FDA Accepts BLA Resubmission for Remestemcel-L in Steroid-Refractory aGVHD

Silviu Itescu, MBBS, FRACP

The FDA has accepted the resubmission of a biologic license application (BLA) for remestemcel-L in the treatment of children with steroid-refractory acute graft versus host disease (SR-aGVHD) under the age of 12 years, according to an announcement by the therapy’s developer, Mesoblast Limited.¹

Mesoblast resubmitted the application in early February 2022,² nearly 4 years after it initiated the rolling submission process for the cell therapy. If the FDA approves the therapy, it will be the first therapy for pediatric patients with SR-aGVHD under the age of 12 years, and the first allogeneic off-the-shelf cellular medicine, in the United States. The agency set a Prescription Drug User Fee Act action date of August 2, 2023, for its review of the BLA.¹

“Over the last 2 years we have worked tirelessly to address the issues previously raised by FDA. We look forward to working closely with the agency over the review period with the aim to make remestemcel-L available as a therapy for children suffering from SR-aGVHD,” Silviu Itescu, MBBS, FRACP, chief executive officer and managing director, Mesoblast, said in a statement.¹

In its announcement, the company detailed the new information that is included in the resubmission, notably new long-term phase 3 survival data up to 4 years, outcome data among those with high-risk disease activity, and propensity-matched survival data, as well as several additional analyses. Those included analyses of prospectively obtained data relating the validated potency assay, clinical data obtained prospectively relating manufacturing changes, data showing low variability and reproducibility of the potency assay, and establishment of a new specification for release of commercial product “to provide assurance that future batches of remestemcel-L will have attributes supportive of expected survival outcomes,” Mesoblast noted.

The rolling BLA was originally submitted in May 2019, with supporting data from a phase 3 clinical trial (NCT02336230). The company received a complete response letter (CRL) in October 2020 that recommended at least 1 additional randomized, controlled study be conducted in adults and/or children to provide further evidence of the effectiveness of remestemcel-L for SR-aGVHD. It also identified a need for further scientific rationale to demonstrate the relationship of potency measurements to the product’s biologic activity—prompting the additional analyses.

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The most recent update on the phase 3 data came in November 2022, with Mesoblast announcing that remestemcel-L demonstrated a long-term survival benefit in treated children through 4 years.³ Treated children had an overall survival (OS) rate of 63% at 1 year, 51% at 2 years, and 49% at 4 years (median, 2-3 years) in comparison with control data in children and adults (using best available therapy or ruoxitinib for adults) in which the OS rate ranged from 40% to 49% at 1 year and 25% to 38% at 2 years (median, 6.5-11.1 months).

Notably, that comparison also favors the study cohort, as 88% of these children had severe disease with the highest risk of mortality—defined by either International Bone Marrow Transplant Registry Grade C/D or Glucksberg Grade 3/4—compared with 22% to 68% of patients in control studies having severe disease.³ At the time those data were announced, principal investigator Joanne Kurtzberg, MD, Jerome Harris Distinguished Professor of Pediatrics and Professor of Pathology, Duke University Medical Center, stated her excitement with the results, noting that it showed the therapy’s “potential as a highly effective treatment for SR-aGVHD in children. Responses are durable, reducing mortality of this often-lethal complication of hematopoietic stem cell transplantation.”

Additionally, topline data announced in 2021 suggested that the therapy might be beneficial in COVID-19,⁴ showing reduced mortality through 60 days in a prespecified group of ventilator-dependent patients below the age of 65 years with COVID-19 and moderate or severe acute respiratory distress syndrome (ARDS). Notably, though, those aged over 65 years did not see a statistically significant improvement, according to a statement from Mesoblast at the time, and enrollment in the study was halted in December 2020. Despite the halt, the data safety monitoring board did advise that the study should continue follow-up as planned.

In its last update on the treatment in COVID-19, issued in May 2022, data from the initial 90 days of treatment showed that remestemcel-L reduced mortality by 48% compared with controls in a prespecified analysis of 123 patients below age 65 years (26% vs 44%; P = .038).⁵ As previously reported, this improvement was not observed in the 97 patients over age 65.

Additionally, 90-day mortality was reduced by 77% compared with controls in a subgroup of patients treated with remestemcel-L who also received dexamethasone as part of their standard of care (14% vs 48%; P = .0037). These outcomes were maintained at later time points in those under age 65, as well, displaying a 42% reduction in mortality through 12 months and with dexamethasone (P <.05).⁵

REFERENCES
1. FDA Accepts Mesoblast’s Resubmission of the Biologic License Application for Remestemcel-L In Children with Steroid-Refractory Acute Graft Versus Host Disease as a Complete Response and Sets Goal Date of August 2, 2023. News release. Mesoblast Limited. March 8, 2023. Accessed March 8, 2023. https://www.biospace.com/article/releases/fda-accepts-mesoblast-s-resubmission-of-the-biologic-license-application-for-remestemcel-l-in-children-with-steroid-refractory-acute-graft-versus-host-disease-as-a-complete-response-and-sets-goal-date-of-august-2-2023/
2. Mesoblast resubmits biologic license application (BLA) to FDA for Remestemcel-L in children with steroid-refractory acute graft versus host disease (Sr-aGVHD). News release. Mesoblast. February 1, 2023. Accessed March 8, 2023. https://www.globenewswire.com/news-release/2023/01/31/2599031/0/en/Mesoblast-Resubmits-Biologic-License-Application-BLA-to-FDA-for-Remestemcel-L-in-Children-With-Steroid-Refractory-Acute-Graft-Versus-Host-Disease-Sr-aGVHD.html
3. Children treated with remestemcel-L show long-term survival through four years in steroid-refractory acute graft versus host disease (SR-aGVHD). News release. Mesoblast. November 22, 2022. Accessed March 8, 2023. https://investorsmedia.mesoblast.com/static-files/41576351-fa4d-4e1c-93ad-2b822145238f
4. Remestemcel-L reduces mortality in patients less than 65 years old with moderate/Severe COVID-19 ARDS: Topline 60-day results from randomized controlled trial. News release. Mesoblast Limited. April 30, 2021. Accessed March 8, 2023. https://investorsmedia.mesoblast.com/static-files/5e07904d-a452-46fb-977f-6b00cd79b992
5. Survival outcomes in COVID-19 ARDS patients treated with remestemcel-L. News release. Mesoblast Limited. May 31, 2022. Accessed March 8, 2023. https://investorsmedia.mesoblast.com/static-files/527b8bf4-ed8f-433f-a767-89a9c13ce451