FDA Hard-Pressed to Approve Biomarin, But Not Sarepta Drug

When Biomarin late last year bought Prosensa for its experimental exon skipper drisapersen for the treatment of Duchenne Muscular Dystrophy (for $680M plus potential milestones), it exuded confidence about the likelihood of getting approval for the 2’-O-methyl phosphorothioate antisense molecule.  This, despite of the fact that drisapersen failed in a pivotal phase III trial of 186 patients which prompted the old partner GSK to dump the drug and walk away.

Tenuous early evidence for drisapersen in earlier trials

The confidence is largely based on some supposedly successful earlier trials, especially a multi-center, randomized, blinded 53-patient phase II study which had seen improvements in the 6 minute walk distance (6MWD) at week 25, the primary endpoint of the study (Voit et al. 2014).  

This, however was statistically significant only the case in the subgroup of patients that received drisapersen continuously (à treatment in 10 out of 10 weeks with 6mg/kg), but not in patients which were treated identically, except for the small difference in skipping the last week in a 10-week treatment cycle.

At week 49, the difference with placebo failed to reach statistical significance and Prosensa had to resort to pooling both subgroups to claim victory for that time point. Similarly, drisapersen failed in obtaining statistically significant outcomes for other muscle function endpoints.

Since the mechanism of action for the DMD exon skipping candidates is to change splicing of the mutated dystrophin transcript to a form in which the reading frame is restored with recovery of partial activity, it is important to understand the relationship between drug treatment and dystrophin production.

Here, too, the evidence was less than robust.  For example, even when applying the sensitive immunofluorescence technique, no increase or even a decrease in dystrophin was seen in almost half of treated subjects.  With the less sensitive Western blot, an increase in dystrophin was seen in only a third of treated subjects (0 for placebo).

Therefore, given the failed phase III trial and the less than robust earlier evidence in favor of the drug, I struggle to understand Biomarin’s confidence in obtaining approval in 2016.   

The importance of dystrophin as a surrogate endpoint

Part of the difficulty of obtaining statistically significant results for muscle function endpoints is most likely due to the small patient size (orphan disease affecting ~1 in 3500 male births) and the consequent need to pool boys at various stages of the disease together in a given trial.  It would thus not be surprising if say obtaining 10% levels of normal or Becker-type dystrophin will translate into very meaningful clinical benefit in some, but not other boys.

This will be an even more challenging problem for the DMD subgroups that are not amenable to exon 51-based exon skipping which is targeted by drisapersen.  Probably insurmountable for first-generation chemistries like drisapersen.

Accordingly, in both the drisapersen and the competitive PMO-based eteplirsen trials, it has not been possible to correlate dystrophin production with functional outcomes.

For that reason, I strongly support the importance of establishing reliable, quantitative methods to measure dystrophin in clinical trials (there was an FDA workshop related to this last week).  Dystrophin-dependent markers may also be acceptable if they can be measured by means that do not involve taking painful muscle biopsies.  For example, serum-based microRNAs as developed by Rosetta Genomics and Marina Biotech would be of interest here.

Eteplirsen before drisapersen

I thus find it difficult to grasp the notion of rejecting the current crop of exon skippers like drisapersen or eteplirsen should they be found to produce functional dystrophin with few side effects.  After all, it is the loss of dystrophin function that causes Duchenne Muscular Dystrophy and one has to wonder how generating additional dystrophin cannot be beneficial to patients, especially since the principle behind drisapersen and eteplirsen is strongly supported by human genetic evidence (à Becker’s Muscular Dystrophy).

In this world, it has got to be eteplirsen that should be first in line for regulatory approval.  This is because there is overwhelming evidence (e.g. Heemskerk et al., 2009; Sarepta's Barclays presentation March 12, 2015) that the PMO-based drug is much more potent than drisapersen which, let’s face it, is based on stone-age antisense chemistry (2’-O-methyl phosphorothioate).  Such chemistry is characterized by minimal efficacy and dose-limiting toxicities, especially renal in the case of drisapersen.

In a paper comparing 2’-O-methyl to PMO chemistry for DMD exon skipping conducted by researchers close to eteplirsen, it was found that at same doses in mice, PMO chemistry is moderately to vastly more potent than 2’-O-methyl phosphorothioate antisense compounds of a size comparable to drisapersen.  The extent of the difference depended on whether the human or mouse dystrophin were targeted and the target sequence.   Unsurprisingly given the acrimonious competition between the two parties, Sarepta has also picked up on this and continued along these lines by showing that in addition to chemistry, eteplirsen has the edge over drisapersen in terms of the targeted sequence:

Sure, there is the theoretical caveat that PMO and 2’-O-methyl scale differently from mice to humans and that what is the most potent target sequence for one chemistry does not necessarily have to be the most potent one for the other.  Intuitively, however, the differences are too big for these factors to compensate the preclinical evidence.  Also, keep in mind that in the clinic, eteplirsen is being given at 5 to almost 10-fold increased doses than drisapersen and, on top of that, is much safer and better tolerated than drisapersen.

Because of this and the competition, it is not surprising and disingenuous when Biomarin would now suddenly like to de-emphasize the importance of dystrophin as a surrogate biomarker (see last week's workshop).

Dear regulatory agency, if you approve drisapersen, you cannot deny eteplirsen.  Sure, drisapersen has been tested in more patients than eteplirsen and Sarepta has conducted a clinical trial in the worst possible manner and probably ‘embellished’/overstated some of their results, including the dystrophin evidence.  However, given that eteplirsen almost certainly generates more dystrophin than drisapersen, the highly favorable side effect profile of eteplirsen (also in comparison to drisapersen), and in light of the 6MWD issue that applies to both drug candidates, the question is whether the bureaucratic application of rules should trump scientific evidence and patient interests.

Disclosure: I am long SRPT based on the notion that Biomarin, with its orphan disease savvy, will turn out to be the biggest supporter of eteplirsen getting approval this time around.  Additionally, the agency is partly responsible for the long duration of the ongoing eteplirsen trial (close to 4 years soon) and the repeated taking of muscle biopsies, and after all this taking away hope from patients and their close ones is difficult to fathom.

Sarepta, Biomarin Move Over- Here Come tcDNAs

In a head-to-head comparative study in NatureMedicine, Goyenvalle and colleagues claim that tricycloDNAs (tcDNAs), a relatively unexplored constrained nucleic acid analogue commercialized by SYNTHENA have superior efficacy over 2’-O-methyl oligos and PMOs for therapeutic splice modulation in mouse models of Duchenne Muscular Dystrophy (DMD). 

In addition to ~3 to 5-fold enhancements in dystrophin exon skipping in various muscles compared to the competing chemistries, the authors report that only with tcDNAs there was splice modulation also for the dystrophin isoform expressed in the brain.  This was accompanied by improvements in the behavioral and cognitive abnormalities in this model.   Apparently, these neurological defects are another important treatment goal in DMD.

Splice modulation was accompanied by ~2 and 20ug/g oligo concentrations in brain and muscle, respectively, following the administration of relatively large weekly doses of 200mg/kg that were necessary particularly for the correction of the neurological symptoms.

Interestingly, such delivery and target modulation was achieved without encapsulation or further modification technologies.  Whereas a 2012 publication by some of the same authors in collaboration with ISIS Pharmaceuticals explored the use of tcDNAs for RNaseH-mediated gene knockdown in conjunction with the phosphorothioate backbone known to greatly improve biodistribution and cell uptake, tcDNAs here were applied in their naked form.

The authors attribute this to an apparently spontaneous tendency of tcDNAs to self-assemble into ~100nm nanoparticles.   

The results seem to warrant the development of tcDNA for DMD exon skipping.  Critical to their success in the clinic will be the safety and tolerability of tcDNAs in Man with the kidney predicted to be the dose-limiting organ.  

The study is also a reminder that there are now a number of other chemistries, including the high-affinity CRN chemistries by ISIS Pharmaceuticals and Marina Biotech, the latter with a stated focus on DMD, which similarly promise improvements over the trail-blazing 2’-O-methyl and PMO chemistries.  

BioMarin $700M Acquistion of Prosensa Comes Down to Attraction of RNA Therapeutics

Earlier this week, the scientist in me was shocked by the ~$700M acquisition of Prosensa by orphan disease company BioMarin for its Duchenne Muscular Dystrophy splice modulation candidate drisapersen.  My initial surprise was due to drisapersen being a drug that had not long ago gloriously failed a pivotal phase III trial, not least due to a questionable therapeutic index.  All this is not very surprising since drisapersen is based on antiquated oligonucleotide chemistry (2’-O-methyl phosphorothioate).

After a moment of reflection though, I have come to take a more positive view of the deal as it is actually a very bullish sign of the interest by the wider pharmaceutical industry in RNA Therapeutics.   This is because BioMarin is taking the gamble here that it will be able to argue its way to approval by pointing towards drisapersen having shown evidence that it can positively influence the splicing of the disease-causing gene, dystrophin.  So even if your clinical evidence of efficacy is anecdotal at best, it is difficult to argue with the notion that such evidence in combination with being able to positively impact the root cause of a disease is not an important step in treating an orphan disease of very high unmet medical need.

It should be clear to everybody that if drisapersen can get marketing approval, other exon 51 splice skippers with superior chemistries (many of which are pushing forward in development) will eventually replace it as best-in-class.  I would be surprised if BioMarin did not see it the same way, but similar to Roche acquiring Intermune for $8.3B for its IPF drug which had marginal efficacy in a severe disease of high unmet need, the rationale seems to be that being first-to-market in such pioneer indications will allow you to build a strong franchises in those areas.

It will be interesting to see whether this strategy pans out and BioMarin can get accelerated approval in 2015-6 based on some seemingly positive phase IIresults in combination with the dystrophin biomarker evidence.

Regardless, the $700M valuation and ~60% premium of the offer to its stock price is a powerful reminder that part of the reason what makes RNA Therapeutics so compelling is that it often allows you to drill down to the root cause of a disease.  From a commercial perspective this is particularly valuable in an environment favoring drugs for severe orphan diseases.