Well isn’t it amazing that after all these years MSB are finally kicking goals with the FDA.
On this special day, I thought it would be useful to take a deep dive into the design of the P3 CLBP trial because I think this proves that MSB is really bringing home the bacon with the FDA.
The second P3 CLBP trial has flown under radar with all the gvhd excitement but a couple of weeks ago the trial was officially registered.
“Efficacy and Safety of Rexlemestrocel-L Combined With HA* in Participants With Moderate to Severe Chronic Low Back Pain (HyaluronicAcid)”
https://www.clinicaltrials.gov/stud...last&aggFilters=status:not rec&rank=1
This registration has been years in the making and follows from the outstanding success of the first P3 CLBP trial. The first P3 CLBP trial demonstrated reductions in pain and opioid use in post-hoc analyses that failed to account for the effect of any post treatment interventions.
Naturally MSB met with the FDA to discuss next steps in short order. And on 15 Dec 2021 MSB announced the design of the next P3 trial had been agreed with the FDA. The nub of it was as follows:
“Following review of the completed Phase 3 trial data, OTAT agreed with Mesoblast’s proposal for pain reduction at 12 months as the primary endpoint of the next trial, with functional improvement and reduction in opioid use as secondary endpoints.”
HC researchers got to work and there was quite a lengthy Hot Copper thread discussing this annoucment.
https://hotcopper.com.au/threads/ann-fdas-otat-agrees-to-primary-endpoint-for-back-pain.6490682/There were several key take home messages.
First the FDA had agreed with MSB’s proposal. So chalk up a win for MSB. In hindsight this moment probably heralded the beginning of the new dawn in MSB and FDA relations.
Second the 12 month endpoint allowed the trial to be completed more quickly than the previous P3 trial which had had a 24 month endpoint.
Third. The single pain endpoint would be much easier to achieve than the endpoint in the first P3 trial which comprised a composite of pain – function - post treatment intervention.
Finally, the change from a 24 month to a 12 month endpoint signalled that the FDA’s concerns about safety and risk benefit had been allayed after reviewing the results from the first P3 trial.
Recall the first CLBP P3 trial started with 12 month endpoints. But the FDA had forced MSB to change the primary endpoint to 24 months midstream in the trial. The reason for this change (according to SI) was that the FDA were concerned about safety and wanting to be clear on risk-benefit.
At the Conference Call 2019 Q1 SI: “… I think the FDA primarily wanted a risk-benefit analysis through 24 months, which comprises safety as much as it does efficacy.”
So the agreement for the 12 month endpoint not only had methodological significance (a quicker trial) but also substantive importance - it reflected a change in the FDA’s position around risk – benefit.
The announcement reflected the new era in MSB and FDA relations and posters here were suitably impressed:
“Big win for MSB with a single 12 month endpoint (vs 24 months and usually composite, which are riskier). With that clarity, and short duration trial ... MSB can move forward with partnership discussions on funding this trial which is going to be 80% US based.”
“The FDA just told Mesoblast that your pain score primary endpoint was sufficient, and you don't need function for approval. So from an FDA perspective, when Mesoblast take it up for approval... they will look at only one primary endpoint i.e. pain... which means Mesoblast met their primary endpoint. This is the FDA conceding ground, because they were the ones who pushed Mesoblast for a composite in pain and function.”
“I'm glad to see the single primary endpoint.. I was almost certain the FDA would make it a composite with pain and opioid sparring.. which would be complimentary anyway, but this is an even better outcome. “
“Or maybe they wanted a 24 month trial... but instead they are allowing Mesoblast to run a second phase 3 trial using a single pain primary endpoint (the FDA typically require composite endpoints for CLBP, so this in itself is a win), and reduced the endpoint from 24 months to 12 months. That's basically Mesoblast getting everything they asked for.. I don't think the FDA could have been more accomodative.”
…” it was actually the best possible outcome Mesoblast could have achieved from the FDA meeting with a supposed first 'failed' phase 3 trial... and it almost definitely means we are going to get another partner in early 2022.”
“CLBP has just scored a big win with the FDA, and a partner will ensue in the coming months. That's a sizeable upfront payment coming our way. The market can't price that in right now, fair enough.. but once that news drops, and it's coming.. we'll get that sizeable uplift.”
“The next step Mesoblast will take is to partner this program up, that I am 99% sure of as they simply don't have the funds to run the trial themselves and the fact they've secured such a favourable outcome with the FDA on this second trial, it becomes a highly derisked investment for anyone who wants to distribute this product.”
Now two years later from this December 2021 announcement we can compare what MSB had claimed was agreed with the FDA for the design of this trial with what has now been registered.
And there is a bombshell. The registered trial doesn’t resemble what MSB had claimed in the 15 December 2021 announcement at all.
The second P3 CLBP registered trial has two co-primaries. The first co-primary is for pain at 12 months and the second co-primary is for adverse events through to 24 months.
View attachment 6075068In the December 2021 announcement there was no mention of co-primaries, no mention of adverse events and no mention of a co-primary being collected through to 24 months pushing the estimated end date for the trial out to August 2027.
All the HC posts dissecting the entrails of the December 2021 announcement were all completely wrong.
But the surprise is completely to the upside. In reality what had been agreed with the FDA was much better than even the best rampers on HC could ever have imagined.
How exactly?
The two co-primaries (pain and adverse events) means you get two bites of the cherry. Two shots on goal for the price of one. It’s what every company dreams of getting with the FDA. In effect the FDA have brought the risk (adverse events) – benefit (pain) equation into the very heart of this trial in a way that MSB just can’t lose.
From the underpowered P2 trial we know that HA is inert. From the first P3 trial we know that the stems on their own also do nothing. And so there is slight possibility that the treatment arm (stems + HA) might just be 2*0=0 when post treatment interventions are controlled for.
If this were occur (the combined treatment did nothing) that would also mean there would be an absence of adverse events. So MSB would still win. And the converse. If there was a difference in adverse events (as the first P3 trial showed) this must mean the treatment was working and so that would also be a win.
Every which way MSB wins.
But hang on doesn’t the 24 months to collect the adverse events data add an extra 12 months to the trial which has pushed out the estimated end date to 2027?
No; in fact adverse events as a co-primary here can make the trial shorter because it brings early stopping into play.
The pain endpoint is a standard superiority endpoint. MSB seek to demonstrate a statistically significant reduction in pain from a difference in difference model. Where the difference between baseline and 12 months in the treatment arm is hypothesised to be greater than the difference between baseline and 12 months in the control arm.
But for adverse events the opposite is true. This is a non-inferiority endpoint. Here MSB seek to demonstrate there is no difference between the treatment and control arms in terms of adverse events.
So with one co-primary (pain) you want a difference and on the other one (adverse events) you don’t. For a superiority endpoint the more patients you recruit the better the chances for finding a difference which making stopping early difficult. For a non-inferiority endpoint (adverse events) the less patients you have the more likely of not finding a statistically significant difference between treatment and control (which is what you want).
This means is that MSB will seek to stop this trial for an overwhelming lack of adverse events as quickly as possible. Perhaps even within days of starting the trial.
Now I can hear the two doc naysayers on this forum ready to shoot all this down. They will say show me the money … what happened to the 99% big pharma partner that was supposed to fund this trial in 2022?
Superficially this might seem a fair point. But it misses the reality of the world pharmaceutical market. The world market is one third US, one third Europe and one third for the unwashed. The P3 trial is both in the US and Europe, its’ just too big for big pharma.
You really need a national actor – such as the NIH. But here politics would come into play … why would American taxpayers fund bad backs in Italy. Most likely MSB is looking at funding from either NATO, the UN or the Vatican. My guess the Vatican with SI and the Pope nutting out the agreement over the quiet Easter break.
(20min delay)