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Cytokinetics, Incorporated (NASDAQ:CYTK) is gearing up to complete its rolling NDA submission of aficamten for the treatment of patients with obstructive hypertrophic cardiomyopathy [oHCM] in Q3 of 2024. This presents itself as an opportunity because the announcement of the completion of such a rolling submission could yield a higher stock price. Not only that, but from there if the FDA accepts this regulatory application for review, this sets up the ability for an established PDUFA date for review of aficamten for the treatment of this patient population. However, why investors should care about this biotech because there are two pathways to consider for advancement.
That is, aficamten with positive data from the phase 3 SEQUOIA-HCM plus the rolling NDA submission, leads to several other expansion opportunities in two areas. The first of which would be through expanding to other types of HCM such as pediatric patients with oHCM and then adults with non-obstructive hypertrophic cardiomyopathy [nHCM]. If this is one pathway to expand into the HCM in terms of patient populations, then what other opportunities are possible? Well, the rolling NDA of aficamten is only one regulatory application.
There are two other planned regulatory applications of this drug for the treatment of adults with oHCM expected this year. One is the Marketing Authorization Application [MAA] to be submitted to the European Medicines Agency [EMA] and then there is another NDA submission to the National Medical Products Administration [NMPA] in China as well. As far as omecamtiv mecarbil for the treatment of patients with heart failure with reduced ejection fraction [HFrEF] goes, there are plans to get this program going again with a new phase 3 study to be initiated in Q4 of 2024. With the rolling submission of aficamten for adults with oHCM underway, plus the several expansion opportunities discussed above, I believe that investors could benefit from any potential gains made.
Aficamten Rolling NDA Submission Leads To Potential For FDA Review Date
As I noted directly above, aficamten was explored in the ongoing phase 3 SEQUOIA-HCM study, treating adults with obstructive hypertrophic cardiomyopathy [oHCM]. Before going over this specific program of aficamten, it is first important to understand what HCM is and what the possible market opportunity for it could be. Hypertrophic Cardiomyopathy [HCM] is a type of disorder where the left ventricle of the heart becomes thickened and stiff. Why is this bad? Well, the left ventricle of the heart is the main pumping chamber of the heart. Thus, when HCM is present, it leads to not enough blood flow being able to get in and out of the left ventricle. Most patients with this disorder can do pretty well long-term, but the problem is that there is a small group of patients who are at risk of heart failure or sudden death. Now, what about non-obstructive hypertrophic cardiomyopathy [nHCM]? In essence, in this instance, there is still stiffening of the left ventricle wall, but no significant blocking of blood flow. This is still a major issue because wall thickening reduces the amount of blood held in the left ventricle chamber to pump to the rest of the person’s body. The global hypertrophic cardiomyopathy market is expected to reach $1.63 billion by 2030. This is a considerable market opportunity and the hope is that Cytokinetics will be able to target all the patients.
The rolling NDA submission was possible thanks to results from the phase 3 SEQUOIA-HCM study, as noted directly above. This trial recruited up to a total of 282 patients who were randomized to receive one of four doses of aficamten or placebo. The primary endpoint of this late-stage study was to assess peak oxygen uptake [pVO2] measured by cardiopulmonary exercise testing [CPET] from baseline to week 24 of the drug compared to the placebo. This primary endpoint was met, in that treatment with aficamten resulted in a significant improvement of exercise capacity compared to the placebo. This endpoint was met with statistical significance with a p-value of p = 0.000002. To view this in terms of exercise capacity levels, this was the finding:
- Aficamten – increased pVO2 uptake of 1.8 ml/kg/min.
- Placebo – increased pVO2 uptake of 0.0 ml/kg/min.
This drug is highly ideal for these oHCM patients. Why is that? Not only was this drug able to meet the primary endpoint to help patients in terms of peak oxygen uptake [which was necessary to be met for FDA review], but all secondary endpoints were met with statistical significance for this SEQUOIA-HCM trial as well. Matter of fact, there were 10 secondary endpoints where aficamten was able to beat out the placebo, all of which were statistically significant with a p-value p<0.0001. The completion of the rolling NDA submission is expected in Q3 of 2024. This program advancement sets up a few catalysts for investors to look forward to. The first of which is that upon completion of submission, the company could receive confirmation thereafter that the regulatory application of aficamten has been set for review with a specific PDUFA date. From there, the actual PDUFA date itself becomes a catalyst as well, because that is the time by which the FDA would decide upon whether this drug should be approved for symptomatic oHCM patients.
Below, I will go over several of the expansion opportunities I described at the beginning of this article. However, in this instance, I want to go over the ability that the company could achieve in terms of possibly getting its drug aficamten to be used as a first-line treatment for patients oHCM. The use of this drug is being explored in the phase 3 MAPLE-HCM study. In essence, anti-beta blocker metoprolol is typically used as a standard of care [SOC] for these HCM patients. The goal here is to see if aficamten as a monotherapy ends up being superior to metoprolol as a monotherapy in symptomatic oHCM patients. A successful trial of this caliber could provide the possibility to become the new SOC treatment option for these patients.
For now, the timeline for this program is that enrollment completion of this phase 3 MAPLE-HCM trial is expected in Q3 of 2024. The estimated primary completion date for this study is around July 2025. This means before the end of 2025, it is quite possible that data could be released from this particular late-stage 1st-line adult oHCM study.
Expansion Opportunities For Aficamten In Terms Of Other Territories
The thing is that the NDA submission of aficamten for the treatment of adults with oHCM is only the beginning. There was already a meeting with European regulators to discuss the potential of bringing this drug to adult oHCM patients in Europe. Having said that, a Marketing Authorization Application [MAA] to the European Medicines Agency [EMA] of this drug for this patient population is expected in Q4 of 2024. In addition to this, the company is coordinating with Ji Xing Pharmaceuticals to be in a position to submit an NDA of aficamten to the Center for Drug Evaluation [CDE] of the National Medical Products Administration [NMPA] in China. The submission of a regulatory application for the China territory is expected in the 2nd half of 2024. Both of these expected regulatory application submissions are key to expanding the use of aficamten for adults with oHCM in other territories.
Expansion Of Aficamten Goes Beyond Territorial Move
The thing is that Cytokinetics is not only pushing forward with aficamten in only targeting adults with obstructive hypertrophic cardiomyopathy [oHCM]. It is in the process of running a few other studies, which, if successful, would allow the company to use this drug for other patient populations in the HCM space. For instance, it is in the process of running the phase 3 CEDAR-HCM study. What population is this trial going to cover? If it is going to target pediatric patients with oHCM. This trial is being set up so that eventually aficamten can also be used in pediatric patients. While it remains to be seen how this study turns out, it is another good expansion towards a younger patient oHCM patient population. However, it is important to note that the pediatric patient population being explored are those who are between the ages of 12 to 18.
For all the studies I discussed above, they are all in terms of using aficamten to target oHCM patients. What about the other side of the coin, in targeting another subpopulation of HCM? This is where another possible expansion opportunity exists. This is with the ongoing phase 3 ACACIA-HCM study, which is looking to treat patients with non-obstructive hypertrophic cardiomyopathy [nHCM]. The primary endpoint for this trial will be the change in the Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score or KCCQ-CSS. This efficacy endpoint is going to evaluate aficamten versus placebo from baseline to week 36. Remember, while these patients do not have significant blocking of blood flow, they still suffer from left ventricular wall thickening. This in turn still results in a multitude of symptoms for these patients. Enrollment completion for this ACACIA-HCM study is expected in 2025.
Financials
According to the 10-Q SEC Filing, Cytokinetics had cash, cash equivalents, and investments of $1.4 billion as of June 30th, 2024. The reason for the cash on hand is that it was able to bring additional cash into its coffers. The first transaction was the public offering of 11,274,510 shares of common stock, plus the underwriters’ exercise in full to purchase additional shares. With this offering, it raised total net gross proceeds of $563.2 million. Another move it made was to establish a funding collaboration agreement with Royalty Pharma. This deal is expected to bring in up to $575 million to support the commercialization of aficamten for the treatment of adults with oHCM.
In addition, this deal makes note of another pipeline product that Royalty was interested in, which is CK-586. This drug is a cardiac myosin inhibitor being developed for the treatment of patients with heart failure with preserved ejection fraction [HFpEF]. Primary data from this trial is expected in Q3 of 2024 and then a phase 2a study targeting this patient population is expected to begin in Q4 of 2024.
Risks To Business
There are several risks that investors should be aware of before investing in Cytokinetics. The first risk to consider would be regarding the NDA rolling submission of aficamten for the treatment of adults with oHCM to the FDA. There is no assurance that the FDA will accept the rolling NDA submission in its present form. In this case, this could end up being a setback for it for an extended period of time. Even if the rolling NDA is accepted for review, there is no assurance that the FDA is going to approve the drug for the treatment of this patient population.
The second risk to consider would be the potential to move aficamten forward as a first-line treatment for adults with oHCM. There is no assurance that this drug alone as a monotherapy will be able to beat anti-beta blocker metoprolol in the ongoing phase 3 MAPLE-HCM study. If this study fails to deliver, then it could cause the stock price to trade lower considerably.
The third risk involves the expansion opportunities discussed above in terms of moving aficamten forward toward other territories and other subpopulations of HCM. While the drug has shown to work well in adult oHCM patients, there is no assurance that it will also work for the pediatric patient population. Nor, that it will work well in patients with nHCM. In addition, the ability to receive regulatory approvals of aficamten for oHCM in other territories highly depends upon each regulatory body. There is no guarantee that this company will eventually be able to expand the use of this cardiac myosin inhibitor in most or several of these other territories.
The fourth and final risk would be in terms of the development of omecamtiv mecarbil for the treatment of patients with heart failure with reduced ejection fraction [HFrEF]. The company has suffered many setbacks for this program since the Complete Response Letter [CRL] was given by the FDA for it. However, there is a chance for a comeback in terms of potentially showing the effectiveness of this drug with a new confirmatory trial. Thanks to a Type C FDA meeting held, there was a discussion about what the confirmatory trial should entail so that the effectiveness of this drug can be shown in being able to treat this patient population. If all goes according to plan, a phase 3 confirmatory study for this program is expected to start in Q4 of 2024. The risk here is that even though there was a positive discussion outcome with the FDA for this late-stage study, there is no assurance that it will still be enough to eventually warrant U.S. marketing approval.
Conclusion
Cytokinetics has done well to advance its other drug known as aficamten for the treatment of patients with oHCM. The rolling NDA submission of this drug is underway for this patient population and if all goes according to plan, it should be completed sometime during this quarter. As I stated above, this regulatory submission to the FDA brings about a few other catalyst opportunities for investors to look forward to. As long as this first HCM target goes well, this opens the door to go after other HCM subpopulations. This would be a good thing, especially since the global hypertrophic cardiomyopathy market is expected to reach $1.63 billion by 2030.
While aficamten is one cardiac myosin inhibitor, there is another one being advanced by the company, known as CK-586. As I stated briefly above, this is gearing up to be explored in a phase 2a study for the treatment of patients with heart failure with preserved ejection fraction [HFpEF]. But before then, during this quarter, it is expected that primary results from this phase 1 study will be released. Lastly, I want to end on the note that there might be an opportunity to possibly receive regulatory approval for omecamtiv mecarbil for the treatment of patients with heart failure with reduced ejection fraction [HFrEF]. A phase 3 confirmatory trial is expected to begin in Q4 of 2024, but the downside is that such a study could take a few years to complete.
