The US Food and Drug Administration has rejected a small molecule for a rare blood disorder called erythropoietic protoporphyria. Bitopertin, originally developed by Roche and licensed by Disc Medicine in 2021, was an early recipient of one of the FDA’s new Commissioner’s National Priority Vouchers, part of a program that awards recipients with an expedited review if they meet at least one of the agency’s national priorities.
Disc could still submit bitopertin for FDA approval after it compiles additional data. The company had initially sought accelerated approval, an FDA pathway that involves the use of at least one surrogate end point—a marker that scientists agree is reasonably likely to predict a clinically meaningful benefit for patients. But the FDA found “uncertainties” with one of Disc’s surrogate end points, according to a letter the agency issued on Friday (PDF).
People who have erythropoietic protoporphyria, commonly abbreviated as EPP, lack an enzyme called ferrochelatase. The enzyme is crucial in converting protoporphyrin IX (PPIX), a molecule activated by sunlight, into heme, a component of hemoglobin. Without it, PPIX builds up in the blood, causing excruciating pain and leading to liver problems down the line. That reality forces most people with EPP to stay out of the sun.
“It’s almost like a disability,” Karl Anderson, a physician at the University of Texas Medical Branch at Galveston who’s been studying porphyrias for some 40 years, told C&EN in November. “People [with EPP] can’t do a lot of things that other people can.”
Bitopertin is designed to treat EPP by suppressing the uptake of glycine transporter type 1, or GlyT1, a protein involved in the heme biosynthesis pathway. In theory, downregulating GlyT1 should decrease the buildup of PPIX, effectively eliminating EPP’s most troublesome symptoms.
The FDA agreed that Disc’s Phase 2 clinical trials had proved that bitopertin lowered whole blood PPIX. But the agency says it did not see enough evidence that lower PPIX was associated with sunlight-exposure-based end points. “This lack of correlation between the changes in PPIX and clinical outcomes measured leaves significant uncertainty that bitopertin will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in its proposed labeling,” the letter reads.
Disc will now have to seek traditional approval. It is currently running a Phase 3 study that should—assuming it succeeds—form a basis for a second FDA review. The company says in a press release that “the issue raised is readily addressable.”
“While our efforts at utilizing expedited pathways to get bitopertin to patients quickly have not come to fruition, we are continuing to pursue all avenues in support of FDA approval,” Disc CEO John Quisel says in the release. “Confidence in our product and program guides our approach, and we will continue working closely with the FDA to support their review.”
Rowan Walrath is an associate editor and life sciences reporter at C&EN.
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