@Phaedrus, I appreciate your detailed posts and I agree with all the points you make especially regarding the Lassman letter submitted to the FDA (no doubt) on behalf of Incyte. Going forward, the issue raised by
@nosluggos "I don't think there has ever been any misconception that Ryoncil is anything but
'the treatment of last resort' is an important one and I'll add a couple of comments.
What makes a medicine a "treatment of last resort"? In large part it's determined by the nature of the illness and positioning decisions made by the company in testing its product. The FDA makes approval decisions based on the results of FDA-authorized clinical trials. The label affixed to a newly approved medication reflects inclusion and exclusion criteria drawn from those trials. In other words, if clinical trials show that a medication is safe and effective in treating children with SR-aGVHD, and anyone over age 18 was excluded from testing, you obviously can't add to the label "also effective in adults". But the same goes with where the medicine is positioned in the treatment cascade - first line, second line, etc. So, we should look to trial NCT02336230 that led to the approval to get an idea of where Ryoncil is positioned. And indeed, the company specifically excluded patients "who had received systemic agents other than steroids." In other words, if a patient received ruxilitinib, he or she could not enroll in the trial. Indeed, Joanne Kurtzberg et al in their write-up of the trial results make no mention of ruxilitinib or Jakafi. For children with aGVHD that means Ryoncil is squarely positioned as a second-line therapy after steroids have failed... leaving open the question of what to do for children 12 and above. That means it's up to the clinician (with input from insurance most likely) to decide whether Ryoncil should be used before ruxilitinib (or any other immune modulator that might be tried off-label).
Note that in its press release on November 22, 2023 MSB proposed a trial in adults with aGVHD where Ryoncil would be given as a third-line treatment after failure on steroids AND after failure on Ryoncil. So there the company was positioning the medicine more as a treatment of "last resort". If they wanted to position it as second-line therapy in adults, they would have to set up a trial where half of the patients received rem-L and half received ruxilitinib and may the best medicine win. We'll see if the third-line Rx trial design gets modified going forward now that we have an approval in children.
In Covid-related ARDS the company was clearly positioning rem-L to be a "medicine of last resort". We can tell by the trial design. To get into the trial you had to be very sick with Covid pneumonia, ie sedated, intubated, on a ventilator with a P/F ratio below 200. They even accepted patients knock, knock, knocking on heaven's door with P/F ratios below 100 that no other trial would touch. These were patients who had failed multiple therapeutics including vaccines, steroids, anti-virals, antibody cocktails, off-label (and unproven) use of HCQ and/or Ivermectin, Hi-flo oxygen and juggling of various ventilator settings... still going downhill, then they became candidates for remestemcel-L, the "medicine of last resort" for that indication. I consider it a term of endearment, not pejorative at all. And I think it was appropriate positioning for that particular indication. They could have tested rem-L earlier in the treatment cascade but the nature of the illness with a cytokine storm, not to mention logistics and costs, were against it.
By contrast, in children with the rare but deadly post-Covid MIS-C, which trial is still open for enrollment by the way, rem-L is being positioned as a first-line therapy to be given concurrently with IV steroids. So, it depends on a number of factors and it will be interesting to see how the Company positions the medication in the treatment cascade for various illnesses going forward.
(20min delay)