Wednesday, June 26, 2013

Discrepancy in Claimed Injection Site Reaction Frequency with ISIS-ApoCIII

My fundamental believe as to why RNAi is fundamentally preferable over phosphorothioate (PS) antisense for therapeutic gene knockdown, is that PS antisense involves the saturation of various tissues in the body with a sticky chemistry that is associated with inflammation.  By contrast, with RNAi Therapeutics, you only need to transiently achieve relatively high tissue levels so that enough of the RNAi silencing machinery can be fed with the RNAi triggers.  Unincorporated oligonucleotides can, and usually are, then washed out without much or any loss of efficacy.

Especially in chronic settings and systemic administration, this persistent inflammatory herd raises the specter of multi-organ fibroses and other adverse immune effects, including vasculitis.  The mipomersen briefing docs showed that such concern is warranted, especially with the findings of vasculitis in non-human primates and frequent injection site reactions which, in contrast to ISIS management which routinely characterizes them as ‘cosmetic’ and ‘nuisance’ side effects, should be interpreted as indicators of what might be happening more systemically.

As you also know, I am equally wary of the reliability of ISIS’ forward and backward looking statements.

Obviously, when ISIS reported phase II data from theISIS-ApoCIII study showing a deep 88% knockdown of the target gene and impressive >70% reductions in serum triglycerides, the question of whether this is a real drug or another KYNAMRO/mipo-like dud hinges on its safety profile.  Unfortunately, no hard numbers were provided on this front in the initial press release.  Instead, there was much beating around the bush characterizing them as being very infrequent and mild in nature. 

However, in the conference call, one analyst apparently wasn’t satisfied with this and asked for a straightforward quantification of the injection site reactions (the following is an adaptation of the telcotranscript on Seeking Alpha):

Jim Birchenough – BMO Capital Markets
Yeah. Hi, guys. Congratulations on the data. A few questions…And then just final [third] question, if you could quantify injection site reaction profile and contrast it with KYNAMRO, I think that would be helpful…
Richard S Geary (ISIS Pharmaceuticals)
Good. This is Richard, and thank you for those questions...The third question, I don’t think I got.
Stanley T Crooke
Reactions compare and contrast to KYNAMRO.
Richard S Geary
So you will remember that in our Phase 1 experience we actually compared directly with three weeks study in normals and we saw almost a 90% reduction in the frequency of ISRs.
Stanley T Crooke
Compared to KYNAMRO.
Richard S Geary
Compared to KYNAMRO, and I would say that looking at these Phase 2 studies, this is being replicated very low frequency and much less severity. These are very mild and it’s almost all erythema that resolves very quickly.
Stanley T Crooke
So we’re seeing much more mild and much less frequent injection site reactions in this study as we saw in earlier work. Is that a fair way to say it, Richard?
Richard S Geary
Yes.

A 5-fold exaggeration of the reduction in injection site reactions

So while ISIS did not add much regarding the frequency of injection site reactions in the phase II study, at least a relative number was provided for ISIS-ApoCIIIRx.  Going back to the phase I trial for which the results were recently published (Graham et al. 2013), the following was said about the frequency of injection site reactions:

‘The most common adverse event was mild injection site reaction, a typical response to subcutaneously administered drugs.52 No subject dosed with placebo complained of injection site reactions, al- though 13 of 25 (52%) subjects dosed with ISIS 304801 experienced at least one. Approximately 1 of 6 injections (median, 17%) led to an injection site reaction, the majority of which resolved within an hour.’

To test the veracity of ISIS’ comments, you would then have to dig up the numbers for mipomersen.  In the FDA briefing docs, the following can be found about the frequency of injection site reactions:

‘ISRs were the most commonly reported AE in the clinical development program. In the pooled Phase 3 trials, 84.3% (220/261) of mipomersen-treated individuals experienced 3,683 ISR events and 33.3% (43/129) of individuals in the placebo group experienced 139 ISR events.’

Assuming for simplicity that the 261 subjects in the phase III studies received 52 injections minus X due to drop outs (note: this fudge factor actually favors ISIS’ numbers as it increases the injection site rate for mipo) we arrive at around 3683 injection site reactions from 10,000 injections, i.e. a rate of around 37%.  If ISIS’ comments on the 90% drop in injection site reaction frequency were then true, the rate for ApoCIII should be 3-4% and not 17% (according to ISIS the mipo injection site reaction rate would have to be 170% for the numbers to match up).  In a 13-week trial, a 17% injection site reaction rate also means that the majority of subjects will experience such reactions, some more often and severe than others.


Of course, I am just a molecular biologist and know little math. I therefore look forward to the ISIS bulls or even the company itself to point out where I went wrong in my calculations.

15 comments:

tettrazini said...

Dirk,

ISIS has made important strides improving the formulations of their ASOs. You have hardly recognized such changes. Your frame of reference seems to be mipomersen, one of the oldest drugs in ISIS’s pipeline. More recent drugs have greater potency and seemingly far less qualitative and quantitative untoward side effects including ISRs.

Dirk Haussecker said...

I like the prospect of their neurodegenerative pipeline, too. However, the rest we have to see about it. You state improvements in safety, including ISRs, but how then do you explain what I have written? This is an important point and not about being decimals off. So how can you be sure that not everything on PS-antisense safety is just a repeat of the game they have played on mipo safety? The hard evidence tells me nothing much has changed on safety and on efficacy...this is 300mg/week.

Dirk Haussecker said...

The other point which your post reminds me of is that the ISR issue will be largely overlooked for the simple reason that the share price is going up. Also see the class action vultures drop their lawsuit earlier this year, although I think they had good points and are being vindicated by the apparent lackluster sales performance of mipo and the European rejection.

tettrazini said...

I do think statistics can mislead. For example, do you weigh a bit of erythema that dissipates within 15 minutes the same as a more insidious rash that may require steroids to resolve? Both might be considered ISRs, but hardly are they comparable. This may not answer your quantitative question, but even you noted the incidence of ISRs is down sharply, although you question if it is in the low single digit range as you extrapolate from the company’s pronouncements.

At Wednesday’s annual meeting I spoke at great length with one of the scientists who has been with ISIS for more than 20 years. I consider her beyond reproach, and she was emphatic that the science keeps improving and the drugs of today incorporate lessons learned and injection site reactions are not the problem as experienced with mipo. I believe her, but perhaps you are both right.

tettrazini said...

I have often commented that SC has a history of over promising and under delivering. It is my impression that the over promising has subsided. Perhaps it was the lawsuit (dropped) that finally caused Stan to be more cautious, but whatever the reason, this is my impression. I suspect even a skeptic like yourself might have noted the more cautious words regarding drugs under development.

My interest in ISIS is not based on mipo's prospects. I am relieved that it is finally approved and the company is now focused on drugs that I consider more exciting. It's as if mipomersen had been an anchor holding back the pipeline's progress.

tettrazini said...

If I had to summarize the difference between our takes on ISRs, is that I take Richard Geary at his word when he says, "Compared to KYNAMRO, and I would say that looking at these Phase 2 studies, this is being replicated very low frequency and much less severity. These are very mild and it’s almost all erythema that resolves very quickly," and you don't.

Dirk Haussecker said...

Tet, I believe you have the explanation: a 'mild' ISR is no ISR at all. Remember, the mipo ISRs were 'cosmetic' as well until we saw the briefing docs. Remember, they are forcing 300mg oligos under the skin at once. That to me already sounds painful. We shall see.

tettrazini said...

Might ISIS be doing the heavy lifting of identifying high potential RNAi targets for companies such as Arrowhead Research? For example, is there anything in terms of intellectual property or underlying technology that would impede ARWR from designing an RNAi using their DPC technology to go after APOCIII?

Dirk Haussecker said...

Setting aside the issue of oligonucleotide structure (Arrowhead has a few alternatives here) I am not aware of patent positions around certain targets by e.g. Alnylam or ISIS that would prevent it to go after these targets with best-in-class solutions.

I don't expect such direct competition for the next target (possibly another IV formulation as first subQ data only late last year), but after that who knows. A DPC subQ, likely safe and highly effective, watch out...Putting my money where my mouth is, over 80% of my share holdings now in Arrowhead. Have to look hard to find such opportunity in biotech these days. And I give it a 20% chance that we will see first functional cures in the one-shot phase IIa Hong Kong study around this time next year.

tettrazini said...

What happened to diversification?

tettrazini said...

"I don't expect such direct competition for the next target (possibly another IV formulation as first subQ data only late last year), but after that who knows. A DPC subQ, likely safe and highly effective, watch out..."

With the possibility of infrequent subQ dosing it might not be so compelling, but with such minute drug quantities being administered an orally bioavailable formulation might only to be a question of having the financial resources for development. They have plenty on their plate for now.

tettrazini said...

Dirk, in a previous blog you wrote, “For a small biotech company like Arrowhead Research, the enormity of the HBV opportunity also comes with its challenges. The complex course of chronic HBV and probably also the various genotypes mean that clinical development will be equally complex- and costly.”

ARC-520 seems an ideal candidate for the FDA’s newly designated break through status(see below). Furthermore, and this is a relatively big if, if ARC-520 results in functional cures with little safety issues, it is conceivable for a trial to terminate early because it would be unethical to withhold ARC-520 from the control arm. It may not happen frequently, but it is not unprecedented.
(http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm341027.htm)

Anonymous said...

could you comment on Isis paper in BBA:Transfection of siRNAs can alter miRNA levels and trigger non-specific protein degradation in mammalian cells.
thanks

Dirk Haussecker said...

I can. Seems like a repeat of what many other groups have reported before (and that's why it ended up in low-impact journal BBA)...the dose makes the poison. You need very high doses of usually suboptimally designed RNAi triggers to see a small competition effect.

Jim Birchenough said...

I like Jim Birchenough as an analyst. He has a pretty good track record

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