CRL #2 Separating fact from fiction
There has been seemingly endless unfounded opinions on here regarding what MSB may need to do post CRL #2 in order to get approved.
Some may be correct, but quite a few are absolute garbage.
Let's take a quick dive into the important facts to understand why and what is most likely occuring.
The below is cut and past from ODAC meeting notes, and Mesoblast operational highlight..... facts only
ODAC meeing pre initial CRL.
FDA Notes
No clear relationship between TNFR1 levels and clinical effectiveness:
–No differences in mean TNFR1 levels in product lots received by responders and nonresponders in study MSB GVHD001
–No association between mean TNFR1 levels in lots received and survival on Day 100 inMSB GVHD001
–No association with the D28 Overall Response (OR) primary outcome in MSB GVHD001any of the analyses
–Pooled data from three clinical studies (275, 280 and MSB GVHD001) found a statisticallysignificant association between TNFR1 results and survival on Day 100 post treatment,however:
•Different study populations and concomitant medications
•Significance is not observed in MSB GVHD001
•No clear relationship between TNFR1 levels and proposed MOA:
–Knockdown of TNFR1 in remestemcel L reduces in vitro immunomodulatory activity
–TNFR1 levels of remestemcel L lots w/o knockdown do not correlate with in vitroimmunomodulatory activity
Critical Quality Attributes (CQAs) may notby themselves ensure adequate control ofclinical effectiveness of individual lots ofproduct–Product comparability submission underIND with same CQAs was not acceptable
Critical Quality Attributes (CQAs) may notby themselves ensure adequate control ofclinical effectiveness of individual lots ofproduct
–Product comparability submission underIND with same CQAs was not acceptable
MSC identity markers do not capture biologicalfunctional heterogeneity
–Substantial functional heterogeneity exists in MSCs thatmatch Applicant’s identity markers as well as communityconsensus MSC markers
•Potency tests for remestemcel L may not detectfunctionally important differences between DP lots sincethey do not correlate with clinical effectiveness
DISCUSSION: As noted previously, primary endpoint results in Study MSB-GVHD001 were 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 a treatment effect for remestemcel-L in aGVHD, even when reanalyzed using the efficacy endpoint of Day-28 ORR. In fact, a treatment effect has not been identified in any of the previous clinical trials conducted in various disease entities, including: Type 1 diabetes mellitus, Crohn’s Disease, myocardial infarction, or severe chronic obstructive pulmonary disease and the mechanism of action of remestemcel-L in mitigating aGVHD remains unclear.
Product quality attributes measured for remestemcel L are intendedto ensure that key qualities of the drug product (DP) are maintainedconsistently from lot to lot.
1. Please discuss the adequacy of thepotency assay established by the Applicant for remestemcel L.
2.In addition to discussion of potency, please propose and discussother possible product quality attributes or characteristics that couldbe controlled to better assure consistent quality of remestemcel Lwith regard to safety or effectiveness of the product.
a) Please discuss whether the results of Studies 265 and 280 are relevant to the effectiveness of remestemcel-L for the treatment of pediatric SR-aGVHD. In your discussion, please consider not only the similarities and differences in the study populations, but also any other factors (e.g., number of years between studies;
b) FDA may require an additional clinical trial to support the effectiveness of the remestemcel-L in pediatric SR-aGVHD. If so, what are your recommendations regarding the design of such a trial? For example, please discuss the population (e.g., aGVHD or SR-aGVHD; adult and/or pediatric), treatment assignment (randomized vs. single-arm), primary and secondary endpoints (e.g., Day-28 ORR, Day 100 survival, Day 180 survival, etc.), and any other aspects of the trial design.
VOTE: Do the available data support the efficacy of remestemcel-L in pediatric patients with steroid-refractory aGVHD?.... answer 9 out of 10 YES
CRL number 1
The FDA recommended that Mesoblast conduct at least one additional randomized, controlled study in adults and/or children to provide further evidence
of the effectiveness of remestemcel-L for SR-aGVHD.
The FDA also identified a need for further scientific rationale to demonstrate the relationship of potency measurements to the product’s biologic activity. Assays measuring the potency of remestemcel-L will continue to be refined to provide further scientific rationale for its use in severe
inflammatory diseases with high mortality risk, such as SR-aGVHD and COVID-19 ARDS.
Company response:
Mesoblast believes that remestemcel-L meets the criteria for accelerated approval as there arecurrently no approved treatments for this life-threatening condition in children under 12. Mesoblast has formally requested a Type A meeting with the FDA to discuss a potential accelerated approval of
the Biologics License Application (BLA) for remestemcel-L for the treatment of SR-aGVHD in children,with an additional randomized controlled study in patients 12 years and older as a post-approval requirement. Mesoblast expects this meeting will occur in November
Post Type A meeting:
Mesoblast believes that remestemcel-L meets the criteria for accelerated approval as there are currently no approved treatments for this life-threatening condition in children under 12. Mesoblast has formally requested a Type A meeting with the FDA to discuss a potential accelerated approval of
the Biologics License Application (BLA) for remestemcel-L for the treatment of SR-aGVHD in children, with an additional randomized controlled study in patients 12 years and older as a post-approval requirement. Mesoblast expects this meeting will occur in November
2 months later, Mesoblast has in vivo bioactivity evidence presented at 62nd American Society of HaematologyKey conclusions were:
• Clinically meaningful overall responses and survival in children with SR-aGVHD treated with
remestemcel-L were associated with significant reductions in certain biomarkers of
inflammation which have been validated as predictors of mortality risk
• These biomarkers provide evidence of in vivo bioactivity of remestemcel-L in pediatric SRaGVHD, where children under 12 are at high-risk for mortality, with no approved therapies in
the United States
• The durable reductions in blood levels of certain biomarkers associated with inflammatory
diseases of the gut suggest that these could be more generally reflective of remestemcel-L
activity in vivo in other inflammatory bowel diseases such as Crohn’s disease and ulcerative
colitis
Blood levels of soluble suppression of tumorigenicity 2 (ST2)1,2 and MAGIC Biomarker Score (MBS)3,4,
validated biomarkers that predict high mortality in SR-aGVHD and active gut inflammation more
broadly, were measured at baseline and sequentially over 180 days in 40 of the 54 children with SRaGVHD who received at least four weeks of remestemcel-L treatment in the single-arm Phase 3
trial. Both the elevated baseline levels of ST2 and MBS were significantly reduced after remestemcel-L
treatment at Days 100, 160 and 180 (all timepoints p<0.001 for both markers). This was
accompanied by significant reductions in activated circulating T cells. Day 100 survival was 74% in the
54 remestemcel-L children with SR-aGVHD (89% with Grade C/D disease), which compares very
favourably with a
3 months later
Mesoblast held a Type A meeting with the FDA in November 2020 to discuss the review of the Biologics License Application for remestemcel-L. The current review team have not agreed to accelerated approval. However, there was consensus with the review team on the proposed
optimization of potency assays and on use of biomarkers to demonstrate the product’s bioactivity invivo. Mesoblast intends to meet with the FDA during Q1 2021 through a well-established process for continuing discussions on the potential for accelerated approval with a post-approval commitment to
conduct an additional randomized controlled study in patients 12 years and older.
6 months later
Mesoblast continues to be in discussion with the FDA through a well-established process with the goal of achieving approval for remestemcel-L to treat SR-aGVHD.
9 months later - MSB has met with CBER, and progressed to needing to meet now with OTATMesoblast continues to be in discussion with the United States Food & Drug Administration (FDA) through a well-established regulatory process that may include a resubmission with a six month review with the aim of achieving approval of remestemcel-L in the treatment of
steroid-refractory acute graft versus host disease (SR-aGVHD) in children
• As part of this process, Mesoblast recently met with the FDA’s Center for Biologics Evaluation
and Research (CBER). Following CBER’s recommendation after this meeting, Mesoblast as a
next step will discuss with CBER’s review team at the Office of Tissue and Advanced Therapies
(OTAT) our approach to address certain outstanding chemistry, manufacturing and controls
(CMC) items, including potency assay validation
12 months later - Results published in peer reviewed Bone Marrow TransplantationThe study compared outcomes in 25 children from Mesoblast’s Phase 3 trial of remestemcel-L in SRaGVHD with 27 closely matched children from the Mount Sinai Acute GVHD International Consortium (MAGIC)2 who participated in a prospective natural history study and were matched for the Phase 3
trial entry criteria. The objective of the study was to evaluate whether outcomes differed according to treatment with remestemcel-L vs other therapies in children at highest risk of death, namely those with baseline MAGIC Algorithm Probability (MAP) biomarker levels ≥0.291, a level predictive of very high mortality and poor responses to therapy in SR-aGVHD. MAP combines the serum concentrations of two biomarkers, Reg3α and ST2, into a single value that predicts long-term outcomes and significant GI tract damage.
MAP levels ≥0.291 were present in 48% of remestemcel-L treated children (12/25) and 37% of the MAGIC cohort (10/27). Treatment with remestemcel-L resulted in 67% Day 28 Overall Response and 64% Day 180 overall survival compared with 10% Day 28 Overall Response and 10% Day 180 survival in the MAGIC cohort (both p=0.01) when treated with various biologics, including ruxolitinib. These results extend previous observations showing that children who achieved clinically meaningful responses and survival after treatment with remestemcel-L had significant reductions in the ST2
biomarker of inflammation, consistent with healing of the GI tract.3
13 months later - about to meet with OTAT about suitability of potency assays for approvalResults published in the latest issue of the peer-reviewed journal Bone Marrow Transplantation2 showed that children with steroid-refractory acute graft versus host disease (SR-aGVHD) and biomarkers predictive for highest mortality had 64% survival when treated
with remestemcel-L compared with only 10% survival when treated with other available therapies, including ruxolitinib or other biologics
• These data provide further support for the proposed anti-inflammatory mechanism of action of remestemcel-L and its immunomodulatory activity in patients with SR-aGVHD, resulting in improved survival outcomes
• At the upcoming scheduled meeting with United States Food & Drug Administration’s (FDA) Office of Tissue and Advanced Therapies (OTAT), Mesoblast will address the appropriateness of potency assays related to remestemcel-L’s proposed anti-inflammatory mechanism of action
as well as the outstanding chemistry, manufacturing and controls (CMC) items which could support a resubmission of the current Biologics License Application (BLA) for remestemcel-L in the treatment of SR-aGVHD in children
14 months later - OTAT meeting complete, approach to CMC items is reasonable, critical quality attribute is reasonable but relevance to clinical outcome should be extablished.Meeting held with the US Food and Drug Administration’s (FDA) Office of Tissues and Advanced Therapies (OTAT) to address potency assay and chemistry, manufacturing and controls (CMC) items identified in the complete response letter (CRL) for remestemcel-L in the treatment of steroid-refractory acute graft versus host disease (SR-aGVHD) in children
• OTAT indicated that Mesoblast’s approach to address the outstanding CMC items is reasonable
• OTAT indicated that the in vitro immunomodulatory activity Mesoblast intends to measure for potency is a reasonable critical quality attribute (CQA) for the product, and the relevance of this activity to clinical outcomes should be established
• Mesoblast has now generated substantial new data that it believes establish the relevance of the proposed in vitro immunomodulatory activity of remestemcel-L to the in vivo clinical effect of the product in the Phase 3 trial in children with SR-aGVHD, including survival and biomarkers of in vivo activity
• Mesoblast will provide these new data to OTAT, and address other outstanding items as required for the Biologics License Application (BLA) resubmission
Mesoblast requested the meeting to address the appropriateness of a potency assay related to remestemcel-L’s proposed
immunomodulatory mechanism of action as well as the approach to outstanding CMC items identified in the CRL.
OTAT indicated that Mesoblast’s approach to address outstanding CMC items is reasonable, that the in
vitro immunomodulatory activity of remestemcel-L proposed by Mesoblast as a measure of its potency
is a reasonable CQA for the product in the treatment of children with SR-aGVHD, and the relevance of
this immunomodulatory activity to clinical outcomes should be established.
Mesoblast has now generated substantial new data which it believes establish the relevance of the
proposed in vitro immunomodulatory activity of remestemcel-L to the clinical effect of the product in
the completed Phase 3 trial in pediatric SR-aGVHD, including to survival outcomes and biomarkers of
the product’s in vivo activity. Mesoblast will provide these new data to OTAT and address other
remaining CRL items as required for the BLA resubmission.
By demonstrating the relevance of the in vitro potency assay to clinical outcomes, Mesoblast believes
it will be able to show that the remestemcel-L product used in the Phase 3 trial in pediatric SR-aGVHD
was standardized as to identity, strength, quality, purity, and dosage form, and that this will address
OTAT’s recommendation for an additional adequate and well-controlled study.
Mesoblast continues to be in a well-established process with FDA’s Center for Biologics Evaluation and
Research (CBER), and if the resubmission is accepted, CBER will consider the adequacy of the clinical
data in the context of the related CMC issues noted above.
20 months laterMesoblast believes that the proposed potency assay measuring remestemcel-L’s in vitro antiinflammatory and immunomodulatory activity helps establish a clear understanding of remestemcel-L’s mechanism of action in SR-aGVHD, and demonstrates relevance to the in vivo clinical effect of the product in the 54-patient Phase 3 trial in children with SR-aGVHD
• An investigator-initiated controlled study in children with SR-aGVHD stratified by baseline levels of inflammatory biomarkers, published late 2021 in the peer-reviewed journal Bone Marrow Transplantation,3 showed that remestemcel-L provided a significant benefit in terms of both response and survival in children with the highest levels of inflammation and at greatest risk of death compared to best available therapy
• The study compared outcomes in 25 children from Mesoblast’s Phase 3 trial of remestemcel-L in SR-aGVHD with 27 closely matched children from the Mount Sinai Acute GVHD International Consortium (MAGIC). In children with baseline MAGIC Algorithm Probability (MAP) biomarker
levels ≥0.29, a level associated with significant GI inflammation and damage, and which is predictive of poor treatment responses and very high mortality in SR-aGVHD, treatment with remestemcel-L resulted in 67% Day 28 Overall Response and 64% Day 180 overall survival compared with 10% Day 28 Overall Response and 10% Day 180 survival in the MAGIC cohort (both p=0.01) when treated with various biologics, including ruxolitinib
• The proposed potency assay demonstrates a relationship between the product’s activity in vitro and its effects on survival in the Phase 3 trial, with the strongest correlation to survival in those patients at highest mortality risk as measured by clinical severity or high biomarker levels of inflammation
• Additionally, Mesoblast has now generated data from the expanded access program (EAP 275) of 241 children which confirm the ability of the in-vitro potency assay to measure product activity relevant to survival outcomes
• While global supply chain constraints impacted supply of assay kits during the quarter, our GMP contractor is now well resourced allowing final testing of product inventory for the BLA resubmission
• In preparation for the expected FDA review, Mesoblast last week completed a successful mock pre-approval inspection of its GMP manufacturing facility and process comprising both on-site and virtual inspections by external auditors
• Mesoblast will provide these new data to FDA and address all chemistry, manufacturing and controls (CMC) outstanding items as required for the planned BLA resubmission in the coming quarter. If the resubmission is accepted, CBER will consider the adequacy of the clinical data
in the context of the related CMC issues
22 months later
BLA resubmission to FDA expected by the end of Q3 CY2022
• FDA has indicated that Mesoblast’s approach to address the outstanding CMC items is reasonable
• Mesoblast has optimized a potency assay that was in place at the time of the 54-patient Phase
3 trial in children with SR-aGVHD
• Mesoblast has now generated data from the expanded access program (EAP 275) of 241 children
which confirm the ability of the in-vitro potency assay to measure product activity relevant to
survival outcomes
• Development and validation work on the potency assay completed, key to the BLA resubmission
• Mock inspection affirmed BLA-submission readiness at manufacturing site
2 Years later new Clinical and potency data submitted to the IND file
.... has submitted to the U.S. Food and Drug Administration (FDA) substantial new information on clinical and potency assay items identified in the Complete Response Letter (CRL) received from FDA in September 2020 to the Biologics License Application (BLA) for remestemcel-L in
the treatment of children with steroid-refractory acute graft versus host disease (SR-aGVHD). Mesoblast has maintained an active dialog with the FDA since receiving the CRL, and the substantial new information submitted to the Investigational New Drug (IND) file for remestemcel-L in the treatment
of children with SR-aGVHD, as guided by FDA, represents a major milestone in the Company’s complete response to the FDA. Remestemcel-L has been granted Fast Track Designation and BLA Priority Review from the FDA. Survival outcomes have not improved over the past two decades for children or adults with the most severe forms of SR-aGVHD. 1-3 The lack of any approved treatments for children under 12 means that there is an urgent need for a therapy that improves the dismal survival outcomes in children. “The submission summarizes controlled data providing further evidence of remestemcel-L’s ability to save lives” said Dr. Silviu Itescu, Chief Executive of Mesoblast. “Additionally, the improved process controls we have put in place to assure robust and consistent commercial product, together with a potency assay that predicts consistent survival outcomes, makes remestemcel-L a compelling treatment
for these children.”
2 years, 1 month later - new 4 years survival data reported to MSB
• A major milestone in the Company’s complete response to the FDA was the submission at the end of the last quarter of substantial new information on clinical and potency assay items to the Investigational New Drug (IND) file for remestemcel-L in the treatment of children with SRaGVHD, as guided by FDA.
• Mesoblast has optimized a potency assay that was in place at the time of the Phase 3 trial and which demonstrates a relationship between the product’s activity in-vitro and its effects on survival in the Phase 3 trial.
• Additionally, Mesoblast has now generated data from the expanded access program (EAP 275) of 241 children which confirm the ability of the in-vitro potency assay to measure product activity relevant to survival outcomes.
• Today Mesoblast provided new results from a four-year observational survival study performed by the Center for International Blood and Marrow Transplant Research (CIBMTR) on 51 evaluable patients with SR-aGVHD who were enrolled in Mesoblast’s phase 3 clinical trial of remestemcel-L.
• Overall survival in the remestemcel-L cohort was 63% at 1 year, 51% at 2 years, and 49% at 4 years, while across four recently published studies of children or adults with SR-aGVHD who received best available therapy (BAT) or the only FDA-approved agent for adults survival rates of 40-49% at
1 year and 25%-38% at 2 years were seen. 7-10. Moreover, in the observational cohort study 88% of children treated with remestemcel-L had severe
disease with highest mortality risk, defined by either IBMTR Grade C/D or Glucksberg Grade III/IV, whereas only 22% to 68% of patients in the other studies were considered to be severe.1-4 These results reaffirm the potential significance of remestemcel-L as a life-saving therapy for children with SR-aGVHD.
• The new long-term survival data provide assurance that the short-term day 28 responses and early survival through 180 days in the 54-patient Phase 3 trial in children with SR-aGVHD previously presented to FDA in the original BLA submission are unlikely to have arisen by chance and are a
cornerstone of the BLA resubmission.
2 years 4 months - Resubmission of BLA completedMesoblast has responded to the CRL and the further guidance it has received from the FDA and has generated and provided new data and analyses in the resubmission which we believe provide substantial evidence of remestemcel-L's effectiveness in pediatric SR-aGVHD. Specifically, the resubmission
contains the following:
• new long-term survival data of children enrolled in the Phase 3 trial showing durability of treatment effect through at least four years,
• new data showing remestemcel-L’s treatment benefit in high-risk disease activity and on survival in propensity-matched studies of children in the Phase 3 trial and controls stratified by validated biomarkers for high-risk disease,
• new analyses of data obtained prospectively showing that the validated potency assay which was in place and used to release product for the 54-patient Phase 3 clinical trial measures a key product attribute which reflects the primary mechanism of action of remestemcel-L in children with SR-aGVHD, correlates with the product’s in vivo bioactivity, and predicts overall survival outcomes,
• new analyses of data obtained prospectively relating manufacturing changes during product development prior to Phase 3 to progressive increases in potency and to improved survival outcomes in larger studies of remestemcel-L under expanded access in children with SRaGVHD,
• new data showing that the validated potency assay has low variability and can adequately demonstrate manufacturing consistency and reproducibility, and
• establishment of a new specification for release of commercial product based on extensive clinical data which provides assurance that future batch
2 years 4 months - Studies released on immunoactivity, and long term survivalThe studies are titled “The Immunomodulatory Activity of Remestemcel-L on T Cell Activation in vitro is a Direct Measure of Product Potency and Correlates with Clinical Outcomes in Pediatric Patients with Steroid-Refractory Acute GVHD” and “Long-Term Survival in Children Treated with Remestemcel-L for
SR-aGVHD”. The lead author of each study is Dr Joanne Kurtzberg, Jerome Harris Distinguished Professor of Pediatrics and Professor of Pathology, Duke University Medical Center. The data from both studies formed key components of Mesoblast’s recent resubmission of its remestemcel-L Biologics
License Application (BLA) to U.S. Food and Drug Administration (FDA) for children with SR-aGVHD.
2 years 10 months CRL #2
(FDA) has provided a complete response to its Biologics License Application (BLA) resubmission for remestemcel-L for the treatment of pediatric
steroid-refractory acute graft versus host disease (SR-aGVHD) and requires more data to support marketing approval. To obtain the data required, Mesoblast will conduct a targeted, controlled study in the highest-risk adults with the greatest mortality. This adult study is in line with our overall commercial
strategy, which envisioned a sequenced progression from pediatric to adult SR-aGVHD indications. Adults comprise 80% of the SR-aGVHD market.
Mesoblast Chief Executive Silviu Itescu said: “FDA’s inspection of our manufacturing process resulted in no observed concerns, the Agency raised no safety issues across more than 1300 patients who have received remestemcel-L to date, and acknowledged improvements to our potency assay"
Mesoblast intends to enroll adult patients at highest mortality risk with SR-aGVHD where existing therapy has not improved outcomes and 90-day survival remains as low as 20-30%.1 Mesoblast has generated pilot data through its emergency IND program in adults showing a survival benefit with
remestemcel-L in this target population.
2 years 11 months - End of finacial yearly update.. Following the complete response, a Type A meeting with FDA has been scheduled for mid-September and we will discuss the potential paths to
approval via additional potency assay data or new clinical data in adults.
FDA provided a complete response requiring Mesoblast to demonstrate that product used in the
phase 3 trial is similar to product intended for commercial release, as measured by a standardized
potency assay.
• FDA indicates that an additional clinical trial would be needed to establish this link if the company
is not able to do so via additional potency assay work.
• Type A meeting with US FDA scheduled to be held mid-September for SR-aGVHD indication.
• Mesoblast proposes providing FDA with additional potency assay data to provide link between Phase
3 product and commercial inventory.
• Mesoblast proposes providing FDA with new clinical trial data in adults, which could also support
the pediatric indication.
• In line with our overall commercial strategy to progress to adult patient populations, which make
up approximately 5-fold larger numbers than children,3 Mesoblast intends to conduct a targeted,
controlled study in adults with high mortality risk.
• Survival in adults with SR-aGVHD who have failed at least one additional agent, such as ruxolitinib,
remains as low as 20-30% by 100 days.4,5
• In contrast, 100-day survival was 63% after remestemcel-L treatment was used under expanded
access in 71 patients aged 12 and older with SR-aGVHD who failed to respond to at least one
additional agent, such as ruxolitinib.
• Mesoblast is in discussions with world-leading investigators at the Blood and Marrow Clinical Trials
Network (BM CTN), a body responsible for 80% of all US transplants, to conduct the new clinical
trial.
• The costs of this targeted study are expected to be covered by the spending reduction described
above.
2 years 11 months - End of finacial yearly update - Webcast quotes
Si
"The reason for the CRL the FDA remains..... wanting to be convinced that product in the inventory for commercial launch is substantially the same as that used for the phase 3 trial, and our potency assay needs to be substantially the same potency assay as that used in the trial to demonstrate that the two products are the same. We have those data that are being developed. Some are in place, some need to be added, which will be over the next few months."
Krause
"One of the significant positive indicators from the CRL - is that the CRL did not question the efficacy of the product as demonstrated in GvHD001, (which was the case for the previous CRL, BUT The CRL did continue to raise questions about the potency assay, specifically the characterisation and standardisation of the product that went into GvHD001 and the ability to make future product that is similar to that which went into GvHD001. This leaves open the real possibility that by using exactly the same assays that were used to characterise the product that went into the GvHD001 trial, for new commercial product, that it would be possible to show that the new commercial product is similar enough to that which was effective in GvHD001
"
So, if you got this far, well done. The non holders probably haven't - why would they? they don't hold?
Company is starting a trial in adults shortly, and company is providing potency data to see if FDA will approve children while the adult trial runs.
Simple
We should get an update in a couple weeks stating what the FDA want regarding the adult trial specifically, and also if they think the potency data will support pediatric approval.
(20min delay)