Precision curative care.
That was the early slogan delivered at the Cardio3 Investor Day on January 30, 2015. It can be hard to limit cynicism when buzzwords (precision), dubious promises (curative) and supposed empathy (care) are trotted out and put on display for prospective investors.
Cardio3’s lead treatment is C-Cure, an autologous cell therapy for heart failure. The method depends on a bone marrow harvest, followed by isolation of a limited progenitor cell population called mesenchymal stem cells. These cells are subsequently treated with a cocktail of factors to induce them into a “cardiopoietic” cell population that, per preclinical results, more effectively benefits the heart by presumably differentiating into cardiomyocytes and using paracrine effects to promote differentiation of endogenous stem cell populations in the heart. This is a more limited population compared to the crude bone marrow mononuclear cell preparations that have convincingly failed in human clinical trials.
This cell therapy preparation is planned to be tested in two phase III trials, named Chart-1 and Chart-2, that are primarily based in the EU and the US, respectively. The precursor phase II trial, the C-Cure trial, ostensibly showed an improvement in left ventricular ejection fraction (LVEF) in a randomized setting, rationalizing the company’s decision to move forward. That said, there are some factors to consider when appraising Cardio3’s chance of success in heart failure.
Perhaps the largest factor in assessing the chance of phase III success is to examine the underlying phase II data. In the case of the C-Cure trial, there were some concerns in the publication expressed by third parties, culminating in a formal reply by the authors. But regardless of reporting inconsistencies, one factor about the C-Cure trial is consistent: the company made clear in the Investor Day presentation that the outcome of the trial was successful. Perhaps a number was mistakenly reported in one location or an aspect of the protocol was not immediately clear when reported, but when all is clarified, the trial is presented as a successful phase II. This is an important point because the C-Cure method is labour intensive, and success with such a complex product should be respected. Each patient randomized into the treatment arm undergoes a bone marrow aspiration to start the process of producing the 6-700x10E6 cells that is re-injected into the patient’s heart.
Unfortunately, this is perhaps the biggest flag when appraising the phase II data. The results reported by Cardio3 were not presented on an intent-to-treat (ITT) basis. In other words, patients for whom the cell preparation could not be successfully completed were removed from the analysis, effectively making it a per-protocol analysis. This type of analysis can be meaningful for early stages of product development as efficacy signs are looked for in a process that continues to be streamlined and perfected. Nonetheless, for subsequent phase III trials, an ITT population will be the major focus of regulators. For the C-Cure trial, of the 32 patients randomized into the cell therapy arm, 7 patients were subsequently excluded due to the cell collection / expansion process being suboptimal. Along with a few other exclusions for different reasons, only 21 of the 32 patients on the cell therapy arm made it to the per-protocol endpoint.
In short, a phase II trial wherein only 21 of the 32 ITT patients were included in the efficacy analysis on a per-protocol basis ends up on weaker footing than if the efficacy analysis was completed on an ITT basis. This argument isn’t novel, and is in fact noted by an accompanying editorial on the C-Cure trial results. Given the complexity of the cell harvesting and expansion process, it is not unreasonable to expect that Cardio3 will face similar challenges in their registrational phase III trials. However, they are unlikely to convince regulators if they deviate away from an ITT trial analysis. All told, there is reason to be highly cautious of extrapolating the C-Cure results into expectations for Chart-1 and -2.
And perhaps the company feels the same way. Chart-1, the EU-focused trial, has practically completed enrollment. An interim analysis is due in March, 2015, wherein the DSMB will render one of three opinions:
- Continue the trial as is
- Continue the trial but expand enrollment, as the DSMB signals that an aspect of the trial may need more patients to achieve adequate power
- Stop the trial due to clear safety signals or clear lack of efficacy
Outcome #3 is clearly negative. Outcome #2 is very likely a negative sign as well. Expansion of enrollment suggests that the assumptions going into the trial are incorrect, and history has shown that this is usually not a positive occurrence for phase III trials. Outcome #1 is likely neutral and doesn’t denote likely success or failure, simply ruling out overwhelming efficacy or overwhelming toxicity.
With Chart-1 setting itself up for an interim analysis in March, 2015, Chart-2 then stands in a curious place. The company was on record, and the CEO confirmed, that initial guidance had Chart-2 enrolling its first patient by the end of calendar year 2014. That has been pushed back. The claim is that the interactions with the FDA are the cause, specifically a change in the primary endpoint of the trial. Curious. Perhaps this timing gives outsiders a view into the confidence expressed by the company. By pushing back patient enrollment, Cardio3 will likely take in the outcome of the March 2015 DSMB recommendation for Chart-1 prior to actual patient enrollment in Chart-2. It would be reasonable to say that this is a prudent move; however, it would also be fair to say that the confidence in the phase II data is not unwavering.
Coincidentally, approximately half of the Investor’s Day presentation was focused on the company’s recent foray into the CAR-T space. This is definitely a burgeoning area for oncology, with multiple companies and academic institutions taking dedicated steps to develop these treatments. Therefore, it does come as a surprise to see a company called Cardio3 slowly morph into an equal part oncology company. Again, perhaps this is prudent by management. However, long term followers of biotechnology companies will recognize this as the possible first move in a classic Biotech Pivot (Tm). The rules of the Biotech Pivot state that as the day of judgment nears on your lead product, mentions of other pipeline efforts shall increase.
So is Cardio3 executing the Biotech Pivot? Or is this simply prudent management by an experienced team? A prediction is that the March 2015 analysis is benign and that the company continues Chart-1 as is and that Chart-2 enrollment is extremely slow for the first half of 2015. And, luckily for investors, there will be plenty of talk on the CAR-T side to keep them busy... or distracted.