Drug Baron

Even odds-on favourites can lose: lessons from the Prosensa story


With the details from the DEMAND-III study, the full extent of the failure of Prosensa’s exon-skipping drug drisapersen to arrest progression of Duchenne Muscular Dystrophy (DMD) has become clear.

There are few grounds for optimism among the plethora of secondary end-points, no trends, not even a statistically significant post hoc sub-group analysis.  Only pages and pages of convincingly negative data.

While its obviously a relief that concerns about liver toxicities proved unfounded – the treatment was very safe – the safety profile is unlikely to be much consolation for such a convincing lack of efficacy.

But clear-cut as the data is, it leaves one very important question entirely unanswered: was the failure due to insufficient dystrophin production, or – more worryingly – because successfully elevating dystrophin is much less effective than has been assumed?

There are also lessons to be learned beyond DMD: the infinite subtlety of biology means that no phase 3 study is a “slam dunk” – failure lurks round every corner, even in the most unexpected of places.  Public market investors, in particular, can pump up asset valuations on an over-optimistic assessment of early clinical data (as the recent Intercept episode illustrates).  The chastening experience at Prosensa should serve as a warning that translating promise and potential into regulatory approval and sales is often more difficult than it first appears.

Somewhat surprisingly, Prosensa got as far as conducting a phase 3 study in almost 200 boys with DMD without complying with Sabry’s Rule.  This ‘rule’, attributed to James Sabry, the visionary Senior Vice President of Genentech Partnering, mandates the existence of a “target engagement biomarker” before considering any project for clinical development.  Quite simply, you have to know that your therapeutic agent has done what it was intended to do (at the molecular level) in the patients you intend to treat, before you determine if that molecular intervention has successfully treated the clinical symptoms of the disease.

Prosensa obviously intended to do this in two ways: with a qualitative PCR assay for the presence of exon skipping, and a semi-quantitative assessment of dystrophin levels in biopsy samples.  But both approaches were completely equivocal.   Of the 12 placebo patients examined for exon-skipping, 10 were positive (presumably due to the low level of natural skipping that yields detectable full length dystrophin in most DMD patients).  Not surprisingly, therefore, the percentage of patients with exon skipping in the drisapersen treated group was no higher.  In a similar vein, the extreme variation in dystrophin levels measured in biopsies even among the placebo group precluded any robust assessment of whether dystrophin levels had been increased by drispersen treatment for 48 weeks.

Always remember  how bumpy a race-course drug development really is

These analytical findings are not inconsistent with earlier, smaller studies.  Even with 180 patients on study, it was unlikely the analytical methods employed would yield a clear affirmation of Sabry’s Rule.  But, in 2013, more sophisticated analytical approaches are certainly available, and had compliance with Sabry’s Rule been given the appropriate priority, such an answer could surely have been gleaned earlier in the development pathway.

Had such studies been done, and they had clearly demonstrated that dystrophin levels were not effectively elevated by drisapersen treatment presumably the DEMAND-III trial would never have been initiated, and the developers could instead have focused on improving the agent itself.  It is interesting to speculate how much of the strategy was driven by the head-to-head competition between Prosensa and Sarepta, who are developing an alternative exon-skipping therapy almost in parallel.  Without the fear that the opposition would gain a lead, might Prosensa have taken the time to properly evaluate their agent in accordance with Sabry’s Rule?

The situation, then, is even more perilous for Sarepta, as we await the pivotal trial data for eteplirsen, an agent with very similar mechanism of action to drisapersen.  Their data, showing an increase in dystrophin levels with the agent, is subject to the same issues as the Prosensa data.  It cannot be said with much certainty that either agent induces a material increase in dystrophin levels in boys with DMD.

But, as the FDA noted in the recent letter to Sarepta, even if dystrophin is elevated by eteplirsen, the DEMAND-III data (together with the prior failure of PTC124, another drug that apparently increases dystrophin levels by a different mechanism) “raises considerable doubt about the biomarker, and consequentially, its ability to reasonably likely predict clinical benefit”.

That, presumably, comes as something of a shock for the investors in Prosensa and Sarepta.  The assumption from day one has always been that raising dystrophin levels sufficiently, were that only technically possible, would yield a cure.

But that was never so certain.

DMD shares much in common with other inherited myopathies, including cardiomyopathies.  In each case, muscle contraction strength is weakened due to mutations in structural proteins.  But the catastrophic degeneration of function is caused by changes in muscle architecture that results from the initial weakness.  If that were not the case, there would be no reason for muscle weakness to increase as the patient ages (since the direct consequence of the genetic mutation remains the same throughout life).

The culprit is the load-coupling mechanism that induces muscle hypertrophy in response to increased functional demands (such as exercise).  In healthy muscle, its almost impossible push this too far – but in myopathy, when the muscle strength is weak, this loop drives not only cellular hypertrophy but critically also extracellular matrix production (through increased production of TGF-beta superfamily cytokines).  Eventually, the amount of extracellular matrix begins to disorder the fiber structure of the muscle, leading to further declines in strength (because the fibers are no longer neatly aligned along the long axis of the muscle).  This decline in function is no longer a direct consequence of the original mutation, and – beyond a certain threshold – is self-sustaining.

If that threshold has already been passed in boys as young as 6 years old (the population treated in DEMAND-III), as seems possible because they are already suffering continuous decline in muscle function (as opposed to a consistent stable weakness that would be the direct result of the genetic mutation), then even restoration of normal levels of functional dystrophin would be ineffective at halting the decline in muscle function.

DrugBaron raised this spectre as long ago as 2000, in an editorial for the Quarterly Journal of Medicine.  In response to the surge of enthusiasm for gene therapy that accompanied the completion of the human genome sequence, DrugBaron asked (rhetorically) in how many genetic diseases would complete correction of the causative genetic defect lead to a clinical cure?  And using DMD as an example argued that in many cases it likely would not (for precisely the reasons outlined here).

The FDA are right to doubt the utility of dystrophin levels as a biomarker for clinical improvement.  Investors in Prosensa and Sarepta maybe should have been more cautious.  Certainly, they should be cautious now given the double-whammy of uncertainty they are facing: the DEMAND-III data is far from convincing that dystrophin levels are materially increased; but more frightening still is the very real possibility that DMD, even in children as young as six, cannot be cured by restoring near-normal levels of dystrophin.

Does DEMAND-III signal the beginning of the end for exon-skipping in DMD?

With such convincingly negative data it would be easy to draw that conclusion.  But DEMAND-III teaches something important about DMD itself: the inherent variability between patients.  The same variability that rendered attempts to measure dystrophin levels inconclusive surely also contributed to the inability to see an effect of treatment on 6-minute walking time.  One solution is to consider pivotal open label trials, using each patient as his own control.  Placebo effect is not a major issue in these trials, and insisting upon a randomized, placebo-controlled study design (rightly the gold standard in other indications) may deny DMD patients an effective therapy.

Secondly, DEMAND-III robustly demonstrates the safety of the exon-skipping approach, at least with drisapersen.  That opens the door to initiating therapy even earlier.  Apparently, post hoc analysis suggests a possible effect of drisapersen on the youngest patients in the DEMAND-III cohort, providing further encouragement for a trial in the very young.

Lastly, its important to remember that 48 weeks sounds like a long trial (and it is), but the muscle weakening in these boys had been developing since birth (an average of between seven and eight years).  If the consequences of the dystrophin loss were expressed that slowly, its possible that the benefits of restoring dystrophin may also take years to be maximal.  Much longer trials may not be feasible, but at least using an open label design may increase the power to see a small effect sufficient for approval that may grow with continued use of the therapy.

This Prosensa case study amply demonstrates both the importance of Sabry’s Rule and the need for flexibility in clinical trial design, to match the characteristics of the disease under study.  But it also teaches us a third lesson:  there are no certainties, even in late-stage drug development.  Those of us engaged in drug development every day can no longer be surprised by failure, marveling over and over again at the complexity of biology.  The worry is that investors, and public market investors in particular, over-value assets backed by a sound hypothesis and promising early data – under-estimating the risk that remains in late-stage development.

Already in 2014, we have seen Intercept achieve a $5billion market value on the basis of phase 2 efficacy data for its NASH drug obeticholic acid.  These same investors reacted similarly to the phase 2 data from Prosensa and Sarepta.  Such huge valuations of still-risky assets is dangerous for the biotech sector – huge losses from the “surprise” failure of DEMAND-III damage confidence, and repeated too often can lead generalist investors to shun smaller healthcare companies for years or even a decade or more.  Where Prosensa has gone, others could easily follow.  So next time you see an odds-on favorite, remember just how bumpy a race-course drug development really is – and that the last furlong is no smoother than the rest of the track.

  • greyzone513

    You conveniently left out the actual reason for the Drisaspersen failure. Why you would omit such an obvious reason is perplexing. That said, the reason that Drisa failed was quite simply due to the fact that the significant toxicity associated with 2 OME chemistry, forced GSK/RNA to utilize only 6 mg/kg. While their chemistry most likely is able to “skip” whatever it is targeted to skip, they could not administer the drug in concentrations adequate to realize a statistically significant improvement in dystrophin, and thus, actual clinical improvement.

    Your are incorrect in your contention that the P3 showed Drisaspersen toxicity concerns were “unfounded”. In fact, to make such a claim, is basically an attempt to blatantly mislead your readers. During the P3, there were “multiple” AE’s, including hospitilizations……..with an “S”! You either did not follow things closely, or feel the need to mislead. I don’t really care, and perhaps the toxicity was not in the liver, but it sure as hell was found in numerous cases of thrombcytopenia, blood dyscrasias, and injection site severe reactions.

    Had the drug been possible to give in more therapeutic dosages, it is likely that ample dystrophin would have been produced. Toxicity is what kept that from happening. 2 ome chemistry is charged, and as such, far more reactive in “off target” ways…………..i.e., it produces toxicity. ETeplirsen on the other hand, has been perfectly well tolerated in lab animals up to an astonishing 1500 mg/kg!!! Yes that number is correct. And guess what, there were NO INCIDENTS of toxicity noted. ETeplirsen has been given the green light of up to 100 mg/kg, but it is very likely that the drug could be given at far higher doses with no risk of toxicity.

    Drisa is dead because 2 OME chemistry doomed this type of drug design to have unacceptable off target effects. The PMO chemistry that SRPT owns, is far, far different. Eteplirsen has yet to produce AE’s in any human subjects who have been given the drug up to 50mg/kg. Thus, Eteplirsen can be given a almost a 9 fold increase vs Drisaspersen, and thus make it into a therapeutic dosage level. Drisa can not, and that is why Drisaspersen failed it’s P3.

    Your article is interesting, but misleading.

    • davidgrainger

      Thanks for the comment – which makes a useful additional point.

      Its simply not clear whether the dose of drisapersen that was safe was effective at raising dystrophin or not. Arguably, the fact no changes were detected suggests the dose was indeed insufficient. But such was the variability in the analytical end-points that no useful conclusion can be drawn.

      Whether or not the safe dose is simply too low to have the primary pharmacodynamic effect because of the dose-limiting toxicity you describe, the key points of the article remain true: had ‘Sabry’s Rule’ been adhered to, the trial would never have been run (and the Prosensa IPO never launched).

      If the Sarepta product robustly meets Sabry’s Rule, then we are still to find out if that translates into clinical benefit in a Phase 3 setting. I hope it does (as you clearly believe it will) – settling many of the matters that, today as the article is written, remain conjecture. That will be good principally for DMD patients, but also for the biotech investment community.

      But again it does not take away from the central theme – that much-hyped things in biotech fail, and fail for reasons that, though complex, could have been predicted with a sufficiently thorough analysis. Actually, your point only emphasises mine. Reading your comment, one might be tempted to question why anyone bought into the Prosensa IPO.

      As must be obvious from the serious nature of the articles on this blog, it was clearly not intended to mislead. We have no financial position on any of the companies mentioned here, but instead attempt to use the case study to make some general points about the industry. The fact that I did not deal with YOUR point, doesn’t invalidate the conclusions, nor make the overall piece misleading (deliberately or otherwise).

  • redman2

    Let’s fix a couple of things right away. No there was no dystrophin made. Sadly the dystrophin results from earlier trials were never presented for detailed scientific review and were never presented in a meaningful way as a part of their IPO. That is a problem that Prosensa will have to deal with when the lawsuits come. The data that has subsequently been shown is very convincing that dystrophin was NOT made in any meaningful quantity. The methods used were multiple (western blots, PCR, IFA) and any one of those that came up ‘positve’ made that pt claim to be a responder. Despite this low bar less than 70% were scored as positive, and placebo pts were indeed scored as positive. The question is one of methods and cutoffs used for this analysis, it does not question the actual biomarker, it questions the methods and claims made using them. A detailed review post failure is now showing this to be the case, and goes further to the explaining that needs to be done to the IPO investors. In sharp contrast Serepta has shown literally every pts pre and post tx result. Each and every pt was negative at baseline (you avoided discussion of age groups and how that relates to baseline levels of dystrophin). The older group of pts are not variable in expression, they are negative.
    Second correction. Of course there was no liver toxicity noted, but that was never a concern. It was renal toxicity that was dose limiting and seen in 100% of the pts in the ph2 study. This has been noted in every study of AON chemistry ever conducted. Renal tox is always going to be dose limiting for this chemistry. This is why they tested different dosing strategies that used dosing ‘breaks’ (intermittent dosing) as a means of allowing renal protein levels to return to normal range.
    Finally lets discuss natural history as you seem to have fallen for the trick of including pts with Beckers MD and DMD pts across a broad age range into a natural history study and think that appropriately predicts variability for kids over 7, walking 350M at baseline and having an exon 51 mutation. The best data we have today for natural history of exon 51 pts decline is the Prosensa failed trial placebo pts that are over 7 years old. Pts over 7 all show significant functional decline over 48 weeks (-83meters). Compare that to the group treated for 2 years in the SRPT trial and it looks a lot different than comparing to the deliberately mixed bag that is being used for comparison.
    Most investors wont know the chemistry of these compounds and very few will know the analytical methods used to make the various claims that have been made. I do. It would be good if the author did too.

    • davidgrainger

      Thanks. The clarifications are very useful.

      As noted above, though, the two key points I tried to make are unaffected by these ‘details': unarguably, the issues drisapersen faced were predictable before the trial was even run, yet that did not stop Prosensa being viewed as positively by investors. Had Prosensa properly observed ‘Sabry’s Rule, they would never have got as far as an IPO or a Phase 3 trial. I don’t think we disagree on that.

      Second is the point you make even more starkly than I did: “Most investors won’t know the chemistry of these compound and very few will know the analytical method used to make the various claims that have been made”. Exactly, and irrespective of questions that will surely be asked about the was Prosensa portrayed the information it did have, it raises the question whether public markets can properly value such single-asset, pre-market companies. The Prosensa episode surely demonstrates they cannot.

      The one point where my piece may be misleading is the implication that the problems Prosensa suffered from automatically apply to Sarepta. That was not the intention (and, as I tweeted yesterday, like you I believe Sarepta will be successful). The point I was trying to make in comparing Sarepta with Prosensa was that the regulatory challenges are increasing, as the FDA letter illustrates, and that as in all studies, risk remains because biology is complex. Until Sarepta have positive Ph3 data those risks cannot be assumed to be discharged (not withstanding the superior chemistry).

      Consistent with my message, the fact that eteplirsen DOES comply with Sabry’s Rule removes a substantial chunk of that risk. The impressive Phase 2 data removes another substantial chunk. Where we differ is in quantifying the risk that still remains: I believe some risk remains, you believe that the current dataset already proves beyond doubt that eteplirsen will be positive in Phase 3.

      I hope that clarifies my position on the comparison of Prosensa and Sarepta, and removes any risk of misleading anyone, and also prevents the ‘details’ – important as they are – from masking the bigger (more general) points I was trying to draw out and illustrate using the Prosensa experience.

  • Festivus159

    I was also thinking of writing up my thoughts on both Prosensa’s and Sarepta’s newest data & analysis that they presented at JPM14.

    You brought up an interesting point that I hadn’t fully considered, which was that restoration of a Becker-like dystrophin, after the disease has started to progress, might not cause a full course adjustment to the slower Becker-like disease progression due to damage already done and the cycle of hypertrophy.

    However, I looked up what evidence there is in animal models for exon-skipping in earlier versus later stages of the disease. I remembered one paper where PMO-induced exon skipping was used in a canine model of DMD, and I thought they treated at different stages of progression. Here is the paper, by Yokota et al.: http://www.ncbi.nlm.nih.gov/pubmed/19288467

    In Figure 7, they tested the PMO at earlier stages of the disease (2 months of age) or later stages (5 months of age), and found that they were still able to see functional benefit at both timepoints. This is not definitive proof that, at any stage of the disease, muscle function can be stabilized, but it is some evidence that even after considerable functional decline has occurred that production of a Becker-like dystrophin can still be beneficial.

    Thanks again for your analysis.

    • davidgrainger

      To be clear, I didn’t say that raising dystrophin would not be effective – I said that it was not yet proven, and that it should not be automatically assumed to be the case. Clearly, at some point in the disease progression becomes irreversible – and whether that cut off is at 3 years of age, 13 years of age or even later is currently unknown.

      My comments are intended to highlight the general point that some observers and investors ignore real risks that remain – not just in this program but over and over again – and therefore have a tendency to over-value such assets.

      • Festivus159

        I agree with all of the above. :)

        Just mentioning some additional preclinical evidence of benefit even after disease progression begins.

  • Aj1

    Hi David, interesting piece. Isn’t there a fundamental
    problem with the efficacy of delivery of oligonucleotide to the appropriate
    cells? The low success in the gene therapy field has been down to the lack of effective methods to get DNA/RNA efficiently into the correct cells. It is only now with better vectors (e.g AAV) and more localized delivery (e.g subretinal space for ocular diseases) that we are starting to see success in this field. From an outsiders’ perspective (I’ve not looked into the pre-clinical data), I would postulate that by simply injecting the oligonucleotide SC you are not getting enough of the
    oligonucleotide into the muscle cells to get the exon skipping.

  • alphamoney

    It ain’t over till the fat lady sings

    how wrong you all are
    i suggest you rewrite your article