I woke up this morning and saw the after-hours drop in price on NASDAQ, most likely due to the documents released by the FDA in preparation for the 13th August meeting form here: https://www.fda.gov/media/140986/download
After reading and analysing the documents (detailed explanation in post below), I see the following 3 possible outcomes from the ODAC panel (all in my opinion only):
- Overwhelming votes in favour
- Unclear majority in favour or against
- Overwhelming votes against
For both outcomes 1 and 2 above, the documents allude to the possibility that the ODAC and FDA can ask for a further trial to be carried out addressing any concerns. This would mean an extended timeline for remestemcel-L through to approval for aGVHD.
I feel outcome 3 is almost all but ruled out as FDA confirms that safety is not an issue.
What it comes down to is 3 main points:
- Most recent study GVHD001/002 considered on its own (MSB) vs FDA wanting to consider all previous studies as well
- Efficacy as defined by Mesoblast compared to FDA's definition.
- Potency improvements and consistency in every lot - Mesoblast vs FDA
Worst case scenario:
Regardless of the meeting on 13th August and how the ODAC panel vote, if the FDA is unsatisfied with MSB's position on using the most recent study for efficacy, it seems logical that they would ask for a further trial.
Best case scenario:
Panel and FDA are convinced by MSB to not consider the 10 year old trials and go off the most recent one. Efficacy will therefore be a non issue. Potency and consistency of rememstemcel-L will also be satisfactory based on the improvements in manufacturing process by MSB.
Overall, I'm quite satisfied with MSB's responses addressing FDA's concerns.
Based on how the meeting goes, we should be able to get a view for Outcome 1 or 2 and what the likelihood of the best and worst case scenarios are.
As it stands. I have faith in SI and team to get this over the line without needing a further trial.
Further Analysis of Event Materials
The main page for the August 13 meeting is here: https://www.fda.gov/advisory-committees/advisory-committee-calendar/august-13-2020-meeting-oncologic-drugs-advisory-committee-meeting-announcement-08132020-08132020
Note the table of event materials at the bottom of the page. I have pasted a screenshot of it, with what I determined to be the source organisation for each document (highlighted in blue).
As you can see there appears to be only one document prepared by Mesoblast. Its the largest PDF (11.67MB) second from the bottom in the table above. Link here: https://www.fda.gov/media/140996/download
Everything else is FDA / ODAC prepared.
I have seen posts discussing excerpts in different threads and thought it would help to have the discussion in one thread that everyone can link to. Here is my take on things after an initial read of the most important documents.
Full disclosure: I am not a medical expert. I have approached this as a logical / critical analysis, using FDA's question put to Mesoblast and extracting what Mesoblast themselves have provided in their document. Please tag others who have more expertise to add their input. @LeftYahoo and others.
Please tag them if you know they can add value.
All of the below is my interpretation and linking together what I saw as Mesoblast's responses (from their document) to FDA's questions and concerns from their documents.FDA ODAC Questions and Mesoblast responsesThere are 4 draft questions that the FDA has, they are in the AM and PM session PDFs (4th and 5th in the table above) linked here:
https://www.fda.gov/media/141001/download and
https://www.fda.gov/media/141002/downloadFDA questions in red italics, followed by Mesoblast responses in blue.
FDA ODAC Question 1:
Product quality attributes measured for remestemcel-L are intended toensure that key qualities of the drug product are maintained consistently from lot to lot.Please discuss the adequacy of the potency assay established by the Applicant forremestemcel-L.
Mesoblast response (page 35):
The remestemcel-L manufacturing process has been developed to produce a safe, effective, andconsistent product. Over development relevant quality attributes have been established that arerepresentative of product characteristics for identity, purity, safety, and efficacy.
The mechanism of action regarding the product’s immunomodulatory characteristics are welldefined in vitro and in vivo. The relevancy of the product’s potency marker, TNFR1 expressionlevels, have been supported through in vitro data and correlation to clinical outcome measures inthe clinical efficacy studies.
Control of starting materials, raw materials, testing performed at multiple points of themanufacturing process through in-process testing and final release testing, use of sterile singleuse technology materials and a functionally closed manufacturing process, all provide assurancethat the product is safe and manufactured consistently.
The product has been well characterized through long-term stability studies demonstrating that itmaintains a shelf-life of 48 months when stored at ≤ -135°C in LN2 vapor phase. Storage anddistribution process and controls are in place to ensure product quality is maintained from thestart of production through to receipt by the customer.
In conclusion, remestemcel-L has a well-established and robust manufacturing process whichproduces a product that consistently meets product quality attributes.
Pages 31 and 32 have more details on lot consistency.
FDA ODAC Question 2:
In addition to discussion of potency, please propose and discuss otherpossible product quality attributes or characteristics that could be controlled to better assureconsistent quality of remestemcel-L with regard to safety or effectiveness of the product.
Mesoblast response (pages 24,31,35):
Quality Controls / Summary (page 24):- Critical quality attribute (CQAs) have been determined for remestemcel-L and aremonitored at several stages throughout the DCB, DS and DP process.
- Cell Attributes are assessed through batch release testing and extended characterizationof the DCBs and DP.
- Safety of the product is assured through selection and quality control of materials,reagents, components and testing performed on the product at multiple points throughthe process.
- The combination of quality controls around the process, facility, raw materials,components and monitoring of quality attributes for each lot of ce-MSCs manufacturedensures the final product CQAs for potency, identity, purity, safety and potency areconsistently maintained.
Process Improvements / Summary (page 31):- Extensive experience regarding manufacture of remestemcel-L exists overdevelopment.
- Manufacturing improvements to the Osiris original process have optimized andstreamlined the manufacturing process. These have been carried through for theproposed commercial product.
- CQAs were maintained throughout development to monitor product and demonstrateproduct comparability.
- Process improvements and controls introduced through manufacturing developmenthave produced product with consistent quality attributes relative to the desired clinicaloutcome.
FDA ODAC Question 3: Limitations of the single-arm study design of MSB-GVHD001 include, butare not necessarily limited to, the following:
a) limited ability to ensure that baselineprognostic factors, both known and unknown, were similar in MSB-GVHD001 and theApplicant’s control;
b) limited ability to ensure that unknown and known potentialconfounding factors (e.g., additional salvage therapies for treatment of aGVHD) that couldinfluence efficacy outcomes were similar in MSB-GVHD001 and the historical controlgroup;
c) potential bias with selection of patients, subjective nature of the assessments toscore aGVHD d) the adequacy of the historical data to support a null hypothesis.Please discuss the strengths and weaknesses of the design of Study MSB-GVHD001. Mesoblast response (page 92 onwards):
Study GVHD001 was a Phase 3, multicenter, single-arm, open-label trial to evaluate efficacy andsafety of remestemcel-L in pediatric patients with aGVHD who had failed to respond to systemicsteroid treatment (Figure 18). Study GVHD001 was conducted as a single-arm study due to theseriousness of the condition, the rapid clinical deterioration of affected patients, the mountingliterature suggesting a meaningful treatment effect, and the position in the medical communitythat a randomized controlled trial was neither feasible nor ethical in this patient population.
Selection of patients
FDA ODAC Question 4: As noted previously, primary endpoint results in Study MSB-GVHD001were statistically significant; the measured response was durable (median 54 days). However,the results of Studies 265 and 280, the two randomized trials, did not provide evidence of atreatment effect for remestemcel-L in aGVHD, even when reanalyzed using the efficacyendpoint of Day-28 ORR. In fact, a treatment effect has not been identified in any of theprevious clinical trials conducted in various disease entities, including: Type 1 diabetesmellitus, Crohn’s Disease, myocardial infarction, or severe chronic obstructive pulmonarydisease and the mechanism of action of remestemcel-L in mitigating aGVHD remainsunclear.
a) Please discuss whether the results of Studies 265 and 280 are relevant to theeffectiveness of remestemcel-L for the treatment of pediatric SR-aGVHD. In yourdiscussion, please consider not only the similarities and differences in the studypopulations, but also any other factors (e.g., number of years between studies; pathophysiology of adult aGVHD / SR-aGVHD vs. pediatric aGVHD / SR-GVHD)that you deem relevant.
b) ) FDA may require an additional clinical trial to support the effectiveness of theremestemcel-L in pediatric SR-aGVHD. If so, what are your recommendationsregarding the design of such a trial? For example, please discuss the population (e.g.,aGVHD or SR-aGVHD; adult and/or pediatric), treatment assignment (randomizedvs. single-arm), primary and secondary endpoints (e.g., Day-28 ORR, Day 100survival, Day 180 survival, etc.), and any other aspects of the trial design.Mesoblast response (page 76 onwards):
History of the various studies FDA cites, 265, 275, 280 and the most recent one GVHD001/002
Clinical Development Program
In the clinical development program, 309 children with SR-aGVHD received remestemcel-L across protocols 280, EAP 275 and the pivotal Phase 3 Study GVHD001/002. Earlier studies of remstemcel-L in different populations include new onset GVHD in adults (Protocols 260/261 and 265) and other non GVHD indications (AMI, COPD, Crohn's Disease, and T1D).
Protocol 265 was a randomized, double-blind, placebo-controlled study in patients with newonset aGVHD. The results showed that remestemcel-L did not show a difference from placebo incombination with corticosteroids; however, corticosteroids are typically effective in early stage(New Onset aGVHD) disease, and the patient population is not the target population forremestemcel-L. Subsequent development of remestemcel-L focused on SR-aGVHD.Additionally, this study used remestemcel-L produced by the original process with lower TNFR1potency and used a reduced dosing regimen (6 total doses over 4 weeks) compared to the dosingregimen used in SR-aGVHD protocols (8 total doses over 4 weeks with additional treatment forpatients with incomplete response at Day 28). Therefore, this study is not considered to berelevant to the focus of this Advisory Committee meeting to discuss remestemcel-L treatment insteroid refractory pediatric patients with aGVHD and is not detailed in this briefing document. Efficacy Conclusion (page 112): Results from analyses presented in this briefing document demonstrate significant and clinicallymeaningful efficacy of remestemcel-L treatment of pediatric patients with SR-aGVHD, asmeasured by clinical response and survival. Throughout development, learnings from eachprotocol provided critical insights to inform the design of Pivotal Study GVHD001 regardingdose, severity, target population, and line of therapy.
In Protocol 280, although the primary endpoint of DCR was not met, post hoc analyses ofDay 28 OR in patients with severe disease (Grade C/D) showed improved responses vs. thecontrol group (61% vs. 50% in Grade C/D disease). An analysis of pediatric patients (n=14)demonstrated a higher Day 28 OR with remestemcel-L of 64% (9/14) vs the control group, 36%(5/14). While these were post hoc analyses and the pediatric cohort was small, results suggesteda potential signal in severe patients overall that was consistent in children.
In EAP 275, a relatively large ‘real-world’ population of 241 children with SR-aGVHD who hadfailed to respond to systemic corticosteroids and multiple lines of treatment responded toremestemcel-L. The Day 28 OR with remestemcel-L was 65% and Day 100 survival was 66% inthis group of children with highly refractory disease. Taken together, Protocol 280 and EAP 275suggested that children with SR-aGVHD, including those with severe disease, would likelyrespond to remestemcel-L at the doses given and informed the design of the pivotal study.
In Pivotal Study GVHD001, patients with predominately severe disease (89% Grade C/D) whowere refractory to steroids only were treated with remestemcel-L and Day 28 OR was 70%.Reponses were consistent across disease severity, including Grades C/D where other treatmentsoften fail. OS was 74% at Day 100 and 69% at Day 180. These clinically meaningful resultswere consistent with EAP 275, show the robust efficacy of remestemcel-L in the targetpopulation of children with SR-aGVHD, and were consistent with the optimization of themanufacturing process resulting in increased potency of the product.
Final concerns from FDA and possible responses from MSB
The other important document is the FDA briefing document for the PM session (3rd from the bottom in table above). Linked here: https://www.fda.gov/media/140996/download
FDA concerns (from: https://www.fda.gov/media/140986/download page 31,32)
The Applicant is seeking approval of remestemcel-L for the indication of treatment ofsteroid-refractory acute graft-versus-host disease in pediatric patients based on results from asingle trial, Protocol MSB-GVHD001. Although the study reached the primary endpoint goal ofa 28-day ORR at 69.1%, it is unclear whether this one single-arm trial provides evidence ofclinical benefit in the treatment of SR-aGvHD in pediatric patients. Furthermore, it is unclear ifthe durability of response requires continued infusions of remestemcel-L. Finally, the relevanceof the two previously conducted randomized, double-blind, placebo-controlled, multicenterstudies that failed to meet their primary efficacy endpoints is uncertain.
Topic for Discussion #1: Protocol MSB-GVHD001 was a single-arm trial designed to determineif the Day-28 ORR exceeded 45% for pediatric patients with SR-aGVHD grades B-D treatedwith remestemcel-L. Although the null rate and hypothesis were prespecified in the SAP, therewere some limitations with regard to how 45% was chosen for the null rate, and it is uncertain asto whether the data cited for use as historical controls are sufficient to establish the nullhypothesis for the purposes of quantitating a treatment effect in a single-arm trial of a newtherapy for SR-aGVHD in pediatric patients.
Given these limitations, what are the strengths and weaknesses of the study design?
Topic for Discussion #2: The primary endpoint results in MSB-GVHD001 were statisticallysignificant, the measured response was durable (median 54 days), and the study results wereconsistent across subpopulations and secondary efficacy endpoints. However, the results ofProtocols 265 and 280, the two randomized trials, did not provide evidence of a treatment effectfor remestemcel-L in aGVHD even when reanalyzed using the efficacy endpoint of Day-28ORR. In fact, a treatment effect has not been identified in any of the previous clinical trialsconducted in various disease entities, including: type 1 diabetes mellitus, Crohn’s Disease,myocardial infarction, or severe chronic obstructive pulmonary disease.
Therefore, how are the results of one positive single-arm trial interpreted in a landscape ofmultiple negative clinical trials, including several randomized, controlled trials that failed toshow a treatment effect of remestemcel-L?
Does the fact that Study 265 and Study 280 were conducted over ten years ago impact how theyshould be considered in this context?
Is an additional clinical trial in the SR-aGVHD population required for confirmation of theeffectiveness of the product? What trial design trial would be required to provide evidence ofeffectiveness in this indication?Mesoblast response (page 95 onwards):
Calculation of Null Hypothesis and Determination of Sample Size
For establishing the statistical evidence of a treatment effect, a historical control response ratewas constructed for the purpose of sample size calculations and hypothesis testing.Based on results from EAP 275 it was assumed a minimum Day 28 overall response rate (ORR)of 65%. It was also assumed a clinically meaningful effect of 20% absolute improvement inDay 28 OR. This resulted in a null hypothesis of 45%.
This assumption was justified as follows.
1. In the control arm of Protocol 280, there was a Day 28 ORR of 54% overall and 36% inthe 14 pediatric patients. Due to the small sample size, it was uncertain whether thepediatric results alone would be sufficient to properly power the study. It was also notcertain that pediatric and adult responses should be expected to vary significantly.
2. Further, control response rates in Protocol 280 differed significantly by disease risk status(MacMillan et al, 2012): 37% (16/43) of patients with high-risk disease responded atDay 28 compared to 74% (28/38) of patients with standard-risk disease. However,response rates in the remestemcel-L arm did not vary by disease risk: Day 28 ORR was58% for high-risk and 59% for standard-risk disease. This finding showed that thehypothesized control response rate would need to be estimated using risk-adjustmentmethods.
3. In EAP 275, it was found that at least 75% of patients had either severe disease (IBMTRGrade C/D) or high-risk disease (MacMillan et al, 2015). Therefore, it was assumed thatat least 75% of patients enrolled in GVHD001 would have severe disease.
4. Risk adjusting the Day 28 ORR observed in Protocol 280 control patients by a 3:1 ratio(ie, 75% high-risk) results in a risk-adjusted control response rate of 46% (for a studywith approximately 60 hypothetical control patients with 75% high-risk patients: 45 x0.37 observed ORR high-risk + 15 x 0.74 observed ORR standard=16.65 +11.1=27.75/60=46%).
5. Finally, referencing published literature (Martin et al, 2012b), it was found that for 5studies that treated 143 patients with a variety of second-line therapies, and that reportedDay 28 ORR as the primary efficacy endpoint, Day 28 ORR was 52% (75/143).
Together, these results suggest that the hypothetical control Day 28 ORR could be as low as the36% observed in the Protocol 280 pediatric controls (n=14), or as high as the 52% observed inpublished literature (n=143 in 5 studies). It was determined that the most reliable estimate wasthe risk-adjusted estimate from the full control arm of Protocol 280, or 46%, providingconfidence that the 45% null hypothesis was reasonable. Subsequent to completion of StudyGVHD001/002, additional information is now available that confirms not only the originalassumption of a 45% control Day 28 ORR, but also the original assumption that the controlresponse rate should be adjusted for disease risk or severity.
First, data obtained from the MAGIC Consortium on pediatric and adult patients treated with avariety of second-line agents for SR-aGVHD shows that Day 28 ORR was 43% in the 30pediatric patients and 35% in the 95 adult patients (see Section 5.3.4.1 for full details).Additionally, the recently approved treatment for SR-aGVHD, ruxolitinib, showed significantlypoorer Day 28 OR in patients with severe disease (Glucksberg Grade III/IV) compared to thosewith non-severe disease. Though the overall Day 28 ORR was 55%, it was 44.4%, 40.7% and100% in Grades IV, III, and II, respectively (Jakafi prescribing information, 2020).
Sample size for GVHD001 was determined using a normal approximation to the binomialdistribution under the assumption of a 2-sided test of significance level 5% for a singleproportion and a difference in proportion of 20%. This was equivalent to 1-sided testing at 2.5%of the null hypothesis that the Day 28 OR rate is at most, 45%, versus the alternative hypothesisthat the Day 28 OR rate is 65% or greater. The minimum sample size required to meet theprimary objective with 80% power was 48 for the FAS population. To account for potentialdropouts/missing data and to ensure that this study has sufficient power, an additional increasedenrollment of up to 10% of the minimum required enrollment (48) was planned.Remestemcel-L Potency and Efficacy Results (page 108)
MSB calculation of Null Hypothesis and Determination of Sample Size
Further research required
Study designs for the older studies are described in detail in MSB's document but I couldn't see anything specifically addressing how to interpret the GVHD001/002 results with or without the old studies in terms of efficacy.
Potency and safety as I said at the start, have been addressed by MSB, given the changes from the Osiris therapy and manufacturing process improvements. Safety has extensive commentary in the document detailing adverse reactions, deaths etc. and I didn't look at in detail once I saw that FDA accepts the safety consideration.
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Any errors above are all mine. If I have time, I'll try and read it more thoroughly. Others are welcome to add to this discussion.
(20min delay)
