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.