Hello all,
I have recently taken a position here.
While I concede I am perhaps a little late to the party, better late than never as they say - and on one view, the timing could not have been better as it MSB appears truly to be on the cusp of what might appropriately be described as the “pointy end” of its hopeful transition into a major global player in the company’s fields of aspiration!
Although I have not trawled through all of the many pages of analysis and insights contained within the vaults of this forum, from what I have seen there has been some excellent posting and thank you to those who have given up their time to share some undoubtedly valuable commentary.
MSB indeed appears to have “many irons in the fire”, and the imminent Oncologic Drugs Advisory Committee ("ODAC") review meeting scheduled to take place on 13 August 2020 was logically the first place for me to try to understand better via research and for the purposes of considering MSB's most immediate prospects. The information set out below has been collated principally for my own interest's sake, is publicly available on the web and I do not vouch for the accuracy of the same. As always you should not rely on it for investments decisions and it does not constitute advice in any form. Hopefully it provides some impetus to undertake your own research and invites further commentary in this forum.
For those who have not yet looked, the ODAC meeting announcement and information for 13 August 2020 can be located here:
ODAC - what is it?
According to Wikipedia, the ODAC receives requests for technical and clinical evaluation of new "drugs" by the FDA. The committee, consisting of members from academic and clinical oncology biostatistics, the general public, and the pharmaceutical industry, makes non-binding recommendations to the FDA about the advisability of approving new medications to treat cancer.
Perhaps a better description and insight was provided by Leslie A Vaccari in their 2004 publication entitled: "The Role of the Oncology Drug Advisory Committee in the FDA Review Process for Oncologic Products." (my emphasis added):
"Oncological products presented to ODAC may be drugs, biologics, or combination drug- or biological-device products. Biological products may be presented before either the ODAC or the Biological Response Modifier Advisory Committee. The presentation of an oncologic product to ODAC is a milestone for both the product development timeline and also for the FDA's application review timeline."
And further:
"The function of ODAC is consistent with other FDA advisory committees that meet to provide independent expert medical and scientific advice to the FDA regarding the safety, effectiveness, and appropriate use of products that are under its jurisdiction. In the last decade, the performance and availability of the resources afforded by advisory committee meetings has enhanced the FDA review of all drug and biological products for the treatment of cancer.... All advisory committee recommendations are offered as advice and are not binding on the FDA decisions for the applications under review."
Accordingly, it would be fair to say the ODAC is a significant and integral part of the FDA approvals process in the context of oncological products in the United States, and their role and influence should not be underestimated in any way.
Data - ODAC and FDA decisions
Needless to say, the article is amazingly useful in the context of the MSB's upcoming date with destiny, and I commend it to you for reading as it provides many useful insights.
Some key points from the article can be summarised as follows (my emphasis added and further comments of relevance):
- The article research covers all ODAC meetings between January 2000 and December 2014.
- Primary sources of data used for the article were the ODAC meeting transcripts. If transcripts were not available, other sources were consulted, including webcasts, agendas, summaries of minutes, waivers, slides of presentations,labels, and medical officer review documents.If available, individual conflict of interest documents were also consulted for all committee members and voting consultants.
- A total of 165 meetings held by ODAC advisory committee were analysed. Of these, 139 (84%) were product-specific meetings, and 93 meetings (67%) included voting questions. After excluding meetings discussing devices or diagnostic tests (n = 4), noncancer drugs (n = 5), and meetings discussing general questions (n = 2), transcripts from 82 meetings were available for analysis. In these meetings, ODAC discussed and voted on 60 oncology products.Products were sponsored by 43 pharmaceutical companies,and in 34 cases (79%) the sponsor was a US-based pharmaceutical company.
- Table 1 (which I have set out below) confirms that 17% of the analysed cases involved "Biologic licensing". NB: We know that the 13 August 2020 ODAC meeting is to review the data supporting MSB's Biologics Licence Application in relation to RYONCIL.
- The committee voted favouring the drug in 41 cases (50%) and against the drug in 41 cases (50%). There was a very high level of agreement between ODAC committee recommendations and subsequent FDA approval; FDA approval was received for all 41 drugs for which ODAC recommended approval. Additionally, the FDA approved 7 out of 41 agents which were not recommended for approval by ODAC.
- A conflict of interest statement was read prior to 79 of the 82 meetings analysed, and no details about conflicts of interest were available for 3 meetings. At 47 meetings (59%), at least 1 conflict was declared for at least 1 committee member voting. In 32 meetings (41%), no conflicts were reported for all committee members. The most common conflict type for both advisory committee members and voting consultants was stock ownership and other investments (n = 91 [47%]) followed by consultancy (n = 71 [36%])
- The approval of new cancer drugs by the FDA is based, usually, on the demonstration of efficacy with acceptable safety in adequate and well-controlled studies.However, predictors of recommendations for approval by advisory committees and of subsequent approval are less clear.
- The main predictor of a favourable vote from ODAC members and of final FDA approval was the number of trials supporting the application.This result is consistent with the FDA’s published recommendation for at least 2 adequate and well-controlled studies, each convincing on its own, being required to establish efficacy. The data also show that a large proportion of applications supported by nonrandomized trials were approved, many under the FDA Accelerated Approval Program.
Oncology therapies where approval was argued are set out in table 1 to the journal article:
Predictors of ODAC recommendation and subsequent FDA approval are set out in the following table 3 to the journal article:
In conclusion the journal article states:
“ODAC members and the FDA were more likely to approve drugs when more than 1 trial supporting the application is available. Methodological quality such as the use of randomization appears less important with approvals occurring for drugs studied in single-arm trials in diseases or those for which there is no available therapy. Declarations of FCOIs among voting members of ODAC were frequent but have decreased significantly over time. There was no apparent influence of FCOIs on ODAC recommendation and subsequent regulatory approval.“
Application to MSB
According to the FDA website meeting link posted above, with respect to the ODAC meeting for MSB on 13 August 2020:
"The meeting presentations will be heard, viewed, captioned, and recorded through an online teleconferencing platform. On August 13, 2020, the committee will discuss biologics license application (BLA) 125706, for remestemcel-L (ex-vivo culture-expanded adult human mesenchymal stromal cells suspension for intravenous infusion), submitted by Mesoblast, Inc. The proposed indication (use) for this product is for the treatment of steroid-refractory acute graft-versus-host disease in pediatric patients. The morning session will discuss issues related to the characterization and critical quality attributes of remestemcel-L as they relate to clinical effectiveness. The afternoon session will discuss results from clinical trials included in BLA 125706"
If we apply some of the research set out above to MSB's case, attributes that would may favour the company's prospects of approval at the ODAC meeting (based on statistics) arguably include the following:
- We already know that MSB has undertaken a number of seemingly comprehensive and well-controlled clinical trials involving RYONCIL in the context of GvHD and which on the face of things stand on their own, including the following as reported in the company announcement dated 25 May 2020:
"1. Study 275: An Expanded Access Program in 241 children across 50 centers in eight countries where RYONCIL was used as salvage therapy for steroid-refractory acute GVHD in patients who failed to respond to steroid therapy as well as multiple other agents.
- Day 28 Overall Response (OR), the primary endpoint, was achieved in 65% of subjects. Survival through 100 days was significantly greater in patients who achieved a day 28 OR (82%) compared with patients that did not achieve day 28 OR (39%), with 67% overall day 100 survival.
2. Study GVHD001/002: A Phase 3 single-arm trial in 55 children across 20 centers in the United States where RYONCIL was used as the first line of treatment for children who failed to respond to steroids for acute GVHD.
- Consistent with the findings in Study 275, Day 28 OR was achieved in 70% of children. This was statistically significant compared to the pre-specified control value of 45% (70.4% versus 45%, P =0.0003). As in study 275, clinical response at day 28 was highly predictive of improved survival through day 100 (87% compared to 47% in patients that did not achieve day 28 OR P = 0.0001). Similar predictive value of day 28 was also seen in survival through day 180 (79% vs. 43.8%, P= 0.003). Overall survival was 74.1% at day 100 and 68.5% at day 180.
- These results were significantly higher than those from matched control pediatric subjects from the contemporaneous database of the Mount Sinai Acute GVHD International Consortium (MAGIC), accessed to provide an unbiased and independent estimate of response rates and outcomes in matched pediatric control patients treated with institutional standard of care. In the MAGIC controls, Day 28 OR was 43% and Day 100 survival was 57%.
3. Study 280: A Phase 3 randomized placebo-controlled trial in 260 patients, including 28 children, across 72 centers in seven countries where RYONCIL or placebo were added to second line therapy in patients with steroid-refractory acute GVHD who failed to respond to steroid treatment.
- Among high-risk children and adults who had the most severe disease stages, day 28 OR was significantly greater in the RYONCIL treated group (58% versus 37%; P = 0.03) compared to placebo. Among the standard risk patients there was no significant benefit of RYONCIL treatment. Within the pediatric patients in this study (n=28) day 28 OR was significantly greater in the RYONCIL group compared with the placebo group (64% vs 36%, respectively, P=0.05).
- These Phase 3 results provide prospective, randomized controlled data which are supportive for the use of RYONCIL in children and high-risk adults with steroid-refractory acute GVHD."
- While founded in Australia, MSB is now seemingly "US based" noting it is also listed on the NASDAQ and has its office in New York. Furthermore, I suspect that the recent appointment of Dagmar Rosa-Bjorkeson to the role of Chief Operating Officer (COO) based in New York may be of some assistance.
- MSB has been given priority review and according to the company: "There are currently no FDA-approved treatments in the United States for children under 12 with SRaGVHD" - hence the company seeks to bring novel therapies to patients with "critical unmet needs".
- I have not yet located information to suggest that any ODAC committee voting members have any form of conflict of interest in so far as MSB is concerned (if so this may be disclosed in due course); but in any event the research outlined above appears to suggest that this unlikely to be any real impediment to ODAC approval.
Conclusion
Having regard to the matters set out above, on balance my view is that MSB's prospects based on the statistical data available from the journal article suggests that its application arguably has a number of the "hallmarks" of ODAC approval, and hence it would then follow that if the ODAC approves then it is more likely than not statistically that the FDA would then approve.
It is also important to note that based on that data that there appear to be a material number of FDA approvals where the ODAC hasnot given its approval; hence rejection by ODAC does not constitute the "end of the line".
That said, it perhaps goes without saying that:
- The only decision that matters is the one that concerns us - statistics and data are only as good as the next decision. It is the devil in the detail and the subjective view taken of the same by committee members that will ultimately determine the outcome, and no amount of historical data can tell us the position in advance.
- Nothing in life is"in the bag until it is in the bag"!
I welcome the critique and commentary of others in this forum. Please note that I am rather new to this stock and have pulled the above together quickly.
Very best wishes to all shareholders of MSB, and I look forward to seeing what unfolds over coming weeks.
(20min delay)