A recent U.S. Food and Drug Administration (FDA) memorandum to the agency’s Peripheral and Central Nervous System Drugs Advisory Committee expresses skepticism regarding BioMarin Pharmaceutical Inc.’s Muscular Dystrophy drug candidate Kyndrisa (drisapersen) for treatment of Duchenne muscular dystrophy in patients with mutations amenable to exon 51 skipping.
Duchenne muscular dystrophy (DMD) is a progressive muscle disorder that leads to serious heart or respiratory-related complications by early adulthood. Primarily affecting boys, DMD is diagnosed in approximately 1 in every 3,500-5,000 live male births, making it the most common fatal genetic disorder diagnosed in childhood.
DMD, the most severe form of dystrophin-deficient muscular dystrophy, is caused by genetic mutations in the dystrophin gene essential for muscle function that result in the dystrophin protein’s near absence. Without dystrophin, boys living with Duchenne experience progressive muscle weakness, and degeneration of skeletal and cardiac muscle.
BioMarin Pharmaceutical’s drisapersen is an investigational antisense oligonucleotide drug candidate for treatment of the largest subset of DMD patients, those for whom skipping of exon 51 restores the proper dystrophin reading frame, potentially providing a therapeutic benefit. That particular cohort is about 13 percent of all DMD patients, and Biomarin estimates that some 2,000 patients in the U.S. would be candidates for drisapersen treatment.
Drisapersen is designed to induce exon skipping to provide a molecular patch for dystrophin transcripts produced by certain mutated dystrophin genes. Exons are the parts of a gene that contain instructions for generating a protein. In applicable cases, skipping an exon near the mutation allows for production of a truncated but functional dystrophin protein. In June, the FDA granted drisapersen Priority Review status, which is designated to drugs that promise major advances in treatment, or provide a treatment where no adequate therapy exists. The FDA has also granted drisapersen Orphan and Fast Track status, as well as Breakthrough Therapy designation.
The FDA Briefing Memo, released Nov. 21, is titled “Peripheral and Central Nervous System Drugs Advisory Committee Meeting November 24, 2015, NDA 206031 Drisapersen,“ and its co-authored included Ronald Farkas, MD, PhD, Clinical Team Leader, Division of Neurology Products, CDER, FDA; and Billy Dunn, MD, Director Division of Neurology Products, CDER, FDA.
The reviewers note that dystrophin is thought to maintain the structural integrity of the muscle cell membrane by connecting the cytoskeleton to the surrounding extracellular matrix, and to act as a scaffold for several signaling molecules that also contribute to normal muscle physiology. Immunological and inflammatory processes downstream of dystrophin deficiency contribute to muscle pathology in DMD, and corticosteroid therapy is considered standard of care, delaying loss of ambulation and respiratory decline by several years. No other drugs have been established as effective in DMD and, consequently, a large unmet medical need remains.
That need notwithstanding, the FDA reviewers provisionally conclude that evidence for the clinical benefit of drisapersen is still lacking, and long-term data submitted by BioMarin does not support approval of the drug at this time.
The FDA reviewers acknowledge that a carefully planned and thorough drug development program has been undertaken for drisapersen, and affirm their belief that the sponsor, and the patients and caregivers who participated in the referenced clinical trials, should be recognized for their contributions to scientific understanding of the drug’s safety and efficacy. However, “it is not clear to the primary review team that substantial evidence of effectiveness has been presented for drisapersen or, consequently, that drisapersen has an acceptable risk-benefit profile,” they wrote. “The conclusion of this review is that substantial evidence of clinical efficacy was not established for drisapersen in the treatment of exon 51-skip amenable DMD.”
But the reviewers stress that their evaluation is not the final word: “No final decision has been made, however, and the entire review team greatly looks forward to the insights that [committee members] can provide at the Advisory Committee meeting.”
Specifically for DMD, the FDA reviewers observe that there is obvious interest in dystrophin expression as a surrogate marker, but “whether an effect on a biomarker such as dystrophin might reasonably predict clinical benefit in DMD is inseparable from such factors as the magnitude and character of the effect on the biomarker, and might also depend on patient factors such as age, disease stage, or secondary inflammation or autoimmunity.”
“Importantly,” they continue, “the evidentiary standards for effectiveness are not lower for biomarker endpoints used to support Accelerated Approval, nor should Accelerated Approval be used to compensate for weak or inconsistent clinical findings. Negative clinical findings in studies of adequate design and conduct to assess such findings would ordinarily preclude Accelerated Approval on the basis of associated biomarker effects. Finally, if efficacy is established, the next question is whether a drug’s benefits justify its risks. This consideration is made in the broader context of the seriousness of the disease, other treatment options, unmet medical need, risk tolerance of the patient population, etc. Risk-benefit assessment should consider that tolerance for risk may vary among individuals, and may be affected by factors such as disease stage and severity.”
The Prescription Drug User Fee Act (PDUFA) action date for completion of the FDA’s review of the drisapersen and its New Drug Application is Dec. 27, 2015.
U.S. Food and Drug Administration (FDA)
BioMarin Pharmaceutical Inc.