Biomarin – testing the boundaries of evidence-based medicine

As an outside observer to the rare disease community, I find the recent acquisition of Prosensa (RNA) by Biomarin (BMRN) puzzling. To me, Prosensa’s drisapersen was just another case where promising phase II results were not corroborated in phase III. This happens frequently with oncology drugs (metmab, iniparib, tivantinib, palifosfamide etc.) and typically leads to termination of the program. Judging by Biomarin’s optimism, drisapersen’s fate may be different, which raises questions regarding approval of drugs despite negative P3 outcome. As background, Prosensa’s lead drug, drisapersen, is being developed for the treatment of DMD (Duchenne muscular dystrophy), a devastating and fatal muscle-wasting disease that affects young boys. The drug addresses 13% of DMD cases and works by a new mechanism (exon skipping). Sarepta (SRPT) is developing a competing drug (eteplirsen) that works by the same mechanism.

Promising phase 2 data…

Prosensa went public based on positive results from a 53-patient randomized phase II (DEMAND II). The trial compared 2 regimens of drisapersen (continuous and intermittent) to placebo, with 6-minute walk distance (6MWD) as the primary endpoint. 6MWD measures the distance a patient is able to walk over a period of 6 minutes and is regarded as a reliable way to assess disease progression. In DMD, the minimally clinical improvement is considered to be 30 meters.

The continuous drisapersen arm demonstrated a ~35 meters after 24 weeks, which was maintained at 48 weeks. The difference at 24 weeks was statistically significant whereas the benefit after 48 weeks was almost statistically significant (p= 0.051).

DEMAND II… not corroborated in phase III

Based on these promising results, Prosensa advanced drisapersen to phase III, which failed to show any benefit after 24 or 48 weeks. The absolute difference at 48 weeks was 10.3 meters in favor of drisapersen, which was not statistically significant (p= 0.42) and is not considered clinically meaningful.DEMAND III In parallel, Prosensa and its partner at the time, GSK (GSK), released results from another small phase II (51 patients) which evaluated two doses of drisapersen vs. placebo. The higher dose led to a 27-meter benefit over placebo after 24 weeks but the difference was not statistically significant (although it was close: p=0.069).

Mixed signals

This created a situation where the drug had positive readouts from two different randomized phase II trials but a completely negative readout from a large phase III study.

In order to reconcile this discrepancy, Prosensa and Biomarin argue that the phase II trials, coupled with other long term open label studies, represent the true activity of drisapersen. The phase III failure was blamed on trial design issues such as patient heterogeneity, a high proportion of more advanced DMD patients and insufficient follow-up.

A quick comment on data presentation

In an attempt to convince investors and regulators that the phase III had a different patient population, Prosensa created a slide (see below) that compared baseline characteristics across the different studies. To me, the slide is misleading because the graphical presentation makes the differences look more dramatic than what they are (X and Y axis do not cross at 0). For example, the “time since diagnosis” graph gives a sense of a 3-4 fold difference while in fact the actual difference was only 29%. When companies use these tricks it should be viewed as a major red flag.

Baseline - ProsensaIn Biomarin’s defense, they changed these graphs, and in their presentations the differences look much more subtle.

Baseline - BiomarinReality check

Going back to Biomarin’s claims regarding trial design issues as the reason for the phase III failure, the arguments provided to date focus on disease severity and insufficient follow up.

Disease severity – Subset analysis of the phase III data based on age and disease severity did not reveal much in terms efficacy. Subset analyses are unreliable by nature and in this case, they didn’t even lead to a significant benefit. The best subset analyses improved absolute difference between the drisapersen arm and placebo to 21-25 meters but this did not come close to statistical significance, with a sample of 47 and 79 patients, respectively. This is notable given the fact that the two positive phase II studies were able to show a statistically significant (or on the verge of stat. significance) with 34-36 patients.

DEMAND III - subset analysisPTC Therapeutics (PTCT), which is developing ataluren for another subset of DMD patients, also used subset analysis from its randomized phase II and reached the opposite conclusion. PTC decided to recruit older patients with more advanced stage DMD for their ongoing phase III study based on the idea that it will be hard to show a clinical benefit in patients with early-stage disease because they experience very limited deterioration initially (up to 48 weeks). This can also explain the spectacular results with drisapersen in small single arm studies: Some patients do very well, regardless of treatment (see right graph below).

PTCLonger follow up – The need for long- term follow up in order to see an effect contradicts the signals observed in the phase II studies, where a clear effect was seen even after 24 weeks. Therefore, this argument discredits the efficacy signals from the phase II trials.

At JPM, Biomarin’s CEO presented updated results from the phase III extension study, in which patients from the placebo arm crossed over to receive drisapersen (patients originally assigned to drisapersen vs. patients who crossed over from the placebo arm). After 2 years there was a 49.2 meter difference between the two arms. No p value was provided so one can assume the difference wasn’t statistically significant.

DEMAND III - long term FURegardless, this analysis is very hard to interpret as the drug is compared to itself from the 48 week time point and included a small number of patients. As not all patients continued to receive the drug, the two arms were probably not carefully balanced. Therefore, the difference between the two arms could be a result of natural variability between the groups. In addition, landmark analyses are unreliable if they are not defined prospectively before results are available. Without this, one can go over the graphs looking for a single time point in which the difference is maximal.


Drisapersen generated intriguing signals that may merit further evaluation but in my opinion, the totality of data fails to prove drisapersen provides any benefit in DMD. If Biomarin truly believes the drug is effective, the right thing to do is a new pivotal trial applying the new selection criteria and endpoints. Instead, Biomarin intends to file for approval with a predominantly negative package which is full of inconsistencies and inherent discrepancies.

The phase III failure and the lack of any positive subset analysis are an order of magnitude more reliable than any positive indication from smaller studies (either placebo controlled or single arm). Despite this, Biomarin believes drisapersen could receive accelerated approval, which is quite unusual for a drug that proved ineffective in phase III. There is no doubt that new DMD treatments are urgently needed but one has to wonder whether this can be an excuse for approving drugs based on unmet need while ignoring basic tenets of  evidence-based medicine.

Portfolio updates

We are selling one of three positions in Foundation Medicine (FMI) following the 100% jump earlier this month (in order to limit exposure to 10% of total holdings).

Portfolio holdings – January 25TH, 2015

Biotech portfolio - 25-1-15biotech etfs - 25-1-15

72 thoughts on “Biomarin – testing the boundaries of evidence-based medicine

  1. Hi Ohad,

    What you think of MEIP? Pracinostat, a HDAC inhibitor showed Impressive data so far on AML and MPS in combination with CELG Azacitidine. Low evaluation @86M. Thanks! Jinyu


  2. Ji (STML) – I view it as a high risk bet and intend to keep a small position. I like the strong preliminary efficacy in a niche indication (BPDCN) but am still concerned about immunogenicity and competition from MGNX.

    Jinyu (MEIP) – I am still struggling with this one. I agree valuation is low but the recent AML update was somewhat disappointing. For the time being I am out but I have a month to change my mind….



  3. Hello Ohad! There was quite a movement in Arqule today {2/11/2015}…….Do you have any comments? I am also interested in your insight in to the recent news on Curis!? Thank you in advance!


  4. Bouschka – Re: ARQL, I am not aware of any particular development. Re: CRIS, I liked the IRAK program they got from Aurigene, the small molecule PD-1 inhibitor is less attractive and quite risky imo.



  5. Hi Ohad,
    Do you think AGIO is worth its market cap? It looks to be a great short candidate. Aside from some individual stocks, do you see much upside for the biotech sector for 2015. Maybe I’m wrong, but I sold all my FMI and half my ARRY today. I did buy a decent chunk in ARQL (probably one that is fairly valued).


  6. Hi Ohad

    I read your comments on ESPR and AERI. As someone who doesn’t hold stocks in any of those two, do you think it’s still a good idea to jump into those two?


  7. hi Ohad,

    I have the feeling that some strange things are going on at ARRY, e.g. just from today’s 8K:

    are they clearing the ship for a takover??

    everything is contingent on the Novartis-transaction. maybe they already have a buyer who will swallow them once the ok for the Novartis/GSK-deal is there?


  8. Manish – Re: AGIO, I think the stock is overvalued but I also thought so when it was at $50…. In general I agree that biotech as a sector is somewhat overvalued, ARQL clearly isn’t but it’s a very high risk play so I plan to keep my exposure low.

    Ji (ESPR/AERI) – I believe that at least one of them will be acquired during 2015 so I intend to hold and add on weakness. From a philosophical standpoint, holding a stock is the same as buying it.

    Christian (ARRY)- I don’t expect a buyout wit the present valuation, a licensing agreement looks more likely imo.



  9. Dear Ohad:
    Your analysis of the DMD drugs from Biomarin/Prosensa and Sarepta was excellent. I looked into these drugs some time ago when the first results were coming out. Sarepta showed data from biopsied muscle to show how much dystrophin was being made in boys who were taking the drug. They had two kinds of measures. First, they used microscopy and antibodies against dystrophin to measure the percentage of muscle cells that contained dystrophin. Without drug, that number was zero, and with drug, that number was high (I can’t remember the number, but let’s say 75%). So, a lot of the muscle cells were indeed making at least a little bit of dystrophin. Second, they showed one Western blot in which the amount of dystrophin in the muscle cells was assayed, compared to normal muscle. That Western blot showed that the absolute amount of dystrophin was really tiny. I did a rough estimate at the time, which again I cannot exactly remember, but I think it was around 1% of normal, or even less. So, the Sarepta drug was inducing about 1% of normal levels of dystrophin in about 75% of cells. There are several published studies looking at mice producing very low levels of dystrophin. These tend to say that (a) there is some slight benefit to very low levels of dystrophin, but (b) it is a very slight benefit, sort of proportional to the amount expressed. Putting all this together, I guess that both the Prosensa/Biomarin and the Sarepta drugs will produce tiny benefits, but unfortunately those benefits will be really pretty small.

    Since there is published data (from mice) on the effects of small amounts of dystrophin, it seems the two companies could clarify things substantially by telling us how much dystrophin is being made (i.e., not the number of cells that are positive, but the amount of dystrophin).


  10. Hi Ohad

    Have you ever come across Cytori Therapeutics (CYTX). They are working in the field of adipose derived stem cells. Last management was crap and the balance sheet still looks bad – though the technology seems to work and very promising.

    Thanks for your thoughts!


  11. Dan S. (AERI) – News about potential disease modifying properties of Rhopressa are positive for the overall prospects of the drug (needs to be validated in humans, of course), but the upcoming p3 data are an order of magnitude more important. The preclinical program in AMD has good data but I am still cautious as small molecules for AMD are inferior by definition due to duration of exposure.

    Bruce (BMRN) – Thanks. Quantifying dystrophin is tricky by definition as the methods currently used may be biased due to fluctuation or subjective interpretation. I agree that perhaps the disappointing clinical results stem from subtle potency, which, if amplified could be clinically meaningful.

    Kevin (CYTX) – Haven’t looked at them for a long time.

    Alex (TKAI) – Don’t know them too well, but their data even in AR-V7 patients were not a home run imo.

    Alex (OGXI) – I still think their drugs don’t work.



  12. OGXI – I never shorted a stock yet but what do you think about shorting it?

    TKAI – you meen as opposed to –
    Analyst Dr. Brian Klein of Stifel initiated coverage at “buy” and a price target of $20. He said galeterone has shown compelling early evidence of efficacy in a genetically defined and underserved population in Phase 2 testing. “We believe similar results in Phase 3 would be a home run.” October 13, 2014 ☺


  13. Hello Ohad,

    Valeant Pharmaceuticals bought Dendreon Corp due to its prostate cancer vaccine Provenge for $ 400 Mio. Medigene has a more effective new generation dendritic cell vaccine in development which can be produced very cost effective – in contrast to Provenge. Medigene has a market cap of EUR 55 Mio. Wouldn’t this be an interesting – of course speculative – play? Thanks.



  14. Hello Ohad,
    Do you have any opinions on Xenon Pharmaceuticals Inc. (XENE), specifically it’s platform.
    Also, what do you think of the recent increased institutional investment activity in Advaxis, Inc. (ADXS).


  15. Alex – I don’t do shorts. Regrading TKAI, Brian is a very smart guy and probably knows them much better. The totality of their data was not compelling imo, will check again when I have an opportunity to do so.

    bj – Sorry can’t discuss te CAR space.

    Bouschka (AERI) – Inotek just did an IPO, they have positive P2 data but their story is not as compelling a AERI imo.

    Toby – DNDN’s Provenge is the only dendritic cell vaccine that led to a survival benefit in P3. In general, I am somewhat cautious about cancer vaccines in development although the sentiment has improved in the past couple of years.

    Frank – Sorry, I am not very familiar with both.



  16. Ohad,
    I read some of your blogs, you covers a wide variety of life science and biotech topics. you did good job in presenting yourself as an expert in almost all the topics you blogs – certainly a very useful skill. You seemed holding very strong opinion in this article – not sure why. An unbiased analysis of the topic would be more valuable than throw out an opinion at readers. I think most readers of your blogs are well educated, they would rather form their own opinions if you could just provide unbiased evidence and analysis. I like the evidences JQ brought up.
    Every drug has a long list of side effects. Look at tylenol – everyone use it. do you think people will stop using tylenol after reading this article?
    You probably know that people have higher tolerance in side effects when dealing with difficult-to-treat life threatening diseases (e.g. cancer, DVD…) versus none life threatening diseases.


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