My Fragile Excitement

A number of readers have emailed me to ask my thoughts on the Neuren Phase II outcome in Fragile X. I initially wasn’t inclined to pass comment, mainly because I didn’t feel like getting a lot of flack from angry parents of Fragile X patients, criticising me for my lack of faith in Neuren (ASX : NEU). But then if I am going to be a reasonable human being – and in consideration of my generally lukewarm sentiment toward this company – I should be fair and acknowledge interesting results when they arise.

And the stated results from Neuren’s Phase II study in Fragile X (NCT01894958are interesting.

As usual, it was an appropriately sensationalist ASX disclosure, including a nice trading halt for additional impact, but the data is interesting (I repeat). Based on what Neuren has presented, there does appear to be a dose-dependent relationship for the secondary outcome (behaviour-related measures), though it does need to be recognised that these are fairly tough endpoints to quantitate and this is a very small study. Still, considering the high quality of the clinical sites and the basic structure of the trial design, it looks like Neuren got something more than just a basic safety signal, which is great.

Shareholders should be happy.

Having said this, there really was never going to be much of a concern about safety for this drug because it has already been studied in a fairly large number of patients, and in a sense that’s the slightly annoying thing about this trial. It’s like somehow we were supposed to have forgotten about the history of this drug. As such, the study is constructed as though there really are safety/AE concerns at this dose range, when there probably aren’t. Therefore the headline that the study met its primary end-point is a bit of a yawn if I am being candid with you. On the other hand, if I am being kind to Richard and the team, I suppose the rationale for such a small study (25 or less patients per arm) is that perhaps these patients aren’t so easy to come by in a clinical trial setting.

Hopefully that’s the reason for such a small study that basically isn’t powered to study anything other than safety.

The data, as presented, looks nice but it is still worth noting that the error bars have fairly significant overlap between dose cohorts (and placebo) and the rating scales, as presented, are a little bit arbitrary. The data summary shows trends, but there is also a lot of quasi-science in the presentation of the information that, as usual, gives me the shits. The key piece of information, which is “the effects observed following treatment with the low dose of trofinetide (35 mg/kg twice daily) were less consistent and the magnitude of improvement did not meet pre-specified targets, but there was evidence of a dose response” is mostly buried in a lot of enthusiastic rah rah.

And… the company has presented a visual and “quantitative” compilation of what are supposed to be several distinct data points. If you look at the clinicaltrials.gov entry for this study, one can clearly ascertain that the various secondary outcome measures as presented by the company are basically combination scores. As such there really isn’t enough data presented to tell you whether or not this data is more than just a little bit exciting. It would have been nice to see the individual measures as a function of dose/placebo, rather than “scorecards” (i.e. rolled-up numbers). By my count there should be at least 8 graphs for behaviour-related secondary endpoints and 12 or more graphs for outcome measures (depending on how you compare “during” and “post”-therapy for such an incredibly short study).

So my take on the data? It looks interesting, but it also looks incomplete. It probably does pave the way for further clinical development, though whether this amounts to more than just another Phase II study at a higher dose will be mostly up to the FDA. They’ll care about the minutiae of the data, but they will also be keen to see drug candidates progress in a very difficult patient population like this. Since the FDA’s biggest concern is safety, the company certainly has more than a “shot” at moving ahead.

Oh, and of course, the company will no doubt publish the data in a top-tier neuroscience journal where all the data is laid bare for the world to see. Just like they did with all their other clinical studies that reported positive and exciting outcomes.

2 thoughts on “My Fragile Excitement

  1. Thanks for your thoughts on NEU’s results, Chris.

    I studied those results pretty hard when they came out and kept thinking “be careful. They’re trying to trick you!”

    I wish that these biotechs had to agree to a pre-arranged way of reporting their data to stop them thinking up clever ways to present the results to make them look as good as possible.

    NEU said towards the end of their reporting that the high dose composite score was significantly different from the placebo. But I don’t know if that was after they showed a significant difference doing a one-way analysis of variance across all three groups first, or whether they just compared composite score in placebo with composite score in the extreme dose group.

    A scientific journal would require them to follow correct statistical procedure, but when these companies report to us, the would-be suckers, they might be giving us the prettiest interpretation that is not statistically justified.

    My other thought is “If these fragile x patients are so hard to come by, and thereby making this study expensive and time-consuming, why not run the study for just a few more weeks?”

    Adding an extra few weeks wouldn’t add too much more to the cost, but it would make the subjective behavioural assessments a lot more meaningful.

    I had this paranoid thought: what if these asx-listed companies don’t want definitive, robust findings? They just want just positive-enough findings. In this case, maybe NEU chose not to do a longer trial because it might have increased the risk of the initial benefits plateauing or disappearing.

    I think they might be fighting a battle between two values: to discover the truth about their product vs to keep the incremental steps tiny but probably positive to keep themselves in the game as long as possible.

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