MESOBLAST (MSB) - FDA will likely approve Ryoncil (analysis)
MSB is developing Ryoncil - an IV stem cell therapy for the treatment of acute graft versus host disease (aGVHD) in paediatrics. aGCHD is a potentially life threatening (up to 70-90% mortality) complication of bone marrow transplants (indicated for leukemia/lymphoma etc). Ryoncil has been accepted by the FDA for priority review with a PDUFA action date of US 30th September (1st Oct in AUS).
Why might the FDA approve Ryoncil?
Probability wise:
- Oncology therapy's have an average 88% probability of being approved once they have been accepted for review (data averaged from results from Wong et al (2018), Thomas et al (2016), Hay et al (2014), and DiMasi et al (2010)).
- As part of the review, the FDA requested a recommendation from the Oncologist Drugs Advisory Committee (clinical oncology academics and statisticians) who on Aug 13th voted 9:1 that the available data supports the efficacy of Ryoncil.
- Ryoncil has been approved in Japan for the last 5 years with strong yoy growth.
Benefit-risk ethics analysis:
- There are no FDA approved treatments for aGCHD in pediatrics and no therapies are considered standard of care.
- Ryoncil is effective vs placebo (28d survival 64% vs 38%, 100d survival 79% vs 54%).
- Adverse Effects of Ryoncil were not statistically different from placebo. In fact unapproved treatments (steroids) carry high risk of toxicity.
- aGCHD has a 70-90% mortality rate, there are no FDA approved treatments, Ryoncil appears to be effective, risk of doing harm by approving Ryoncil is low. It seems like the ethical decision is to approve Ryoncil.
Why might not the FDA approve Ryoncil?
- The FDA prefers double-blinded, placebo-controlled RCT's to show effectiveness. However, due to the high mortality rate of aGCHD, enrolling children into an RCT is clearly not ethical. I'd argue that the single arm study comparing to an external control population is as good as you're gonna get. It also does not need to be blinded as the primary endpoint is mortality. The 9:1 ODAC vote seems to support this.
- The study was small (N=14, N=13). It might be reasonable for the FDA to ask for another (potentially larger) study to replicate the results which is a risk.
- Quality control concerns. The FDA raised concerns that the way MSB measure the potency of the Ryoncil (CQA's) may not be enough to ensure the clinical effectiveness of the product. I'm no expert in this part but when MSB responded to these concerns in the webcast, they kind of just reiterated the CQA's from their manufacturing were very high but didn't really address the concern that the CQA's might not translate to clinical effectiveness. It might be reasonable for the FDA to ask for more data on this.
- Even if more data is requested, Ryoncil can still be provisionally approved.
Conclusion:
The FDA will likely approve or provisionally approve (with the request of more data) Ryoncil therapy for pediatric aGVHD in the US which will strongly improve the revenue potential of MSB.
Why might the FDA approve Ryoncil?
Probability wise:
- Oncology therapy's have an average 88% probability of being approved once they have been accepted for review (data averaged from results from Wong et al (2018), Thomas et al (2016), Hay et al (2014), and DiMasi et al (2010)).
- As part of the review, the FDA requested a recommendation from the Oncologist Drugs Advisory Committee (clinical oncology academics and statisticians) who on Aug 13th voted 9:1 that the available data supports the efficacy of Ryoncil.
- Ryoncil has been approved in Japan for the last 5 years with strong yoy growth.
Benefit-risk ethics analysis:
- There are no FDA approved treatments for aGCHD in pediatrics and no therapies are considered standard of care.
- Ryoncil is effective vs placebo (28d survival 64% vs 38%, 100d survival 79% vs 54%).
- Adverse Effects of Ryoncil were not statistically different from placebo. In fact unapproved treatments (steroids) carry high risk of toxicity.
- aGCHD has a 70-90% mortality rate, there are no FDA approved treatments, Ryoncil appears to be effective, risk of doing harm by approving Ryoncil is low. It seems like the ethical decision is to approve Ryoncil.
Why might not the FDA approve Ryoncil?
- The FDA prefers double-blinded, placebo-controlled RCT's to show effectiveness. However, due to the high mortality rate of aGCHD, enrolling children into an RCT is clearly not ethical. I'd argue that the single arm study comparing to an external control population is as good as you're gonna get. It also does not need to be blinded as the primary endpoint is mortality. The 9:1 ODAC vote seems to support this.
- The study was small (N=14, N=13). It might be reasonable for the FDA to ask for another (potentially larger) study to replicate the results which is a risk.
- Quality control concerns. The FDA raised concerns that the way MSB measure the potency of the Ryoncil (CQA's) may not be enough to ensure the clinical effectiveness of the product. I'm no expert in this part but when MSB responded to these concerns in the webcast, they kind of just reiterated the CQA's from their manufacturing were very high but didn't really address the concern that the CQA's might not translate to clinical effectiveness. It might be reasonable for the FDA to ask for more data on this.
- Even if more data is requested, Ryoncil can still be provisionally approved.
Conclusion:
The FDA will likely approve or provisionally approve (with the request of more data) Ryoncil therapy for pediatric aGVHD in the US which will strongly improve the revenue potential of MSB.