The US Food and Drug Administration (FDA) has granted approval to Nulibry (fosdenopterin) for reducing the risk of death associated with molybdenum cofactor deficiency type A (MoCD Type A), making it the first treatment for the ultra-rare, genetic metabolic disorder. The approval was granted to BridgeBio Pharma, Inc. (Nasdaq: BBIO) and its affiliate Origin Biosciences, Inc. (Origin). BridgeBio is dedicated to developing therapies for genetic diseases with unmet needs.
MoCD Type A usually presents in the first couple of days after birth and causes intractable seizures, brain injury and death. Patients have severe encephalopathy (brain abnormalities) which causes atrophy of brain tissue, leading to rapid, progressive neurological damage and severe developmental delays. Most children with the rare inherited condition die in early childhood from infections.
The disease results from the accumulation of toxic sulfite metabolites in the central nervous system, which, in addition to seizures, also cause difficulties in feeding and muscle weakness. While babies with the condition appear normal at birth, the feeding difficulties and intractable seizures begin within a week.
MoCD Type A affects less than 150 patients globally with a median survival of four years.
Nulibry was approved, in injection form, as the first therapy to reduce the risk of mortality in patients with MoCD Type A.
Prior to Nulibry’s approval, the only treatment options included supportive care and therapies to manage complications associated with the disease.
BridgeBio said in an announcement that the novel therapy was developed based on “BridgeBio’s commitment to developing a treatment for MoCD Type A in collaboration with the experts and families in the MoCD Type A community.” The announcement was made on Rare Disease Day, which raises awareness about the impact of rare diseases on patients and their caregivers.
“Today’s action marks the first FDA approval for a therapy to treat this devastating disease,” said Hylton V. Joffe, MD, director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine in the FDA’s Center for Drug Evaluation and Research, in a press announcement from the FDA. “The FDA remains committed to facilitating the development and approval of safe and effective therapies for patients affected by rare diseases — an area of critical need.”
What is Molybdenum Cofactor Deficiency Type A?
MoCD Type A is an autosomal recessive, inborn error of metabolism caused by mutations in the molybdenum cofactor synthesis 1 gene. It is characterized by a deficiency in molybdenum cofactor production.
Patients with MoCD Type A are unable to produce cyclic pyranopterin monophosphate (cPMP), an enzyme that catalyzes an early step in the synthesis of molybdopterin. Molybdopterins are a class of cofactors found in most molybdenum-containing and all tungsten-containing enzymes. When complexed with the chemical element molybdenum (Mo), they form molybdenum cofactors.
Molybdenum cofactors are essential for the activity of several enzymes, including sulfite oxidase, xanthine sulfite and aldehyde oxidases. Human molybdenum cofactor deficiency leads to the pleiotropic loss of all three of these molybdoenzymes. Decreased sulfite oxidase activity leads to accumulation of sulfite and toxic secondary metabolites, such as sulfocysteine (SSC) in the brain, causing neurological damage and early mortality.
Nulibry is a first-in-class cPMP substrate replacement therapy. It is administered as an intravenous medication, delivering the enzyme to allow for the formation of the molybdenum cofactors.
Nulibry Trial Results
The efficacy of Nulibry in the treatment of MoCD Type A was demonstrated by data from three different clinical trials, which was compared to data from a natural history study. In the analysis involving 31 patients, 13 were treated with Nulibry and compared to 18 genotype-matched untreated patients from the history control group. Patients that were treated with Nulibry had a survival rate of 84 percent at three years, compared with 55 percent for the untreated patients. The risk of death was reduced by 82 percent in treated patients compared to untreated.
In addition to the survival analysis, Nulibry treatment led to reduced urine concentrations of SSC in MoCD Type A patients, and long-term treatment sustained the reduction over a period of 48 months.
“The FDA’s approval of Nulibry means that patients with MoCD Type A and their families have an approved therapy for the first time. It also reflects our belief that every life matters and that no disease is too rare to address. As is often true in rare disease drug development, this was a community effort in which we were able to play a part – we’d like to thank the patients, caregivers, physicians, scientists and advocates who played an essential role in achieving this important milestone,” said BridgeBio founder and CEO Neil Kumar, PhD, in an announcement from the company.
The FDA reviewed Nulibry under Priority Review and received Orphan Drug Designation, Breakthrough Therapy Designation and Rare Pediatric Disease Designation from the agency. Along with the approval, the FDA also issued a Rare Pediatric Disease Priority Review Voucher (PRV) to Origin.
In their commitment to patient access, BridgeBio and Origin have developed a comprehensive patient support program called ForgingBridges to assist patients in accessing Nulibry. The companies say the program also offers tools and resources to help patients and caregivers during their treatment journey with Nulibry.