Aight, I'll continue with paediatric SR-aGvHD. This is an...

Aight, I'll continue with paediatric SR-aGvHD.

This is an interesting one.

• According to the Center for International Blood and Marrow Transplant Research, there are approximately 30,000¹ allogeneic BMTs globally per year for diseases including hematological cancers (NB:// figures from 2012, will be > than that now)
• 25%² of all cases in the pediatric population.
• Nearly 50% of all allogeneic BMT patients develop aGVHD³.
• Liver or gastrointestinal involvement occur in up to 40%⁴ of all patients with aGVHD and are associated with the greatest risk of death, with mortality rates of up to 85%⁵.

If we break this down, that 7,500 paediatric patients per year in the US, of which 3,750 will develop aGvHD. 1500 of these patients will develop gastrointestinal/liver complications and have a mortality of 85%.

3,750 is an extremely small target population. Why did MSB target it?

Probably because it was a strategic decision done by biotech drug development companies to get early validation by getting early revenue from the lowest hanging fruit. Something with such a degree of high unmet medical need in a small population allows for orphan drug designation and an easier regulatory review process (in theory), hopefully generating some revenue early to derisk the company while they go on to develop other indications.

Orphan drug status includes various incentives, such as tax credits of up to 50% of R&D costs, R&D grants, waived FDA fees, protocol assistance and may get clinical trial tax incentives.

Individuals under the age of 18 incur hospitalization costs of >$173,144⁶ so the per-therapy-cost could probably be quite high

So where are we?

• As with all MSB products, we have demonstrated a clean safety profile in a single-arm trial, the same trial design that the standard of care Jakafi was approved on.
• We met the primary endpoint (mortality), a measure that is generally agreed on by the FDA that 'if you meet X by doing exactly Y then that's a tick in our books'
• We went to an ODAC committee, appointed by the FDA in the event that their expertise is insufficient to make a decision by themselves.
• The ODAC, including a prof. of biostatistics, deemed that MSB had done enough to show both safety and efficacy in a vote of 9-1.
• The dissenter was quoted that his criticism was that a randomised controlled trial was required to adequately demonstrate efficacy.
• The trial design had previously been discussed with the FDA and the FDA agreed it was unethical to perform an RCT with such a high mortality rate.
• For the first time ever, the FDA went against a vote as strong as 9-1 and issued a CRL citing concerns over the single-arm design they previously agreed to (if we are to believe SI) and mechanism of action (MoA).
• This MoA has since been agreed on.
• MSB want to go ahead and run a pre-planned adult RCT that they would have run anyway to get a label extension into adults, as a condition to approval in paediatrics.
• They are doing this by progressing down the Dispute resolution pathway - when has a buttload of bureaucracy and time tied in.
• SI said he believed this would have delayed commercialisation by 6 months, which is over tomorrow/today

Now this is where no one can really know what is going on. All 'rules' have been broken, a trial (which design was agreed to by the FDA) met its primary endpoint, went to an ODAC review, passed with flying colours, and was rejected.

When I spoke to a regulations expert, they said that only makes sense if the company had not discussed with the FDA, or had the FDA recommend against the trial design. SI has said that the FDA had previously agreed to the trial design - so I think everyone is just as confused as eachother.

This one is pretty unpredictable. It obviously SHOULD be approved, as it has shown both efficacy and safety - which was agreed by a panel of experts, in a trial that's design was agreed to by the historic FDA.

Will it get approved? That's a coin toss based on politics (which is more favourable now I'd hazard a guess), and whatever obligations the FDA have to follow through on previously agreed on pathways.

Tune in this HY.

Gang gang

¹CIBMTR, Decision resources GVHD Epi Nov 2012

²Number of hematopoietic stem cell transplants registered with the CIBMTR by US centers, 2008 – 2012, by year of transplant

³Decision resources Niche Markets and Rare diseases: GVHD Nov 2012

⁴Jacobsohn, David A and Vogelsang, Georgia B. Acute graft versus host disease. Orphanet J Rare Dis. 2007; 2: 35.

⁵Westin, Jason R. et al. Steroid-Refractory Acute GVHD: Predictors and Outcomes. Advances in Hematology.
⁶Jingbo Yu, Shreekant Parasuraman, Anshul Shah & Daniel Weisdorf (2019) Mortality, length of stay and costs associated with acute graft-versus-host disease during hospitalization for allogeneic hematopoietic stem cell transplantation, Current Medical Research and Opinion, 35:6, 983-988, DOI: 10.1080/03007995.2018.1551193