PERTH, Australia – Australian regenerative medicine company Mesoblast Ltd. saw its stock tumble more than 30% following the release of briefing documents from the FDA ahead of an Aug. 13 advisory committee meeting to review the company’s BLA for Ryoncil (remestemcel-L) for steroid-refractory acute graft-vs.-host host disease (SR-aGVHD) in children.

Although the FDA noted that remestemcel-L reached its primary endpoint of a 28-day overall response rate in patients at 69%, the agency raised concerns about the efficacy of the therapy, which is also in phase III trials for acute respiratory distress (ARDS) due to COVID-19.

Remestemcel-L is derived from allogeneic culture-expanded mesenchymal stromal cells that have been isolated from bone marrow aspirate collected from healthy human donors. The company submitted the final module of a rolling BLA in January, and the FDA set a PDUFA date of Sept. 30.

The Melbourne-based company reported in February 2018 that the phase III trial met the primary endpoint, showing an overall response rate of 69% compared to a historical response rate of 45% at day 28 of treatment (p=0.0003). There are currently no FDA-approved treatments for children under 12 with SR-aGVHD.

Silviu Itescu, CEO, Mesoblast Ltd.

Even so, the FDA had requested additional 180-day survival data, which showed a survival rate of 79% compared to an expected 30% survival rate in its pediatric phase III trial in aGVHD, Mesoblast CEO Silviu Itescu told BioWorld.

The open-label phase III trial enrolled 55 children with steroid-refractory aGVHD between the ages of 2 months and 17 years in 32 sites across the U.S., with 89% of patients suffering from the most severe form of the disease (grade C/D).

Those outcomes were consistent with previous results in 241 children with steroid-refractory aGVHD who failed to respond to multiple biologic agents and were treated under an expanded access program that followed outcomes through 100 days.

FDA raises efficacy concerns

“FDA’s position is that the product attributes the applicant has identified as related to potency and activity do not have a demonstrated relationship to the clinical performance of specific [drug protocol] lots, and that the product’s proposed immunomodulatory mechanism of action has not been demonstrated in vivo in study subjects receiving remestemcel-L,” the briefing document said.

“Without a demonstrated relationship with clinical effectiveness and/or in vivo potency/activity, controlling these [critical quality attributes] may not be sufficient to ensure the manufacturing process consistently produces remestemcel-L lots of acceptable quality,” the agency said.

In questions related to the product’s characterization, the FDA will ask the Oncologic Drugs Advisory Committee (ODAC) to discuss the “adequacy of the potency assay,” pressing the members to propose and discuss “other possible product quality attributes or characteristics that could be controlled to better assure consistent quality of remestemcel-L with regard to safety or effectiveness of the product.”

The agency said that defining product quality attributes that relate to the product’s clinical effectiveness may require more extensive product characterization for cell therapy products than for other biological products.

It also said that because of the complex nature of cell therapy products, trials designed with efficacy endpoints “may not be adequately powered to detect association of clinical outcomes with relevant product attributes.” Also unknown is the durability of the patients’ responses and whether patients will need continued infusions, the briefing documents said.

The FDA pointed to numerous limitations of the single-arm study design of MSB-GVHD001 and suggested it could require an additional clinical trial, with the committee discussing trial designs that would provide evidence of efficacy.

The FDA said remestemcel-L development began more than 20 years ago and that while the product has been tested in multiple trials for a variety of conditions thought to have an inflammatory component, it has yet to be approved in the U.S. for any of them.

Mesoblast raised AU$138 million (US$90 million) in May to scale up manufacturing of remestemcel-L to prepare for a potential launch.

Remestemcel-L is already approved in Japan for aGVHD (branded as Temcell) in both pediatric and adult indications. It was the first allogeneic regenerative medicine to receive full approval in Japan and was launched with partner JCR Pharmaceuticals Co.

Mesoblast has two other stem cell therapy candidates in phase III trials. Its MPC-150-IM is in two phase III trials for chronic heart failure – one for end-stage (class IV) heart failure patients with left ventricular assist devices and another larger trial in advanced (stage III) heart failure.

The FDA granted MPC-150-IM breakthrough therapy designation for the end-stage indication under the regenerative medicine advanced therapies (RMAT) designation under the 21st Century Cures Act.

Mesoblast was quick to point out to the market that the FDA is not bound to ODAC’s decision.

Mesoblast’s shares on Australia’s Securities Exchange (ASX:MSB) fell 31%, ending at $3.36 on market close Aug. 11. Nasdaq-listed American Depository Receipts (NASDAQ:MESO) fell 35% to $11.33.

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