The worst CRLs are to do with safety and / or adverse side effects. We are aware MSB's safety profile is not in question and neither is our manufacturing. Per the Prof's words - inventory has been built up and generally approved by the FDA and the Prof is not someone who throws away such phrases. Safety concerns were also not raised during the ODAC meeting so it's suffice to say it's not worth discussing further.
We need further evidence (discussed below) to provide comfort for the FDA. Dr G added a primary endpoint during the 2 October webcast being survival - if we are confident in the product to replicate and indeed perform as expected, this is not an issue in any further required trials. What MSB needs to do is continue to build that 'body of evidence'.
Building a body of evidence can be done via an additional trial, which I interestingly note the tone at the ODAC was 'no trial for children', which was in-line with the 2 October webcast's start per the Prof; however, Dr G used the word 'predominantly' adults later in the same webcast. I wonder if we scrutinised MSB's words like we do the FDA's (e.g. when they say "and / or") maybe MSB has some flex on its side as well i.e. can be open to running a trial with some children involved. I suppose the MSB is prepared to do what is required of them, but would much rather not give placebos to children for reasons already discussed in length on these forums and by Pro JK (I'm loving these initials!).
Regardless of an all-adult trial or a
predominantly adult trial, it seems MSB is seeing the FDA with an ultimatum i.e. seeking accelerated approval prior to doing whichever trial they land on. I think this is the right approach (caveat my bullish nature I have already flagged).
The FDA did not question Ryoncil's endpoints - survival at Day 28 endpoint was met with "very good" survival rates in the Phase 3 trial. The FDA merely wants a continued (at least a base) understanding of Ryoncil's product characteristics in vitro to predict patient outcomes using biomarkers - ongoing assays that will continue to be refined irrespective of the current environment for pipeline products.
I do not think the FDA is as corrupt as some posts make them out to be - neither are they as incompetent. I was as surprised as most upon the CRL issuance; however, we need to keep in mind this is not a slightly tweaked Panadol. MSB isn't looking to win the game, but rather change the game in its entirety. There will certainly be obstacles in achieving anything close to this. The FDA and the relevant individuals need to understand what MSB is doing first before approving it and risking egg over their faces. It may be called cowardly, but I do not think it's pure corruption.
Accelerated ApprovalAccelerated approval allows "drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint" allowing for a quicker approval process. Example markers or surrogate endpoints can be "a laboratory measurement, radiographic image, physical sign or other measurement that is thought to predict clinical benefit, but is not itself a measure of clinical benefit". Note the Ryoncil Phase 3 trial arguably did not meet a surrogate marker; however, satisfied its primary endpoint i.e. survival.
One of the "go-to" examples in the field of Accelerated Approval / CRLs (after decades of debates re Conditional Approval and similar) is Sarepta Therapeutics' drug Exondys (Eteplirsen), which gained approval based on 12 patients (now, why does this 12 sound familiar)… Sarepta is also an example of receiving a CRL and the FDA reversing its decision within three-to-four months of issuing the CRL. Part of the reason was the FDA's Director cautioned if Sarepta did not receive accelerated approval, it may run into funding problems to further study the disease it was aiming to cure and develop similar drugs in its pipeline (I know we have over $100m in the bank, but please see the commercial reality point here).
Another similarity is the Eteplirsen treatment was for children and Sarepta claimed it would be unethical to conduct a RCT / placebo trial on this basis. This, along with other reasons, granted Eteplirsen Conditional Marketing Authorisation by the European Medical Agency because it satisfied the criteria being the benefit / risk is positive, comprehensive data
will be provided (i.e. by undergoing further studies
after a quasi approval, it is an unmet medical need that offers a benefit that outweighs the risk.
It's also unfair to compare the FDA / USA laws and regulations to Japan's and claim "if it's approved there, why isn't it approved here"? By that logic, the USA approves shooting trespassers, but we can't in NZ?! Does that mean NZ is in the wrong? This argument unfortunately fails because each nation has its own laws - to suggest otherwise would be illogical. This is not the right forum to go into detail; however, Japan has a "lower bar" for approving regenerative medicines since 2014, which allows it to do so (cf. the USA). Japan reached its state after many years of debate - similar to what the USA is going through currently and the calls for Accelerated Approval and Conditional Approval date back until at least (per my research) the early 1990s.
Step cell therapies - especially the products MSB is proposing are still in their infancy of being understood by the medical profession. There will always be a time lag between new therapies, drugs, treatments etc. and our processes to have them examined and approved. If this lag does not exist, it is nothing new and our asymmetric investment in MSB would not be asymmetric.
Time is required for such a therapy to receive Accelerated Approval, unless...
Rem-L and ARDSBy 2 October, the Prof noted this trial has "surpassed" the number of patients required for the second interim (45%) readout i.e. we should hear news on this by 6 Nov.
One of the key points with this 300-patient, RCT is that it ticks all the boxes required to show any markers to satisfy the FDA (and "cover themselves") if they were to approve and it was in fact designed "in conjunction" with the FDA. We're playing the game per the FDA's rules with respect to this Phase 3 trial. I have little-to-no doubt if MSB achieves a survival endpoints along the lines of what was shown several months ago in Mt Sinai, the treatment would be immediately approved. I have noted in my previous posts you cannot argue with ARDS data (I noted this well before the CRL for SR-aGVHD). If results in the ARDS trial are replicated there will be no argument on MOA, assays, RCT or any other technicalities one can come up with. Complying with 'the gold standard' and the current state of the world with COVID-19, the FDA does not have the luxury of knocking it back to 'further understand' how things work. If replicated, we're looking at guaranteed approval.
In addition to the above, MSB has been collecting blood samples in a 'very orderly manner' and examining a 'wide range' of biomarkers, known to be related to COVID. These biomarkers will be evaluated and have direct correlation of biologic properties 'of our product'.
I won't comment to what this may or not mean for other pipeline products.
I say immediate approval because the potential pathway via experimental use authorisation is designed to fast-track treatments or products to benefit humanity during diseases of major importance i.e. the current pandemic.
Price Movements Closing RemarksAs I jested in my intro, we're 20c above the point from one of my more recent posts i.e. the infamous ODAC briefing notes release. I have commented in several of my posts (in mid August)
Post #: 46479576 - share price is likely going to be between $3.90 and $4.30 before a meaningful ARDS readout and
Post #: 46579207 - the price floor has increased from $1 to about $3.30 following the 9-1 ODAC decision. If we head towards FDA knocking MSB's ultimatum back and do not land on a middle-ground, we are likely heading towards $2.50 (subject to any conclusive news from ARDS). There is no reason to panic - there never is. Granted it's easy for me to say this as I am in the green and invested in the business before some of the hype; however, I've averaged up and bought shares as high as $5.21 and do not think it's a bad purchase in the slightest. I may buy more if we go ~$3. My wife understands the honeymoon may then be on hold until the 60% readout.
In closing, SR-aGVHD is pending approval post-discussion with the FDA. Data is clear. ODAC is clear. The overwhelming 9-1 vote is clear, along with pro JK. We simply need to clue-up the FDA a little more and ensure they are comfortable with what they're signing off on.
ARDS is also pending approval, following its Phase 3 trial - I speculate we get the green light at the 60% read-out and perhaps move all placebo patients onto Rem-L.
It will be a very bumpy ride over until Christmas. If you truly understand what you have invested in, you're aware of this and it won't phase you. I was showing something on my phone to a friend when an alert popped up "your account ### is down $XXX" to which he was shocked and said "so that means you were $YYY up?!". Yes, I was. Did it matter? No. I'm not selling before legitimate and conclusive news - whether positive or negative. Until then, it's all merely noise.
MSB is like my high-school email address - next big thing. Condolences are unnecessary.
Kia kaha
AM.
(20min delay)