Novartis lands Breakthrough Therapy designation for PKC412

FDA designation granted for indication in newly diagnosed FLT3-mutated acute myeloid leukemia

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BASEL, Switzerland—Feb. 19 saw Novartis announce that the U.S. Food and Drug Administration (FDA) had granted Breakthrough Therapy designation to PKC412 (midostaurin)—this is an investigational treatment for adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy.
Since PKC412 is investigational at this time and is expected to be submitted for FDA approval, Novartis opened a Global Individual Patient Program (compassionate use program) and a U.S. Expanded Treatment Protocol to enable PKC412 access. Patients 18 years of age and older with newly diagnosed FLT3-mutated AML who are able to receive standard induction and consolidation therapy will be considered.
In addition, to help identify patients who may have a FLT3 mutation and potentially benefit from treatment with PKC412, Novartis is collaborating with Invivoscribe Technologies Inc., which is leading regulatory submissions for a companion diagnostic.
“For more than 25 years, medical developments have been limited for AML patients and the chemotherapy treatment strategy has essentially remained unchanged,” said Dr. Alessandro Riva, MD, global head of Novartis Oncology Development and Medical Affairs. “We look forward to working closely with the FDA to bring PKC412, the first potential AML targeted therapy, to patients as quickly as possible.”
The Breakthrough Therapy designation for PKC412 is primarily based upon the positive results from the Phase 3 RATIFY (CALGB 10603) clinical trial. This study was conducted in partnership with the Alliance for Clinical Trials in Oncology and presented during a plenary session at the 57th American Society of Hematology Annual Meeting. Breakthrough Therapy designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint. The designation includes all of the Fast Track program features, as well as more intensive FDA guidance on an efficient drug development program.
Patients who received PKC412 and standard induction and consolidation chemotherapy experienced a significant improvement in overall survival (OS) compared to those who received standard induction and consolidation chemotherapy alone. The median OS for patients in the PKC412 treatment group was 74.7 months vs. 25.6 months for patients in the placebo group. No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events in the PKC412 treatment group vs. the placebo group. A total of 37 deaths were reported, with no difference in treatment-related deaths observed between groups.
In the United States alone, about 20,000 people were diagnosed with AML in 2015, the majority of whom were adults. According to the latest research, approximately one-third of AML patients also harbor a FLT3 gene mutation, which is associated with worse outcomes and shorter survival than in those without the mutation. PKC412 is reportedly the first drug targeting FLT3 to demonstrate an overall survival benefit in AML.
PKC412 is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia.
The PKC412 follows some other good news for Novartis on the FDA front in the past month or so, the company having announced in mid-January that the FDA had approved Cosentyx (secukinumab) for two new indications: the treatment of adult patients with active ankylosing spondylitis (AS) and active psoriatic arthritis (PsA). AS and PsA are both lifelong, painful and debilitating inflammatory diseases that affect the joints and/or spine. If not treated effectively, both conditions can lead to irreversible joint and/or spinal bone damage caused by years of inflammation.
With these new approvals, Cosentyx is now the first and only interleukin-17A antagonist approved for AS, Novartis notes, as well as moderate to severe plaque psoriasis and PsA, which impacts as many as 30 percent of patients with psoriasis. Cosentyx was approved for adult patients with moderate to severe plaque psoriasis in January 2015 and more than 13,000 patients with this disease in the United States have already been treated with Cosentyx.
“We were inspired by patients to pursue new indications for AS and PsA, because these diseases can result in significant pain and impede the simplest of tasks in a person’s daily life,” said Christi Shaw, U.S. country head, president at Novartis Corp. and Novartis Pharmaceuticals Corp. “The approval of additional indications for Cosentyx represents an important milestone for AS and PsA patients, their caregivers and their doctors.”
The approvals are based on the efficacy and safety outcomes from two AS and two PsA placebo-controlled Phase 3 studies which included more than 1,500 adult patients with either AS or PsA. In the studies, Cosentyx met the primary endpoints achieving statistically significant improvements versus placebo in the signs and symptoms of AS and PsA, as measured by at least a 20-percent improvement in the Assessment of Spondyloarthritis International Society criteria  at Week 16 and a 20-percent reduction in the American College of Rheumatology (ACR20) response criteria at Week 24, respectively.
As noted in an article at about Novartis’ PKC412 news, “It’s been a big week for drugs receiving Breakthrough Designation status,” with the article noting that on Feb. 17, AstraZeneca and its global biologics research and development unit, MedImmune, announced Breakthrough Therapy designation from FDA for MEDI4736 (durvalumab)—the compound is a human monoclonal antibody that targets programmed death ligand-1 (PD-L1), and is being investigated for treatment of PD-L1 positive inoperable or metastatic urothelial bladder cancer when the tumor has progressed during or after treatment by a platinum-based therapy.
On the same day, Roche Group announced it had received Breakthrough Therapy designation from the FDA for Ocrevus (ocrelizumab) for the treatment of primary progressive multiple sclerosis (MS).
“Ocrelizumab is the first investigational medicine for MS to be granted Breakthrough Therapy Designation by the FDA,” said Sandra Horning, chief medical officer and head of global product development for Roche. “With no approved treatments for primary progressive MS, ocrelizumab has the potential to address an important unmet need. We are committed to working with the FDA to bring ocrelizumab to people with primary progressive MS as quickly as possible.”

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