As you may remember, I had become quite bullish about ISIS the stock for the potential of its lead drug candidate, the ApoB-antisense inhibitor mipomersen for the treatment of hypercholesterolemia, to surprise to the upside. Based on the combined phase I and II data, the recent phase III data in the homozygous and heterozygous familial hypercholesterolemia populations appeared to have been on the lower end (~25-30% LDL-c reductions) of what I thought might be the true efficacy of mipomersen and maybe influenced by the genetic background of those patients. More importantly, the rate with which patients from these earlier studies were supposed to have entered the open-label extension studies and the apparent absence of increased safety liabilities with consequent prolonged dosing made the extent of the analyst scrutiny of the liver enzyme elevations appear overly alarmist.
Well, so I thought and was waiting for the release of the data from the phase III trial in the patients with severe hypercholesterolemia, the patient population with arguably the largest commercial potential for mipomersen, when, without much, or should I say any fanfare, a paper (Akdim et al, 2010) on a phase II study for which top-line data had been announced in a press release in November 2007 came out. I have followed biotech long enough now to know that companies like to put their topline data in the best possible light which is usually followed by the subsequent revelation of a few warts here and there. In light of the published data, however, I found in this case the take-home message of the press release to have been sufficiently misleading to warrant this blog entry and take back some of my optimism with regard to mipomersen…both efficacy-wise and, more significantly, with respect to safety.
This analysis claimed that, while on treatment, only 3% of the more than 250 patients exposed to mipomersen had experienced ALT elevations of 3-5x upper-limit of normal (ULN), the same percentage as in the combined placebo group, and none experienced more than 5x ULN. Taking into account also the follow-up periods (‘entire study period), the numbers would increase to 5% (placebo) and 7% (mipomersen), a slight, but not worrisome increase it would seem. Only by studying the tables, one would have noticed that there was one case of >5x ULN that apparently occurred during the follow-up of dosing part of the study (‘entire study period’). Injection site reactions that, as we now know, poses a number of development challenges for ISIS/Genzyme (soon daily injections?), were mentioned as a side-effect but characterized as ‘cosmetic inconveniences’ of no medical concern.
The fact that there were 2 more patients in the Akdim et al. paper than in the press release for the 200mg cohort could be due to many things (including drop-outs), but it is quite unfortunate that with the enlarged patient group LDL-cholesterol lowering suddenly would drop from the 48% in the PR to 36% in the paper. Well, 36% should be a degree of knockdown that the company should be able to live with, but sets off alarm bells that maybe some of the other data could have been presented in an overly positive light as well.
And indeed this is my conclusion after seeing the safety data: 5 out of the 10 patients (granted a small population, but this is 50%, nothing like the 3-7% mentioned in the press release!) in the 13-week 200mg cohort had an ALT increase of >3X ULN, 4 of which on 2 consecutive occasions! One patient even experienced an increase of >5x ULN and subsequently dropped out before all planned doses had been administered (which was then included in the ‘entire study period’ group, but not on-treatment group). Also not mentioned in the original press release was the fact that the ‘cosmetic’ injection site reactions applied to almost all patients receiving mipomersen (much, much less in placebo obviously) and that these accounted for 2 drop-outs in the 10-patient 200mg cohort.
Everybody, of course, has to form his/her own opinion about how much to rely on press releases reporting top-line clinical trial data. The way these phase II data were handled, however, rocks my confidence in how much to trust management’s contention that the wide-spread mipomersen concerns are ill-founded. The company does not have to be surprised that its credibility in the investment world is what it is and will be difficult to repair without structural changes. This is unfortunate, because I believe ISIS has otherwise made an admirable contribution to the development of oligonucleotide-based therapeutics.
PS: The purpose of this blog entry is not beat up on ISIS for the sake of it. Unfortunately, attempts to resolve my concerns first with the company directly failed as an email to ISIS investors relations (info@isisph.com) two days ago remained unreplied to.
11 comments:
There is an excellent response on the Investor Village message board to Dirk's ISIS blog:
http://investorvillage.com/smbd.asp?mb=1373&mn=17145&pt=msg&mid=8907055
Will this credibility issue affect Regulus in any meaningful way?
Dirk
Excellent article and well uncovered. Hopeful for ISIS, it's a shame to read that they've chosen to present findings in this way.
Good comments on investor village though. Both views worth considering
They are good comments. On the scientific side, it is a valid question whether lowering ApoB/LDL-c too quickly can lead to some liver toxicity as this might overwhelm the liver’s capacity to adapt to the new lipid realities. The correlation between leaving out the initial loading dose with decreased incidence of elevated ALTs is consistent with this idea as is ISIS’ contention that it has not seen similar ALT elevations with its other second generation drugs (targeting other genes).
Until here, I agree with Marc at least to the extent that this is a good possibility especially with the data obtained after 2007 in larger patient numbers and with prolonged dosing (mind you, the jury is still out whether the liver tox problem could be for real). He is saying, however, that ISIS must be thinking very lowly of its investors (maybe also the reason why my email to them was without reply; I must say other companies are quite a bit more responsive, even to criticisms), and rather than confusing them with complicated science, take the chance with this, at the time very risky hypothesis and hope that it will be all forgotten. The problem really here is ISIS’ credibility. It would not be the first time in biotech that investors have a rude awakening after a drug has been rejected by the FDA based on obscure pre-clinical and clinical tox data that was never, ever brought up with investors. Do you feel that the way the 2007 press release was handled could be reflective of how the company might be tempted to deal with other similar ‘small’ problems?
I'm sure ISIS is wary of responding to any investor whose questioning the way ISIS reported data considering the attacks MIPO has encountered at ever step.
I'll just add a couple of points. ISIS and the expert cardiologists and lipidologists involved have never seen isolated ALT elevations without bilirubin, Hy's law or other signs of liver toxicity as a big problem but just a consequence of the degree and mechanism of cholesterol lowering though I know it becomes an issue for some others with every trial. From all the trials the ALT elevations tend to trend down or resolve with time even with continued dosing. As to the 5/10 patients with >3x ULN ALT elevations on two consecutive occasions, I believe there was about 7 days between measurements. So the patients were relatively blasted over 12 days and since the whole trial was only 13 weeks there would not have been much of a chance for the ALTs to fall spontaneously on continued treatment. So I fully understand what you're saying Dirk but I think there's less there than you think particularly when ISIS always gives fairly scant data in these top line releases and leaves the details for the conference or journal article. I don't know if this is the place for an extended comment like this so if it isn't I apologize in advance
I appreciate your comment, and the more detailed the better.
We can probably agree that ISIS' technology has tremendous value, but disagree with the way they are presenting results which may appear to some to be purposefully misleading- making ISIS even more vulnerable to attack. You can't just release buoyant press releases and then keep stumm when the real data comes out of which the take-home is quite contrary to the original press release.
No offense to Stan. He was the right person and has done a great job to get ISIS to where it is now. I'm wondering where oligo Rx would be without him. As companies evolve, however, such as ISIS from a platform creating company into a bottom line-focussed commercial company, it may require a new type of management to get the company to the new stage. As I've stated before, a merger between Alnylam and ISIS would be one solution and have a number of benefits for both parties.
There may be many advantages to a combined ALNY and ISIS, but better management probably would not be one of them. Stan’s greatest fault may be he over promises and under delivers. But as far as execution, ISIS’ track record is superior to ALNY’s.
Now that Genzyme is in charge of mipo, trial results are being reported on an intent-to-treat basis. We are also starting to see the data presented in important peer reviewed journals such as Lancet and JACC. Also helpful with understanding the data and keeping management’s spin in check is the commentary of outside experts such as yourself and leading lipidologists (who have been involved with the trials, but independent of the company). For all its public relations faults, ISIS does deserve credit for being transparent by including these lipidologists in a number of their presentations. At their annual meeting ISIS will once again be convening a panel of lipidologists to discuss the mipo findings and their potential application.
Is there any chance we might get to meet you at ISIS’ annual meeting?
I take your point that ISIS enjoys significant support by the relevant key opinion leaders, and that's an encouraging sign both scientifically and when it comes to future commercialization (note, however, the tone of the Akdim paper was somewhat more cautious than what you would hear Kastelein speak at company-sponsored occasions).
I disagree, however, with you on the ISIS business model, and believe that (independent of the technology differences) Alnylam's has the potential to be much more rewarding for shareholders. Forever relying on royalties is not the way to built a major biopharmaceutical company, even if the platform is very strong (almost reminds me of XOMA in the monoclonal space; also every other 1st and 2nd gen MAb platform company eventually had to re-focus on their own pipeline or eventually was acquired). Instead, you need to believe in some key product candidates and go all the way, as Alnylam does, and with ALN-TTR Alnylam could become a major biotech before ISIS does. The ISIS model more or less preserves the status quo and, for this reason, benefits mostly ISIS management (evolution into a commercialisation-focussed company would presumably require fresh blood). Alnylam already has staffed for such future needs.
...annual meeting...would love to go, but unfortunately, already have other commitments on that day. thanks for the friendly invite though.
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Although good execution is fundamental, there is no one “formula” for building a successful pharma business. ISIS has only out-licensed one drug, mipomersen, post proof of concept. But the deal with Genzyme speaks loudly about ISIS’ ability to monetize its science at the value inflection point. That deal one of the biggest ever consummated by a biotech company, brought in hundreds of millions of dollars and royalties that will range between 30 and 50 percent. Not bad for a drug that had not yet embarked on PIII. It won’t take too many similar deals for ISIS to gain recognition as an important factor in biotech. While Wall St focuses on mipomersen, it is only one (and probably not the most significant) potential blockbuster drug candidates coming from ISIS’ pipeline.
Your assumption seems to be that deals of mipomersen magnitude will not be repeatable, let alone be repeatable again and again. Time will tell, but I think such an assumption may be true because if drugs in ISIS’ pipeline continue performing strongly the company will be bought out.
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