MSB to dispute FDA finding in Type A meeting, page-367

Accelerated Approval

Firstly, I would like to record my thanks to @stockrock@dplane & @Zenox for some well founded research. After all the drama of Friday morning, many people’s confidence is pretty badly shaken upand some will probably questioning if Mesoblast will have to initiate a further phase 3 clinicaltrial, possibly delaying approval for Ryoncil , for treatment of steroid refractory acute GVHD by a number of years.

After two days of research into the early hours of the morning, I can now see a clear pathway towards “accelerated approval”...and woe betide the FDA if they try to deny us this option, because as you will be able to reference in the slidesbelow, we must surely meet all the criteria comfortably.

So,..Where does Mesoblast stand post this CRL ?

What timetable will we have to follow ?

Will all our existing data hold us in good stead?

What potency assays and Critical Quality Attributes (CQAs) will be required

What relevant biomarkers will we need for submission ?

I believe, Mesoblast will , within 7 days , prepare a detailed response to the issues brought up in the CRL.The Company then expects to formally requesta Type A meeting with the FDA to be held no later than 30 days time. This is when Silviu will finally be able to determine what the FDA is playing at. Without question , I believe the FDA may have acted in an irregular and inconsistent manner in dealing with our application. The management of Mesoblast must be incandescent with rage as they have almost certainly followed FDA guidance, re the design of their successful trial(GVHD001) and will have been in regular contact with the FDA...who were supposed to provide informed guidance and support as part of the rolling BLA submission.

Mesoblast has often waited until they receive the official minutes of their FDA meetings before informing shareholders of what is required to navigate the path to an accelerated approval...so we will probably have to wait up to a further 30 days to be advised of what has been agreed.

The burden of proof to obtain accelerated approval is lower than a full blown BLA and fortunately I have been able to find conclusive proof of what is specific required for refractory acute GVHD patients because i came across an FDA slide presentation which specifically covers the topic...see below.

On the basis of what is stipulated in those slides, you are able to determine that :

1. “In ( steroid) refractory settings , single arm studies are fine for use.”

(Mesoblast, of course have gone one stage further and commissioned a retrospective benchmarking/patient pairing analysis from the Magic Consortium, who matched our results against efficacy of a comparable cohort group.)

1. Single arm trials ...should follow the 1998 FDA Effectiveness Guidance, the key requirement are listed on the slide...all of which i believe our clinical trial( GVHD001) would satisfy.

1. Accelerated Approvals have prescriptive requirements with regards to post marketing studies and a further confirmatory trial ....because this pathway is a conditional approval which can be withdrawn if subsequent studies do not confirm efficacy. This is not a problem as we have started designing for quite some time an adult trial for circa., 150 patients for adultAcute srGVHD. There is also some pretty fierce labelling restrictions and warnings which are far more detailed and cumbersome than with a conventional full authorisation. Our therapy would effectively be on probation allowing the FDA total control although we would be able to seek reimbursement...normally on a cost plus basis, which will help to recover considerable costs.

@stockrock has quite rightly drawn attention to the smaller percentage of therapies that make it through the accelerated approvals programme. However, Mesoblast has already been through the exhaustive BLA process and with our safety record not in dispute and having achieved overwhelming efficacy with a “gold standard” clinical endpoint (as opposed to a mere surrogate endpoint ) I believe Ryoncil has met the specific qualifying criteria. As if that were not enough, the FDA is aware that we have successfully navigated a full ADCOM with a panel of experts who overwhelmingly voted in favour of our approval. I believe that those in the higher echelons of the FDA will be acutely aware of the unmet need which is still there in children under 12 and that public opinion is about to turn on them savagely as a consequence of their previous ruling.

The FDA has Mesoblast where it wants them. If you want to get accelerated approval, tow the line, show efficacy by a further trial in adults and if your long term safety data or the efficacy in your new trial is below the required standard...we will shut you down !

It was obvious the FDA were not comfortable allowing a first in class stem cell therapy to be authorised without great oversight...I believe they will have achieved this with accelerated approval.

On the other hand , Mesoblast may not have to go though the expense of a further trial if the current ARDS phase three clinical trials proves overwhelming efficacy based on the similar immunological pathways and dosages ....the latter trial has a large number of clinical biomarkers which should help reinforce the relationship between the potency assays at therapeutic “activity”.

https://www.cibmtr.org/Meetings/Materials/GVHDworkshop/GvHD%20Workshop%20Library/01_FarrellGVHDconference.pdf

So why do I believe are the FDA inconsistent ? Well, take for example , the latest approval for Chronic GVHD, Ibrutinib(Imbruvica) which was a single arm study of just 42 patients submitted by Pharmacyclics LLC.....Out of interest, you may recall that a certain Shawn Tomasello who is a Board Director of Mesoblast , was previously Chief Commercial Officer of Pharmacyclics, which was acquired by AbbVie Inc., for $21bn in 2015....so I guess we have had plenty of constructive advice internally as well about what would have been required by the FDA.

It is also noteworthy , that Ibrutinib was allowed very tamepost marketing approval requirements. As shown below, it was exempted, by virtue of being awarded an “orphan designation “ status from the FDA form having to complete a paediatric assessment for its therapy. (See link below)

https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/205552Orig1s017ltr.pdf

It is also interesting to note that the author of the above slides detailing qualifying criteria for accelerated approval was a certain Anne T Farrell ...who I believe now happens to be a divisional director at Centre for Drug Evaluation and Research and whose name appears on the FDA review study of Ibrutinib, so I think we can rely on the guidance notes shown.

https://link.springer.com/article/10.1007/s11136-020-02448-y

• Published: 25 February 2020

FDA review summary of patient-reported outcome results for ibrutinib in the treatment of chronic graft versus host disease

• Bellinda L. King-Kallimanis,Tanya Wroblewski,Virginia Kwitkowski,R. Angelo De Claro,Thomas Gwise,Vishal Bhatnagar,Ann T. Farrell&Paul G. Klue

Abstract

Purpose

On August 2, 2017, the Food and Drug Administration approved ibrutinib (IMBRUVICA) for the treatment of patients with chronic graft versus host disease (cGVHD) after the failure of one or more lines of systemic therapy. The approval was based on results from a single-arm, multicenter trial that enrolled patients with refractory cGVHD. This paper describes the FDA review of patient-reported outcomes (PRO) data from Study PCYC-1129-CA and the decision to incorporate descriptive PRO data in the FDA label to support the primary clinician-reported outcome results.Published: 25 February 2020

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Conclusion,

In summary, Ryoncil is a perfect candidate, in my opinion , for accelerated approval , based on the specific criteria for steroid refractoryaGVHD which i have presented . Intwo to three months, subject to agreeing a confirmatory trial for adult sr aGVHD (that we had committed to undertaking anyway since 2019), we should get confirmation of our eligibility. If the FDA do not play ball in these circumstances, i think we have an “prima facie” case of abuse of the approval process ...as possibly alluded to by the veritable @dolcevita.

The Mesoblast share price may be currently vulnerable to bear raids, as people need reassurance that Ryoncil will be able to receive authorisation. When people realise that a degree of certainty will be re established in the next 2 months , the shares should recover to previous highs. Indeed, i believe that our phase three clinical trial for Covid 19/ARDS has a good chance of an early stop in the next four weeks....alternatively our Revascor trial is another blockbuster due to report very soon.

Lastly, prepare to be shocked. I have uncovered some pretty breathtaking facts about the clinical trial results for Jakafi (Ruxolitinib) which i look forward to sharing with you in another post shortly. I think it is going to make an awful lot of people extremely angry......watch this space.

Please do not rely on the facts or opinions represented in the above post when making an investment decision. OP