Mechler K, Mountford WK, Hoffmann GF, Ries M.
Genet Med. 2015;17(12):965-70.
Origin Biosciences is developing a treatment for patients with molybdenum cofactor deficiency (MoCD) type A, an extremely rare pediatric metabolic disorder.
Patients
MoCD is an ultra-rare genetic disease that presents itself shortly after birth and progresses rapidly. Untreated, newborns with MoCD experience difficulty feeding and seizures that don’t improve with treatment (also known as intractable seizures).
MoCD occurs due to a gene mutation that affects an important metabolic process. There are three different variants of MoCD: types A, B, and C. When caused by a mutation in the MOCS1 gene, the disease is the “type A” variant.
As a result of this gene error, the body produces too little molybdenum cofactor. The scarcity of this enzyme leads to decreased activity of sulfite oxidase, which is believed to be the cause of the severe neurological damage seen in MoCD. With poor sulfite oxidase activity, the body is unable to break down sulfite, which is highly toxic, and sulfite then accumulates in the brain.
MoCD has an “autosomal recessive” pattern of inheritance. That means that a child with the disease inherited an altered copy of the gene from each parent. In autosomal recessive conditions, parents are carriers of the gene change, but don’t generally experience the symptoms of the disease.
The prognosis is poor, with a median survival of three years. Patients who survive beyond the first several months of life often have severe and irreversible injury to their central nervous system. No approved therapies exist for MoCD and standard of care is limited to supportive therapy, including use of anti-seizure medicines.
Origin’s Compassionate Use/Expanded Access Policy
Currently, Origin does not have a formal expanded access program in place and considers requests for expanded access only on a case-by-case basis. Inquiries regarding expanded access may be sent to info@orgintx.com. You can expect acknowledgment of your message within 5 business days. Patients seeking to enroll in clinical studies should visit www.clinicaltrials.gov for information regarding ongoing studies and current study site locations.
For emergency inquiries regarding investigational drug access, please call 617.322.5165.
Science
MoCD type A is among a class of genetic disorders known as inborn errors of metabolism. It is an ultra-rare pediatric disease with an autosomal recessive pattern of inheritance.
MoCD is characterized by the disruption of the biosynthesis pathway that normally produces an essential substance known as molybdenum cofactor (MoCo). MoCo enables function of certain essential enzymes, including sulfite oxidase (SO).
However, in patients with MoCD type A, an error in the MOCS1 gene prevents the body from producing MoCo. In healthy individuals, biosynthesis of MoCo involves converting guanosine triphosphate (GTP) to cyclic pyranopterin monophosphate (cPMP). In patients with MoCD type A, this process does not happen as it should, and cPMP is not created. Thus, MoCo is not produced at required levels. To the right is a representation of the molybdenum cofactor biosynthesis pathway and the impact of the three variants of MoCD on MoCo synthesis.
Deficiency in MoCo results in reduced activity of three key enzymes: sulfite oxidase, xanthine oxidoreductase and aldehyde oxidase. Decreased activity of sulfite oxidase is believed to be the causative factor behind the severe and rapidly progressive central nervous system damage seen in patients with MoCD, as sulfite oxidase normally degrades highly toxic sulfite through conversion to sulfate. With increased levels of sulfite, S-sulfocysteine (SSC), typically low or undetectable in healthy children, accumulates, resulting in brain injury. Below shows a portion of the metabolic pathway in a healthy child and changes in the pathway with MoCD Type A.
In previous work with a recombinant form of cPMP, 11 patients with MoCD Type A showed normalization of biomarkers within two days, eight patients showed complete or substantial suppression of seizures, and three patients showed near-normal development.
For information on clinical trials for MoCD visit clinicaltrails.gov.
Publications
Origin is a member of the BridgeBio family
BridgeBio is a clinical-stage biotech company developing novel, genetically targeted therapies to improve the lives of patients. The BridgeBio approach combines a traditional focus on drug development with a unique corporate model, allowing rapid translation of early stage science into medicines that treat disease at its source. Founded in 2015 by a team of industry veterans, the company has built a robust portfolio of nineteen transformative assets, each housed in its own subsidiary, ranging from pre-clinical to late stage development in multiple therapeutic areas including oncology, cardiology, dermatology and endocrinology. The company’s focus on scientific excellence and rapid execution aims to translate today’s discoveries into tomorrow’s medicines.
