Federal advisers dealt a setback to the developers of the experimental medicine stannsoporfin for newborns who cannot quickly clear bilirubin and thus risk developing jaundice, by a 21-3 vote recommending rejection of manufacturer Mallinckrodt’s application for approval of the drug.
The US Food and Drug Administration (FDA) posed a pivotal three-part question on stannsoporfin at a joint meeting of the Gastrointestinal Drugs Advisory Committee and the Pediatric Advisory Committee on Thursday.
Twenty-one panelists voted no, saying that the overall risk-benefit profile of stannsoporfin does not support its approval. Another three panelist voted in support of approval if a Risk Evaluation and Mitigation Strategy (REMS) were in place. None of the panelists voted in support of a third option, which backed approval of the drug without a REMS.
Stannsoporfin is a tin metalloporphyrin that’s meant to reduce the production of bilirubin in infants at risk for severe neonatal jaundice. That approach sets it apart from the phototherapy that’s now used to treat excess bilirubin in the bloodstream and skin of infants, the company said. The current practices for screening and treating neonatal hyperbilirubinemia have also reduced the incidence of exchange transfusions of blood or plasma, according to the FDA.
Neonatal jaundice is considered a common condition for newborns, with yellowing of the skin and the whites of the eyes seen in the first few days after birth. It does not require treatment in most cases, but untreated hyperbilirubinemia can lead to significant morbidity and premature mortality, Mallinckrodt said.
The company conducted three trials, with the application for stannsoporfin resting strongly on results from a randomized phase 2B study with an initial enrollment of 91 babies who were given the drug as a single 3.0-mg/kg or 4.5-mg/kg intramuscular injection, compared with a placebo arm with phototherapy.
Panelists and FDA staff were clearly uncomfortable with the bid for approval of the drug without data from a third and final stage of testing usually done before seeking US approval of medicines.
The idea of approving stannsoporfin based on current data with a REMS program “seems like an end-run around a Phase 3 study” and would be “doomed to failure,” said Peter L. Havens, MD, a panelist who is a pediatrics professor at the Medical College of Wisconsin in Milwaukee. This approach would not produce the data needed to convince “anybody that the drug is safe and clinically effective,” he said.
Approving the drug without robust data would leave it for physicians and families to do the monitoring for potential complications, according to Havens. Havens instead advised Mallinckrodt to hew to a more normal drug development plan if it intends to continue development of stannsoporfin.
“They should do it in a standard way, which is a Phase 3 study that follows the current Phase 2 data that we have, and do it the right way and spend the money instead of hoping that the healthcare system and parents will undertake the burden,” Havens said.
Mallinckrodt officials maintain that the results of the pivotal phase 2 study bolster the case for the drug’s approval, citing statistically significant reductions in total serum bilirubin levels at 48 hours in the 3.0 mg/kg and 4.5 mg/kg treatment arms compared with the placebo arm (P < .0001).
Approval With REMS
Panelist Sarah Hoehn, MD, argued for considering approval of stannsoporfin with a REMS program as an alternative for babies in need of a bilirubin treatment whose families refuse transfusions. The REMS program could seek to restrict use of the drug to high-level neonatal intensive care units and those whose excess bilirubin persists after phototherapy, she said.
“I think it should exist somewhere,” said Hoehn, who is a pediatric palliative care specialist at the University of Chicago, Illinois. “So people have access to it for families who are refusing blood products.”
Still, Hoehn and colleagues clearly worried about the signals for complications seen in the relatively small groups of babies tested.
Looking broadly at the patients given stannsoporfin and placebo in testing, the FDA found larger numbers of concerning side effects for those given the higher dose of the drug. FDA staff reported that 19.2% of the babies given stannsoporfin at a dose of 4.5 mg/kg had nervous system disorders compared with 11.8% of those given placebo.
There were no nervous system disorders observed among infants given stannsoporfin at a 3 mg/kg dose. Deafness and labyrinth disorder also emerged as concerns, affecting 6.8% of those in the 4.5 mg/kg group and 2.7% of those in the 3.0 mg/kg group, while none were seen in the placebo group, according to the FDA staff.
In wrapping up the meeting, Francis Sessions Cole III, MD, acting chair of the panel, said that the consensus opinion is that further studies are needed on this medicine. While noting positive signs seen in studies of stannsoporfin, FDA staff and panelists expressed concerns about indications of neurotoxicity and the limited pool of data available for the drug.
In a statement, Mallinckrodt said it was disappointed with the panel’s vote on stannsoporfin. The company said it will work closely with the FDA as the review process continues, while “evaluating alternatives for this development program.”
FDA officials will consider the recommendation of Thursday’s advisory panel but are not obliged to act on it.
Stannsoporfin has not yet been granted marketing authorization for any indication after a long development history.
Mallinckrodt said that the first Investigational New Drug (IND) application for stannsoporfin, IND 029462, was initiated in 1987 at Rockefeller University for the management of jaundice and was later expanded to include newborns. WellSpring Pharmaceutical Corporation acquired the rights to stannsoporfin in 2002 and submitted a second IND for the prevention or treatment of neonatal hyperbilirubinemia, he said. This IND was transferred in 2005 to InfaCare, a firm that Mallinckrodt acquired last year.
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