A closer look at the Blautix trial and what to take away from itDrug Development
Posted 15 October 2020 - 04:50 AM
As some of you may have seen by now the live bacterial formulation Blautix developed by 4D pharma produced some rather underwhelming results the other week in their Phase 2B (NCT03721107) IBS trial. I’ll be going through the trial data more closely in this report and explain some details that might have gotten lost in the news stories. I would also like to mention that I do not consider it my job to sugar coat anything in this report, especially if it means shielding a pharmaceutical company which is likely bending over backwards to protect its million dollar investment already. My responsibility is to the individual IBS patient who wants to access and understand the data.
Table of content
What was the therapeutic intent of Blautix
Design of the trial
Efficacy endpoints explained
Results in detail
Why I’m not surprised
The company’s messaging
The therapeutic intent
Blautix is a pharmaceutical product containing the live bacteria Blautia hydrogenotrophica which consumes intestinal gases. Contrary to popular understanding the goal of this one bacterial species was never to ‘fix’ the microbiota, but rather to use its gas consuming properties therapeutically to reduce bloating, abdominal pain and abnormal bowel frequency. To what extent these gases underlie the condition in the first place is something I’ll get back to in the “Why I’m not surprised….” part.
Design of the trial
The Phase 2B trial was a large, well designed study based on previous results from a Phase 1B exploratory trial. As you can see in Fig1 IBS-D and IBS-C patients were separated into cohorts and received either Blautix twice daily or Placebo. Note that 4D Pharma decided to measure efficacy for subtype specific and combined IBS cohorts. This is in line with what we would expect from a well designed study.
Figure 1 Trial Design
To measure the efficacy in a trial we need to have pre-defined study endpoints which are basically goals the investigators agree should be considered a success before the start of the trial. In this case the investigators chose the FDA recommended endpoints for a registration trial which are as follows:
A patient should be categorized as an overall responder if the patient achieved the prespecified improvement in weekly or daily response for at least 50 percent of the weeks or days of treatment (e.g., 6/12 weeks or 42/84 days).
A patient is categorized as a weekly responder if the patient is a weekly responder in both pain intensity and stool consistency.
An Abdominal Pain Intensity Weekly Responder is defined as a patient who experiences a decrease in the weekly average of worst abdominal pain in the past 24 hours score of at least 30 percent compared with baseline.
A Stool Consistency Weekly Responder is defined as a patient who experiences a 50 percent or greater reduction in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline.
A patient is categorized as a weekly responder if the patient is a weekly responder in both pain intensity and stool frequency.
An Abdominal Pain Intensity Weekly Responder is defined as a patient who experiences a decrease in the weekly average of worst abdominal pain in the past 24 hours score (measured daily) of at least 30 percent compared with baseline weekly average.
A Stool Frequency Weekly Responder is defined as a patient who experiences an increase of at least one complete spontaneous bowel movements (CSBM) per week from baseline.
Here we also find our first potential ‘flaw’ which explains at least part of the mediocre result. The endpoint for the Blautix trial is a composite endpoint in which both Abdominal Pain and Stool Consistency or Stool Frequency are included into the same measurement. Keep this in mind for later.
Looking at the Results in detail
The Endpoints were not met and showed only a positive trend at best. One can discuss the appropriate p value for this trial, I won’t do that however. If we take a look at the details in Fig2-4 we can see that Blautix performed far worse on Pain than in Stool Frequency/Consistency in both cohorts including the combined analysis. Note also that the Y-axis is not set to 0% for the Pain graph in Fig4.
The Stool Frequency/Consistency in both cohorts were not strong but clearly showed some improvement. The combined cohorts showed a stronger result, how the p value was generated to be 0.007 I don’t know so I’ll let it stand for now as the individual cohorts were close to but did not beat 0.05.
The composite endpoint is obviously disadvantaged by the fact that both measurements (Pain and Stool Frequency/Consistency) have been combined into the same measurement. This might be considered a ‘flaw’ at first, but given the precedence set by the FDA Guidelines and the fact that the investigators could not possibly know this, it is still valuable for us to have measurements on the combined and separate endpoints. This explains in part why the results were so lackluster. Since this was a proof of concept trial and not a registration trial it was the best choice for the investigators who needed to answer the question of which signal would turn out to be the strongest.
Figure 2 Results Combined Cohorts
Figure 3 Results IBS-C Cohort
Figure 4 Results IBS-D Cohort
Why I’m not surprised
My first thought was that I’m not impressed by the data. The endpoints are already generous enough in my opinion and we have seen numerous drugs make it to approval which we can say with some hindsight have questionable efficacy. The fact that the composite endpoint did not deliver is no major disappointment. Breaking down the data as we did the endpoints on bowel habit were unfortunately not convincing either. I can tell you that I was not surprised however. Blautix is not a painkiller nor is it a motility drug. It was created specifically to combat gas and bloating. I have thought for some time that I should write a piece on “Do IBS patients actually suffer more gas?” Most of you will probably think I’m kidding and get ready to tell me multiple stories about how bloated you were this one time. But first let me offer a perspective; several studies indeed show excess gas production in IBS patients, however it is far less extensive than one might expect. One major contributing factor to the sensation of bloating is the hypersensitivity of the nervous system suffered by many patients. This leads them to not only have more gas but crucially to perceive the bloating as far more excessive than it actually is. This underlying hypersensitivity which enhances pain from numerous other stimuli than just bloating is something Blautix never aspired to treat. This is clearly a limiting factor. Together with the composite endpoint mentioned before I did not expect strong results from this trial. Still I had hoped it could fill a gap left open in our current therapeutic landscape namely to deal with intestinal gas. The results did not live up to that hope, however there might be patients suffering from a lot of gas which could have benefitted from it. This is entirely speculative of course and I do not know how flexible the FDA would be in permitting subgroups outside of the declared guidelines.
The company’s messaging
While 4D pharma sees this as a partial success, my experience tells me whenever I read a top line results press release in which the headline does not include the words ‘positive results’ it is generally not considered successful. It seems markets agree with this sentiment as the stock price fell more than 30% upon announcing the results. After watching the company’s press conference I haven’t changed my mind. The focus on IBS-M as an additional indication, the safety profile and potential efficacy of new endpoints in additional subgroups compared to approved therapies is clearly an attempt to save a priced asset and mark it out as potentially competitive in a market full of already mediocre therapies. I have seen this many times before and the only reason I think I should even mention the company’s messaging is because the uninitiated might get a very different impression if they were to blindly trust the company’s representatives. I encourage everyone to look at the data instead and take nobody's word for it.
Here is the video from the press conference:
I hope you enjoyed this walkthrough even though the results were not as we had hoped. If you have any questions do not hesitate to comment below. Have a nice day everyone!