Not all clinical trial results are cut and dried. Sometimes the outcome is obvious, with clear failures marking the end of the road for a particular drug candidate and clear successes immediately leading to the next step of development. But oftentimes the results present a mixed picture that requires companies and their investors to really dig into the details to determine their true meaning and the best path forward.
Cardiol Therapeutics Inc. (Nasdaq: CRDL) (TSX: CRDL) recently announced results from its Phase II trial in acute myocarditis that fall into the “mixed picture needs analysis” category. Its other advanced program, in recurrent pericarditis and studying the same drug candidate, immediately led from a successful Phase II to the ongoing Phase III trial. This time around the study’s primary endpoints were missed, one of them very narrowly, and investors have apparently deemed the trial a failure. The company and expert advisors are not of the same opinion, and here we will take a look at why.
The Trial
Cardiol’s Phase II ARCHER trial of its lead drug candidate CardiolRx™ for the treatment of acute myocarditis was an ambitious swing at an unsolved problem. Acute myocarditis is a leading cause of sudden cardiac death among people under 35 years of age and has no FDA-approved treatment. The trial’s two primary endpoints were extracellular volume (“ECV”) and global longitudinal strain (“GLS”). The results were negligible for GLS and promising, but barely missing statistical significance, for ECV.
The results did indicate that CardiolRx™, in a relatively short period of three months, significantly decreased left ventricular mass, or LVM. LVM basically means swelling of the heart muscle, and the complications that result from that swelling are far-reaching and very serious. Numerous indications are greatly impacted by increases or reductions in left ventricular mass (LVM), with two particularly relevant to Cardiol: heart failure with preserved ejection fraction (HFpEF) and myocarditis patients who present with LV dysfunction. Both conditions are of great interest to both the medical community at large and to Cardiol Therapeutics as it plans next steps.
Myocarditis Next Steps?
In a conference call discussing the full release of the ARCHER trial results, both of these conditions were covered. First, regarding myocarditis, it is important to realize that the patient population was not selected based on increased LVM or on preserved ejection fraction. Here is a quote from Dr. Dennis McNamara, Professor of Medicine, University of Pittsburgh, Director, Center for Heart Failure Research, UPMC, & Chair of the ARCHER trial:
“I certainly would like to see whether cannabidiol [CardiolRx™] can make a difference in those patients who present with hemodynamically significant myocarditis, the patients who present with LV dysfunction. As you know, we did not reach the primary endpoint of global longitudinal strain, in part because LV function was relatively preserved.
Looking in the smaller fraction of patients that had LV dysfunction, there appeared to be at least a trend towards significant improvements. And I would hope that cannabidiol [CardiolRx™] could make a difference for these patients. These were intermediate risk patients hospitalized with troponin elevations for the most part, but for the most part had preserved LV function. I think cannabidiol [CardiolRx™] could make a difference for more severe patients, and I hope to see that in one way or another looked at in the future.”
From Dr. Leslie Cooper, Chair, Department of Cardiovascular Medicine, Mayo Clinic, Florida & Co-Chair of the ARCHER Steering Committee:
“And most importantly, at the end of the day, the reduction in LV mass related to a combination of both extracellular and intracellular volume supported the hypothesis that you can remodel the heart with a specific targeted therapy aimed at myocardial inflammation and specifically edema early in the course of myocarditis.
So for me this study is exciting. I think that it should be developed further for inflammatory heart conditions. And those could include, of course, myocarditis, which we studied, recurrent pericarditis, as well as the growing problem of checkpoint inhibitor myocarditis, which is the consequence of some cancer therapies.”
Studying a checkpoint inhibitor myocarditis patient population or patients who present with hemodynamically significant myocarditis with LV dysfunction would certainly be a potential next step for Cardiol to consider, and the doctors responsible for conducting the trial are pointing in that direction. The company has yet to disclose plans for further clinical trials in detail, but it is clear that the door has not been closed on further trials focused on myocarditis.
Keep in mind that acute myocarditis is an orphan-drug-eligible indication, affecting a relatively small number of patients and meeting the requirements of the FDA’s Orphan Drug Designation (ODD). CardiolRx™ was granted the ODD for pericarditis and could pursue the designation for acute myocarditis. The ODD is designed to encourage development of treatments for rare diseases that might otherwise be overlooked, and offers benefits like extended market exclusivity, fee waivers, and tax credits.
Heart Failure Next Steps?
Heart failure is one of the most common and deadly forms of cardiac disease. Heart failure affects more than 64 million people globally. Over 6 million Americans over the age of 20 are living with heart failure, and this number is projected to increase to >8 million by 2030. Healthcare costs associated with heart failure exceed $30 billion annually in the U.S. alone.
Cardiol’s subcutaneous drug candidate, CRD-38, is in the pre-clinical stage of development for heart failure. Pre-clinical data demonstrates improvement in cardiac function and reductions in cardiac hypertrophy, remodeling, inflammation, and cell death – key underlying mechanisms in heart failure.
CRD-38 and CardiolRx™ share the same active ingredient, though CardiolRx™ is administered orally. The ARCHER trial results, which demonstrated a significant reduction in LVM, provide clinical evidence that CardiolRx™ mitigates inflammation-driven structural damage in the heart—aligning with Cardiol’s pre-clinical data and supporting the acceleration of CRD-38 to clinical trials for this substantially larger indication.
In a recent press release, CEO David Elsley says:
“As recruitment in our pivotal Phase III MAVERIC trial gains momentum, with several prominent centers across the U.S. now enrolling patients, we are pleased to have secured a direct investment of US$11.4 million to strengthen our balance sheet and accelerate the development of our novel heart failure drug, CRD-38, based on the recently reported findings from our ARCHER trial…
Notably, blockbuster drugs that reduce LV mass have been shown to lower heart failure-related death and hospitalization, underscoring the clinical potential of Cardiol’s differentiated anti-inflammatory mechanism to address a large unmet need in heart failure, where five-year mortality rates still exceed 50%.”
Of course, advancing a heart failure drug is a significantly more involved undertaking – especially in terms of trial size and complexity compared to developing a therapy for an orphan disease. From the recent ARCHER results conference call, Elsley explains Cardiol’s approach:
“We now have this translational moment where we’ve shown the active pharmaceutical ingredient deployed by both CardiolRx, and now the more next-generation, CRD ‘sub-Q’ 38 formulation. We now have this translation. So our key area of developmental focus is to accelerate the IND enabling work, which is ongoing now, to speed this next generation into Phase I development. And that’s really the point at which the pharmaceutical industry increases their interest.
We are in discussions currently with many members of the international pharmaceutical industry, with particular focus on those dominant in heart failure research. And their key interests lie in heart failure medicine. And that is why we’re excited to push this new drug forward and ultimately partner with them for its development in broader areas, with Cardiol staying focused on the key areas of the orphan designation programs, which is recurrent pericarditis and myocarditis.”
Investor Takeaway
3 Key Implications from the ARCHER Trial:
- The ARCHER results showed promise in treating acute myocarditis patients based on the significant reduction in LVM. Increased LVM is a hallmark of a range of serious heart conditions, and its reduction is a proven indicator of improved outcomes. Notably, the patient population for this trial was not selected for that attribute.
- Further clinical development is warranted along these lines, and Cardiol’s next milestone is focused on completing the fully-funded pivotal MAVERIC Phase 3 trial in patients with recurrent pericarditis.
- Cardiol already has a drug candidate, CRD-38, in the pre-clinical stage for heart failure, a massive indication. The findings of the human trial greatly reinforce the promising lab results and merit accelerated development.
Although the market’s initial response to Cardiol’s trial has been cautious, the results highlight promising structural improvements in the human heart, positioning CardiolRx™ as a potential game-changer for inflammatory heart conditions, offering hope for broader applications in cardiac care. CRDL stock closed on August 5 at $1.35/share. The next day the company announced topline results and the stock plummeted, closing down 21% at $1.07/share. The price still hasn’t recovered even since full results were announced on December 1, and the stock now trades around $1.00/share. Savvy investors may see that there is greater value to the implications of the results for Cardiol Therapeutics than meets the eye.
