https://www.fda.gov/media/84949/download?attachmentPediatric Information Incorporated Into Human Prescription Drug and
Biological Product Labeling Guidance for Industry
What's been bugging me is Si saying - my words- we just have labelling to go - everything so far has been ticked off.
I thought labelling was just packaging and labels attached for storage, safety, rules, dosage , shelf life.
I just had a dig and found the above link which is specifically for pediatric patients- and this department apparently assesses whether it was an adequate and well controlled study. So that explains why , to me anyway, we hit a snag at the last hurdle.
Safety, tick, Manufacturing tick, Efficacy tick - then whammo - labelling questioned the trial controls- specifically the potency assay in place during 001.
In the annual report 05/12/2023 Silviu Itescu stated Further, to support approval for the pediatric indication,
we are currently generating additional data using the
IL-2R alpha inhibition potency assay which was in place during the pediatric Phase 3 trial to provide the needed
link assuring consistency between the RYONCIL product that was used in the pediatric Phase 3 trial and available
commercial inventory.
31/01/2024 Quarterly update
The
new potency assay data show that the RYONCIL product made with the current manufacturing
process that has undergone successful inspection by FDA, demonstrates greater potency than the
earlier generation product, providing context to its greater impact on survival.
• Showing that the product used in the completed pediatric Phase 3 trial was standardized as to
potency and characterization could provide support for approval of the pediatric indication given the
absence of any approved therapies for children.
29/02/2024 Half Year reporting
For our product Ryoncil® (remestemcel-L) for life-threatening steroid-refractory acute graft-versus-host
disease (SR-aGVHD) ahead of our upcoming meeting in March we have provided the FDA with new data
from a second potency assay
that provides additional product characterization as requested by FDA.26/03/2024
“We thank the agency for their collaborative approach. The responses and guidance from FDA are clear
and provide us with a high level of confidence to refile our BLA for remestemcel-L in children with SRaGVHD,” said Mesoblast CEO Dr. Silviu Itescu.
Mesoblast intends to file the resubmission during the next quarter, seeking to address all remaining
product characterization issues.So the FDA requested additional product characterization- Meso provided it- FDA checked it- said it was sufficient.
Will the FDA accept the IL-2R alpha inhibition potency assay as a suitable control for the 001 trial? Let's check in with our dear old friend Professor Joanne Kurtzberg
Professor Kurtzberg presented the following back on February 16 2023Alloreactive T cells are a key driver of aGVHD development and progression. The immunomodulatory activity of remestemcel-L (Rem-L; ex vivo cultured adult mesenchymal stromal cells) on alloreactive T cells is a key mechanism by which Rem-L improves clinical outcomes in aGVHD. In a phase 3 trial of Rem-L as a treatment for SR-aGVHD in pediatric patients (MSB-GVHD001, NCT02336230), theD28 OR primary endpoint was met, 1-yr survival was 63% and durable survival was seen through at least 4 yrs.Moreover, in high-risk children withMAGIC algorithm probability (MAP) ≥0.29, D180 survival with Rem-L was 64% vs 10% in matched children from the MAGIC cohort (p=0.001).In vitro, Rem-L is characterized by T cell immunomodulatory activity, inhibiting T cell activation, proliferation, and inflammatory cytokine production.To evaluate whether Rem-L’s in vitroimmunomodulatory activity on T-cell activation, as measured by % IL-2Rα inhibition, is a suitable measure of product potency in aGVHD, this study investigated thein vitro/in vivo relationships between %IL2-Rα inhibition by Rem-L lots and clinical outcomes.
Stratifying patients in MSB-GVHD001 (n=54) by treatment with Rem-L product lots within vitroactivity of mean % IL-2Rα inhibition > median or ≤ median showed a positive association between % IL-2Rα inhibition and D180 survival (85% vs. 54%, p=0.01). This was preceded by a greater duration of the D28 OR among responders who received product with higher %IL-2Rα inhibition. The relationship between greater survival and mean % IL-2Rα inhibition > median vs ≤ median was most evident in patients with the most severe form of the disease and at highest risk for death: Minnesota high risk (D180 OS 89% vs 50%, p=0.01), MAP>0.29 (D180 OS 100% vs. 17%, p=0.003) or Grade D disease (D180 OS 91% vs. 50%, p=0.03).
There was a significant relationship between % IL-2Rα inhibitionin vitro as a measure of Rem-L lot potency and reduction in activated T cells through 28 days, as measured by T cells expressing CD3+CD4+CD25+HLA-DR+ activated phenotype, in patients who received a single Rem-L lot (r=-0.76, p=0.009). At screening, patients with high MAP (>0.29) and high-risk for mortality had significantly higher levels of inflammatory biomarkers (IL-2R, TNFR1, HGF)vs patients with low MAP (<0.29). Rem-L product lot IL-2Rα inhibitory activityin vitro also correlated with decreases in inflammatory biomarkers in high-risk patients with MAP>0.29, in parallel with reduced risk of death.The inhibitory activity of Rem-L on IL-2Rα levels on activated T cells in vitro correlates with Rem-L’s in vivo bioactivity in pediatric aGVHD as indicated by reductions in circulating levels of inflammatory biomarkers and activated T cells and improved survival. Therefore, the inhibitory activity of Rem-L on T cell activation in vitro is a suitable measure of product potency in aGVHD.
https://pediatrics.duke.edu/profile/joanne-kurtzberg
Jerome S. Harris Distinguished Professor of Pediatrics
Professor of Pediatrics
Professor of Pathology
Affiliate of the Duke Regeneration Center
Core Faculty in Innovation & Entrepreneurship
Member of the Duke Cancer Institute
Love your work Jo
Reg
(20min delay)