So, after listening to SI and FG on the conference call, and taking into account what went down at the ODAC meeting. This is what we know so far -
1. They are gonna go for 'Overall Survival' as an endpoint in the post-approval study
2. As a road to conditional approval, they are gonna go for the 'Accelerated Approval' pathway.
This post (sorry for the length!) is my thinking on why the Type A meeting will happen and the Accelerated Approval will be granted.
Here goes!
Upon reflection, I had a hunch that they were going to bring up the data that show 'Day 28 Overall Response' as the predictor of Overall Survival, and I decided to do a bit of forensic literature reviewing to see the rationale for using Day 28 OR.
Turns out, there's a lot of evidence for it!
I thought, let's look through the years to see the progression of the research (bearing in mind that the Kurtzberg article was published in 2016, on top of the earlier article in 2014 so keep that in mind!)Back in
2009, Martin et al published an article
HERE, that said that the current consensus, in the Blood and Bone Marrow Transplant research in treating Acute GVHD was that the
Day 28 OR is the 'optimal endpoint'
In
2010, Macmillan et al published an article
HERE, started out by saying that, in all reality, an optimal primary endpoint is yet to be established, however they conceded that Day 28 responses were similar to Day 56 responses and
are better than Day 14 responses in predicting transplantation-related mortality. In their multiple regression analysis, they found that patients with no response at day 28 were 2.78 times (95% CI, 2.17-3.56 times;
P < .001) more likely to experience TRM before 2 years than patients with a response.
Interestingly, other factors associated with significantly worse 2-year TRM include older
age, high-risk
disease,
severe GVHD, and partially matched related BM/PB. No other differences in response by donor source were observed.
Importantly, they conclude that the data suggests that Day 28 is the best early endpoint for acute GVHD therapeutic trials in predicting 2-year TRM.
So far so good.
In
2011, Westin et al published an article
HERE, starting out by saying that Steroid-Refractory Acute GVHD patients have a very dismal prognosis (mortality
in excess of 90%). In their study on first-line therapies, the patients with Grade I–IV aGVHD were started on
methylprednisolone (MP) according to institutional guidelines.
Tacrolimus was continued at blood levels between 5 and 15 ng/dL. A total of 27 patients (9%) received one or more additional immunosuppressants for frontline treatment of aGVHD, including
infliximab (, 6%),
daclizumab (, 2%),
pentostatin (, 1%), and
basiliximab (, 1%).
Looking at their data, they said it compliments findings of prior studies looking at Day 14 and Day 28 OR as a predictor of overall survival, and that Day 28 OR is
a valid endpoint. This is mentioned in terms of how if a patient does not respond by Day 14, they are likely to achieve an
inferior outcome. Again, suggesting that these are
useful in terms of outcome prediction.
Getting warmer. Looks like the body of evidence is growing. Lets carry on through the years!
In
2012, Pavletic from the BMT crew publish an editorial
HERE, starting out by saying that there are few therapeutic trials for acute GVHD, and currently no agents are approved by the United States Food and Drug Administration (FDA) for either prevention or treatment of acute GVHD. Since 2009, the NIH and FDA was convened to 'inform and assist' in facilitating clinical development programs for products to
prevent or treat acute GVHD.
They acknowledged that in terms of Day 28, Day 42 or Day 50 response assessments have not been formally validated, however, very importantly, citing a study conducted by the MD Anderson Cancer Center
(Saliba et al 2012), in the univariate and multivariate analyses, they found that Day 14
and Day 28 responses were the
most significant predictors of 6mth and 2yr non-relapse mortality. Further statistical analyses reported that the
Day 28 OR was
more predictive than Day 14 and
recommended the use of
this endpoint for future acute GVHD trials.
Similarly, they also reference Levine et al in finding that
Day 28 response
correlated with 9mth survival.
Critically, these studies suggest that
Day 28 is a suitable time point to measure response to first-line therapy in clinical trials for Acute GVHD. These
studies also collectively support the recent expert panel endorsement of ‘
Day 28’ response as a
primary end point in acute GVHD treatment trials aiming for regulatory approval. Earlier time points (days 7 or 14) might not be a sufficient interval for optimal responses, while later time points (
Day 56) carry the
risk of confounding interpretation because patients may develop chronic GVHD or other transplant-related complications.
Lets move on in the years!
In
2014, Yoshihiro et al published an article
HERE, discussing short-term response endpoints for acute GVHD treatment trials, and in their findings, found that it supported the use of
Day 28 CR/PR as a primary endpoint. (Simplistically put of course!).
Their results support the use of CR/VGPR (Very Good Partial Response) at
Day 28 after initial treatment as a short-term endpoint for at least
four reasons.
1) Most patients can be evaluated at the transplant center at day 28. Moreover, none of the patients in their study developed chronic GVHD before day 28.
2) The rate of subsequent treatment failure was equivalent between patients with CR or VGPR, but was lower than that in patients with other PR or no response
3) The symptom burden at day 28 was lower in patients with VGPR as compared to those with other PR.
4) CR itself was too stringent to serve as an endpoint because the loss of sensitivity outweighed the gain of specificity compared to CR/VGPR in predicting the absence of failure at 6 months
Again, we see an agreement here of Day 28 OR being a very powerful primary endpoint in predicting Overall Survival.
Next, we see quite an important study in the body of research.
In
2018, Bader et al published an article
HERE, discussing using MSCs in treating
Steroidand Therapy-Refractory Acute GVHD. In this study,
51 kids and 18 adults with sr-aGVHD. They ranged from Grade II to IV. The incredible thing was, the
DAY 28 OR rate was
83%, with 61% and 25% of the patients in
complete or partial remission respectively. This was associated with a
SUPERIOR 6mth Overall Survival (read:
DAY 180 OS) probability rate of 71% (range, 61-83) compared to patients
not treated with MSCs.
They acknowledged that once you're refractory to steroids, your
chances of survival drop to
20%. That's an ~
80% MORTALITY RATE.Again, their issues with the MSCs and the different results in the various clinical trials relate to the 'lack of a robust manufacturing process' which could generate sufficient doses with 'batch-to-batch
consistency'.
In their study, of significant interest for the definition of
outcome measures for future aGvHD trials, while many of the PR improved to CR over the course of the observation period, very few of the day 28 non-responders had delayed responses, most remained non-responders throughout.
This led them to conclude that Day 28 OR had a predictive value for overall therapeutic benefit, and suggests its use as a surrogate outcome parameter, in agreement with published work (and here, he references Dr Kurtzberg's 2014 article mentioned earlier). In their study, they too, used Day 28 OR as an outcome parameter.
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So if you consider the body of evidence, while considering the
unmet need in paediatric sR-aGVHD patients, it sets the rationale for
Day 28 OR to be used as a solid endpoint as a predictor of
Overall Survival. The requirements for an Accelerated Approval (as per the document
HERE) is that
A surrogate endpoint used for accelerated approval is a marker - a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. Likewise, an intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).The FDA bases its decision on whether to accept the proposed surrogate or intermediate clinical endpoint on the scientific support for that endpoint. Studies that demonstrate a drug’s effect on a surrogate or intermediate clinical endpoint must be “adequate and well controlled” as required by the FD&C Act.MSB have very strong evidence of
Day 28 OR correlating to Day 180 OS.
FDA themselves have concluded that the "primary endpoint (which is
Day 28 OR) results in Study 001 were
statistically significant, the
measured response was
durable and the results were
consistent across subpopulations and secondary
efficacy endpoints." also that there were "no safety signal concern".
It is very clear that the
Day 28 OR evidence has a statistical significant effect on irreversible morbidity and mortality.
Their more potent cells have demonstrated a relationship to
clinical performance (which ticks the 'predict clinical benefit' box) in that of the increased mean TNFR1 expression and inhibition of IL-2Ra. Don't forget that Lonza themselves have
very strict standards to maintain in terms of GMP, and hence the CQAs are
sufficient to ensure batch-to-batch consistency.
This is why, all things considered, via the "
AcceleratedApproval" pathway, I believe the team at MSB have sufficient evidence to satisfy the requirements for that particular approval pathway.
Add on to that a legally-binding commitment to the post-approval study "predominantly in adults" (as mentioned by FG)?The evidence will be overwhelming across age groups, and the dying kids will get a second lease of life.
This might be the most beautiful story being written for these kids.
(20min delay)