genomically defined population of patients. The treatment is aimed towards 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.

GIST is a sarcoma, or tumor of bone or connective tissue, of the GI tract. Tumors arise from cells in the wall of the GI tract, being most often located in the stomach or small intestine. Diagnosis is usually triggered by GI bleeding or incidental findings during surgery or imaging. In rare cases, GI obstruction and tumor rupture can be the cause of establishing the diagnosis. Most patients get diagnosed between the ages of 50 to 80.

Most GIST cases are caused by mutations in KIT or PDGFRA that force protein kinases into an increasingly active state. Because other available therapies primarily bind to the inactive protein conformations, certain primary and secondary mutations typically result in treatment resistance and lead to disease progression.

In unresectable or metastatic GIST, mutations type can determine clinical benefits from existing treatments. Mutational testing is critical to create therapy to the underlying disease driver and is recommended in expert guidelines. Currently, there are no approved therapies for patients with KIT-driven GIST whose disease progresses beyond imatinib, sunitinib, and regorafenib.

In a clinical trial, 84% of participants responded to the drug. Blueprint has also filed a second application asking the FDA to approve Ayvakit as a treatment for patients with gastrointestinal stromal tumors who have tried three other treatments without success. These tumors are diagnosed in 5,000 to 6,000 Americans each year, according to the World Health Organization.

The drug will target a mutation resistant to all pre-existing therapies

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. 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.

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. The FDA has granted Breakthrough Therapy Designation to avapritinib for two indications: one for the treatment of unresectable or metastatic GIST harboring the PDGFRA D842V mutation and one for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia.

“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.”

A high, but “justifiable” price and serious plans for the future    

With the FDA approval for AYVAKIT, Cambridge biotech Blueprint Medicines Corp. evolves from a clinical-stage startup into a commercial company. Blueprint Medicines plans to make AYVAKIT available in the U.S. within a week. A 30-day treatment with the drug will cost $32,000, which is more than twice the amount forecasted by SVB Leerink investment bank, but analyst Andrew Beren’s considered it “justifiable”, the drug is both effective and unique.

Blueprint’s forecast for 2020 includes submitting three other drugs for FDA approval by the end of the year.

“2020 is off to a great start for Blueprint Medicines with the recent FDA approval of our first medicine and a U.S. launch now underway. As we complete our evolution into a fully-integrated biopharmaceutical company this year, we will also aim to bring a second product to market, expand across multiple indications and extend our global commercial footprint with our first anticipated regulatory approval in Europe,” said Jeff Albers, Chief Executive Officer of Blueprint Medicines. “In addition, our future growth will be fueled by an expanded strategic focus on systemic mastocytosis and related mast cell disorders, which represent a large population of underserved patients with significant medical needs. This focus is anchored by avapritinib, which is now FDA-approved for the treatment of PDGFRA exon 18 mutant GIST. Avapritinib was specifically designed to treat the underlying cause of systemic mastocytosis and has demonstrated remarkable and consistent clinical activity across the spectrum of the disease.”

High hopes for the future and more than double the initial team

Blueprint Medicines included 149 employees at the beginning of 2018, but now has 380, and the recent success is meant to only be the first of many, or so company officials hope.

“Ayvakit is the first of what we hope will be many approved medicines enabled by our research platform,” CEO Jeff Albers said in a statement. “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 explained the FDA administratively split the proposed indications for avapritinib under the initial New Drug Application (NDA) into two separate NDAs: one for PDGFRA exon 18 mutant GIST, approved and announced January 9th, and one for fourth-line GIST. The Prescription Drug User Fee Act (PDUFA) action date for the fourth-line GIST indication is currently February 14, 2020. The company stated that a three-month extension will most likely be needed to ensure top-line data from VOYAGER, a Phase 3 clinical trial evaluating avapritinib versus regorafenib in third-or fourth-line GIST, could be delivered to the FDA.