Celladon management engaged in a brief, ~23 minute conference call to review the company’s 4th quarter achievements. It appears only 2 or 3 investment analysts are interested in the story, as the questions posed were few. Admittedly, it can be hard to attract attention in a crowded biotechnology sector, and we wish them luck in drumming up more interest.

As mentioned previously here and here, Celladon is investigating the use of Mydicar, an AAV1 encoding SERCA2a, as a therapeutic for heart failure patients. The company is currently running the CUPID 2 trial, and it is due to provide top line data by the end of April / early May. Their aim is to demonstrate a 45% risk reduction (HR = 0.55) in time to recurrent heart failure rehospitalizations. As noted previously, I’m skeptical that this barrier can be met simply because the company has not provided convincing evidence of SERCA2a protein upregulation in large animal models receiving Mydicar.

During the conference call, the company articulated further their view towards the CUPID 2 data release. Disappointingly, they have steered investors away from expecting data to be presented on an intent-to-treat (ITT) basis. As a teaser, investors were told that the company approached the FDA with a plan to undertake a modified ITT (mITT) analysis wherein they could omit data from patients who did not receive placebo / Mydicar or who had events prior to dosing. As previously discussed, ITT analyses are the gold standard, and companies that attempt to mine trial results for subgroups are often putting on a brave face. In that regard, the red flag raised by this pre-emptive mITT declaration is deep crimson in color.

To be fair, it was noted that if a significant difference exists between the ITT and the reported mITT results (a >5% range was mentioned), investors may be notified of the ITT results. However, if mITT and ITT were close, then investors should not expect the ITT disclosure. But given the a priori declaration of an mITT data presentation, and the flexibility that the company may have in deciding what this modified group is, it brings up two linked considerations for the data release:

- The exclusion of patients who did not receive placebo / Mydicar or who had events prior to dosing may not necessarily be the modification that they use. The company noted that this modification would include less than 5% of the patients in the trial. The corollary here is that the company appears to have access to the blinded data. Otherwise, how else would they be aware of the percentage of patients that fell into this group? Therefore, interested observers have to be accepting of the fact that Celladon may have a lot of leeway in creating the specifics behind this mITT subgroup. Popular subgroups in these types of HF trials often include patients with ejection fraction (EF) less than X% or patients with NYHA HF Class X and Y. Time will tell if Celladon gets creative. In Biotechland, subgroup creativity is inversely proportional to efficacy of the drug.

- Will the mITT description completely obscure the ITT dataset? The company noted that if the ITT and mITT results are close, investors won’t be informed of the ITT at this time. But what will they consider ITT? For example, if they find a baseline EF subgroup that showed p = 0.07 for Mydicar versus placebo, but can then fall to p < 0.05 if they remove patients who did not receive Mydicar / placebo as well as removing events prior to dosing, then the EF/dosing-adjusted mITT “reaches” statistical significance. In this case, if your mITT patient base is EF/dosing-adjusted, what is your “ITT” comparator? Only EF-adjusted? That, by itself, is not true ITT either. Again, in Biotechland, your difficulty in finding the ITT outcome in a data release is inversely proportional to the efficacy of the drug.

I suspect the above two points already feature prominently in the canon of skeptical biotech observers. Time will tell how Celladon negotiates this, but all indications are that the data release may well be more “complicated” than first imagined.

Sometimes reiteration makes tasks look harder.

Celladon recently reiterated the case for Mydicar, their AAV1-SERCA2A therapy for patients with heart failure with reduced ejection fraction (HFrEF), at the BioCEO gathering. Celladon has come to prominence based on a subgroup analysis of their CUPID1 trial, wherein the Mydicar high dose arm (n=9) showed statistically significant improvement over the placebo arm (n=14). Although some are convinced by this study result, I’ve expressed my skepticism in an earlier post. Unfortunately the recent presentation makes the Mydicar proposition look less likely to succeed.

In the earlier piece, I’d highlighted strong reasons to question the degree of cardiomyocyte transduction and SERCA2A expression induced by Mydicar therapy. Celladon’s CEO was much more upbeat at BioCEO, describing the administration as one that results in “homogenous uptake” resulting in SERCA2A being expressed “for the life of the cell.” Perhaps that’s a form of confidence in the product. Unfortunately, their data to date provide little support for such unequivocal claims. The discrepancy between the presented scientific data and the company’s claim can be a red flag in and of itself: it is one thing to be confident in your program, but it is more effective if that confidence isn’t accompanied by claims that seem to be undermined by your own published data.

Rather than getting bogged down in the details of the AAV1 mechanism and SERCA2A protein expression, another way to assess this program is to examine the upcoming clinical trial expectations and compare them to historical observations. Celladon is currently running CUPID2, their sequential follow-up to CUPID1. CUPID2 is placebo controlled and enrolling 250 patients (~86% NYHA Class III/IV) split evenly into two arms. Participants will receive the high dose of Mydicar that resulted in statistically significant improvement for 9 patients in CUPID1 compared to their 14 placebo / best available care comparators. In this subgroup analysis, CUPID1 demonstrated an 88% risk reduction. That’s a very large number, especially when compared to our current and upcoming standards of care. To note:

Beta-blockers provided a 19% risk reduction in a HFrEF population that was ~60% NYHA class III/IV
LCZ696, the new offering from Novartis, provided a 20% risk reduction in a HFrEF population that was ~30% NYHA class III/IV

In these multi-thousand patient trials, two drugs, one a mainstay and the other a hopeful newcomer to heart failure treatment, have shown ~20% risk reductions. The trials did not enroll identical patient populations, but nonetheless the risk reduction percentages are eerily similar. In that light, CUPID1’s 88% risk reduction can either appear stellar, or more convincingly a fluke event. It is hard to imagine that this treatment will come out with a risk reduction that is four times those observed in these large trials. This is especially difficult to reconcile since we know that the SERCA2A mechanism of action overlaps with the beta-blocker mechanism of action. In fact, preclinical models have demonstrated that beta-blocker treatment can restore low SERCA2A expression, which is Mydicar’s raison d’etre. If beta-blockers, within their broader mechanism of action, increase SERCA2A expression the way Mydicar is proposed to, is it reasonable to expect that Mydicar demonstrate a risk reduction that is twice as large as that for beta-blockers?

It is not controversial to state that the risk reductions in larger trials tend to be smaller than those in earlier, smaller, proof-of-concept trials. Celladon’s design of the currently running CUPID2 trial suggests that they’re aware of this contributing factor, as the trial was designed to have 83% power to detect a 45 percent risk reduction. This is a more modest target, and the results are due in April, 2015. The company concedes that they need a p value significantly less than 0.05 to make this trial the primary basis of approval. At the same time, the company appears to concede that CUPID2, in and of itself, is unlikely to support registration. They note that a follow-on trial, CUPID3, is under planning and will be used as a phase 3 or phase 4 trial, depending on CUPID2 results and their conversations with US and European regulators.

In effect, for CUPID2 to form the primary basis for registration of Mydicar, the 250 patient trial needs to have an outcome that would come close to replicating the 80%+ risk reduction seen in a 23 patient subgroup analysis. That is a tall order for any drug.