A U.S. subsidiary of Italy's privately held Leadiant Biosciences SpA has won FDA approval for Revcovi (elapegademase-lvlr), a new recombinant enzyme replacement therapy (ERT) for the ultra-rare genetic disorder adenosine deaminase severe combined immune deficiency. The condition, which affects as few as one in 1 million live births in the U.S., leaves infants and young children vulnerable to infections and can be fatal if not diagnosed and treated by age 2.

Though often treated with hematopoietic cell transplant, that approach faces challenges and, even when successful, often involves ERT treatment prior to use. Revcovi will provide patients who need ERT, either for a brief duration or chronically, with a new alternative to Leadiant's own animal-derived product, Adagen (pegademase bovine). Its arrival will also help Leadiant recognize new manufacturing advantages in serving the 37 U.S. patients currently using its therapies for the disease, which commonly goes by the acronym ADA-SCID or the colloquialism "bubble-boy disease".

Leadiant's approval arrives at a time when progress on gene therapies for ADA-SCID has been moving slowly ahead. The small number of ADA-SCID patients in Europe have had access to the Glaxosmithkline plc-developed gene therapy Strimvelis, since May 2016. But now, after GSK divested that product to Orchard Therapeutics Ltd. earlier this year, Orchard is advancing another gene therapy for the condition, OTL-101. It expects to file a biologics license application for the candidate in 2020, the company said as part of regulatory filing for a new $172.5 million IPO of American depositary shares, filed Oct. 4. (See BioWorld, April 13, 2018.)

ADA-SCID is caused by a deficiency in the ADA enzyme. Revcovi works by supplementing levels of ADA. The approval is based on results from two open-label trials that, at the time of approval, had enrolled 10 patients altogether. Data from the studies demonstrated that Revcovi increased ADA activity, reduces concentrations of toxic metabolites that are the hallmark of ADA-SCID and improves total lymphocyte counts. It's delivered via intramuscular injection.

Leadiant's first ERT for ADA-SCID, Adagen, has been approved since 1990, when the company was still known as Sigma-Tau Pharmaceuticals, a moniker it dropped in 2017. With Adagen, Leadiant sources naturally derived ADA from cow intestines and has always had to be very careful to avoid any risk for contamination, especially from bovine spongiform encephalopathy and other potential threats to product purity. Because it's recombinant, Revcovi "totally eliminates" that concern," Michael Minarich, CEO of Leadiant's U.S. division, Leadiant Biosciences Inc., told BioWorld. There's also "an improvement in the quality and purity in terms of certain linkages, so there's an improved shelf life over the animal-sourced Adagen," he said, making Revcovi a little more convenient for patients, doctors and drug distributors.

Pricing for Revcovi is still subject to discussion between Leadiant and the Centers for Medicare & Medicaid Services, but will likely be covered in large part by insurers who are used to paying for Adagen. Leadiant is also expanding its own patient assistance program to help potential patients, of which there are just a few new ones each year, cope with any cost burdens they might face. The company is aiming to move all patients currently receiving Adagen to Revcovi over time.

Revcovi will be made available in Europe on a named-patient basis within the regulatory framework afforded for that in the EU and supported by the evidence that backed the FDA approval. The company is also about halfway through an effort to acquire approval from Japan's national regulator, the Pharmaceuticals and Medical Devices Agency.

As gene therapies advance, Minarich said the lifetime of improvements some have suggested it might deliver remains to be seen, with readouts from long-term follow-up studies necessary to clarify the picture. "We see enzyme replacement as continuing to be one of the three major legs of treatment for ADA for years to come," he said.

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