Orfadin Dosage Reduction Approved for Hereditary Tyrosinemia Type 1

Mathew Shanley

This article was originally published on 09/05/2017 at 10:34am and has since been updated with quotes from Rami Levin, Sobi’s President in North America.

Early this morning, Sobi received approval from the U.S. Food and Drug Administration (FDA) for a reduction in dosing frequency for its drug Orfadin (nitisinone) in patients with hereditary tyrosinemia type 1 (HT-1) ages 5 years and older.

Orfadin was granted the approval for reduced dosing frequency from twice daily to once daily.

HT-1 is the result of a deficiency of the fumarylacetoacetate hydrolase (FAH) enzyme. The absence of or defect in the enzyme leads to an accumulation of toxic metabolic products in several of the body’s tissues, and these issues could lead to gradual liver, renal and neurological complications.

Orfadin is the first nitisinone product approved in the U.S. and Europe, and blocks the breakdown of tyrosine and inhibits 4-hydroxyphenylpyruvate dioxygenase so that toxic byproducts do not accrue. Patients must maintain a special tyrosine and phenylaline-limited diet in combination with Orfadin treatment.

“We are very happy to receive the approval by the FDA of the new dosing frequency for Orfadin. Orfadin is the first nitisinone product approved for once daily use in the U.S. This is an important step towards reducing the treatment burden of people with HT-1 and it follows Sobi’s introduction of Orfadin 20mg capsules and Orfadin oral suspension,” said Milan Zdravkovic, Senior Vice President, Chief Medical Officer, and Head of Research & Development at Sobi in a press release.

The original U.S. approval of Orfadin in 2002 was based on an open-label study of 207 HT-1 patients, in which patients younger than 2 months of age who were treated with dietary restrictions and Orfadin experienced 2- and 4-year survival probabilities of 88% and 88%, respectively.

“If you look at Sobi, yes, Orfadin has been on the market for a while, but as a partner in HT-1, both in the patients and the caregivers, it’s our mission to understand patient needs throughout the journey and trying to address as many of those as possible," said Rami Levin, Sobi’s President in North America in an exclusive interview with Rare Disease Report.

"Last year, we introduced a new dose, and that’s really to help older patients. We launched the oral solutions, and that’s for newborns and children. Now we come again with the once-daily, and that’s because of patient needs and trying to address them. We’re constantly listening to patients and caregivers. We want to potentially make their lives better in dealing with HT-1.”

Approval of the new once-daily formulation was based on the results of a clinical study conducted in 16 patients with HT-1. A 4-week once-daily regimen was compared to a 4-week twice-daily dosing regimen, and while the study shows analogous blood-levels of nitisinone for the 2 regimens, and 2- and 4-year survival probabilities in patients were 94% and 94%, respectively.

“Although HT-1 is a very rare disorder, affecting only an estimated 150 patients in the United States, it is potentially fatal without nitisinone treatment,” said Can Ficicioglu, M.D., Ph.D., Director of the Newborn Metabolic Screening Program and the Lysosomal Storage Diseases Program at Children's Hospital of Philadelphia.

“Before the introduction of Orfadin, fewer than one-third of infants diagnosed with HT-1 before two months of age lived past their second birthday. Today, many HT-1 patients have entered adolescence or even adulthood, requiring increasing doses, so I appreciate that Sobi is providing new dosing options like once-daily Orfadin.”

Common adverse events (AE) in patients with Orfadin include hepatic neoplasm, liver failure, thrombocytopenia, leucopenia, visual system complaints including conjunctivitis, corneal opacity, keratitis, and photophobia.

“We have already long-understood, especially when it comes to rare diseases, it’s not just about the giving the drug and that’s it. There’s so much more that these patients and caregivers need. We work to make sure that everybody who needs Orfadin will get Orfadin,” said Levin.

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