Biotech Values

[DonShimoda]

The ARIA short thesis, as propagated by @adamfeuerstein, would have one believe the EPIC trial's cardiovascular related exclusion criteria was changed in March because of a supposed safety imbalance between the trial arms. What's conveniently ignored by his reporting is that if a significant imbalance between the gleevec and iclusig arms actually did exist, it would have been reported out by the Data Safety Monitoring Board. Very simply, if the DSMB hasn't stopped or changed the trial, then the only reasonable conclusion one can draw is that at least up to now there has been no significant imbalance between the two arms.

Bears also point to the changed EPIC trial exclusion criteria as somehow indicative of Iclusig being a "dirty drug" that causes increased cardiovascular risk. So, let's take a look at the actual changes to the EPIC trial's CV related language and see how it compares to that used by Tasigna in its first-line CML trial:


............................ICLUSIG.....................................................................................TASIGNA...........................

Myocardial infarction, within 6 months prior to randomization...........History of clinically documented myocardial infarction

Unstable angina within 6 months prior to randomization..................History of unstable angina (during the last 12 months)

Congestive heart failure within 6 months prior to randomization.........Clinically significant heart disease/congestive heart failure

Based on the above, at least as far as CV risk is concerned, Tasigna is clearly more restrictive than Iclusig. In fact, Tasigna excludes ANY patients with documented myocardial infarction, while Iclusig allows patients who have had an MI as recently as 6 months. The same is true for congestive heart failure. Ironically, the very changes the shorts use to bolster their claims may actually make it slightly less, not more, likely for a CV event to occur. Why? Enrolling patients with less cardiovascular risk makes an unrelated CV event less likely.

So, what about Sprycel? As far as myocardial infarctions are concerned, Sprycel uses exactly the SAME 6 month exclusion criteria as the Iclusig language. The point is that all of these TKI's have cardiac AE's - the most reasonable explanation is that it's a class effect. Despite these concerns, Tasigna and Sprycel will each have over $1 billion in revenue in 2013. As Biomaven points out cardiac adverse reactions were reported in 7% of 258 patients taking SPRYCELin front-line. To put this in perspective, in the PACE trial which treated much sicker 3/4th line patients, 5% of patients had myocardial ischemic SAEs and the majority of those patients had pre-existing conditions (see ASCO 2013 abstract http://meetinglibrary.asco.org/content/109745-132 )


Finally, the shorts point out that MD Anderson's decision to run an expansion cohort using a 30mg dose must mean there's a safety issue at the 45mg dose. @dsobek did a fine job explaining the fallacy of that logic in his recent article. However, I would also like to point out that the very same investigator, Dr. Jorge Cortes, who is running the 45mg/30mg front-line study is also running a separate 45mg second-line trial. The shorts would have us believe that Dr Cortes would drop the dose in the front-line trial because of safety concerns but then leave both the dose and exclusion criteria in the second-line trial completely unchanged. Not only did Dr Cortes not change the dose in the 2L trial, he kept the unstable angina, myocardial infarction, TIA, stroke or heart failure exclusions at their original 3 months...not even increasing them to the 6 months the bears would have us believe is so disconcerting in the EPIC trial.

Clearly, the 30mg dose expansion cohort is exploratory. In practice, dose titration is common with both sprycel and tasigna so it only makes sense to explore Iclusig at lower doses in small n, IST led trials. But, instead of taking my word for it, thanks to the interwebs, you can listen to Cortes' 2012 ASH presentation and hear what he thinks about Iclusig yourself

So, on one hand, we know the following: 1) to date, the DSMB has reported no issues...none, 2) the CV exclusion criteria in the EPIC trial is actually LESS restrictive than that used by Tasigna, 3) the MD Anderson second-line trial has continued at a 45mg dose with no changes to the exclusion trial at all.

On the bears side, you have a couple of articles written by @adamfeuerstein. I'll let you decide which is the weaker argument but for my money I'm betting Iclusig's prior CV issues are either:

1) a class effect
2) a function of the very sick 3/4th line patients in the PACE trial with pre-existing CV conditions
3) specific to Iclusig

The bears would have us believe it's #3 but, until shown data that proves's otherwise, I think #1 and/or #2 are far more likely which is why I'm more than happy to take the other side of the shorts bet.

@zDonShimoda