Cytokinetics Inc. Investor update

Hello everyone. I'm Diane Weiser, Senior Vice President of Corporate Affairs. I'm pleased to welcome everyone to our investor event to discuss the primary results from ACACIA-HCM, the pivotal Phase III clinical trial of aficamten in non-obstructive HCM. Today's event is being hosted in a hybrid fashion. I'd like to welcome those here in the room with us in Munich, as well as those joining online. I'm pleased to introduce from Cytokinetics, Dr. Fady Malik, Stephen Heitner, and Robert Blum. I'm also thrilled to welcome three leading experts in HCM for our panel discussions today, Dr. Marty Maron, Dr. Ahmad Masri, and Dr. Christina Paitazoglou. Today's agenda will begin with Is it on the slide? We're going to pause for a minute. Turning to today's agenda, Fady Malik will provide some brief opening remarks.

Next, Doctors Masri and Maron will provide an encore presentation of the ACACIA-HCM results that were presented earlier today in the hotline session at the Congress. Then Steve will facilitate a panel discussion and Q&A session. Finally, Robert Blum will close us out providing some remarks. For those online, today's slides are available for download in the webcast. You can submit questions to the panel at any point during the event using the Ask a Question tab on the upper right-hand side of the webcast. For those in person, please raise your hand during the panel discussion to ask a question. Before I continue, as you can see on this slide, today's discussion will include forward-looking statements, which are subject to risks and uncertainties. Please refer to our SEC filings for a discussion of these factors. With that, I'll turn it over to Fady.

Thanks, Diane. I'm very pleased to be here alongside my colleagues and leading experts in HCM and the global cardiology community. Maybe we need to turn the mic off. As we share the primary results from ACACIA-HCM, the pivotal Phase III clinical trial of aficamten in patients with non-obstructive HCM. These results were just presented a short while ago in the hotline session at the Congress, and were accompanied by two simultaneous publications, one in the New England Journal of Medicine and one in the Journal Circulation. This is the first ever positive Phase III clinical trial in nHCM, and the results show that the treatment with aficamten was associated with statistically significant and clinically impactful improvements in both exercise capacity and symptom burden, as well as cardiac biomarkers.

As we'll discuss today, these results create the potential for aficamten to become the first and only cardiac myosin inhibitor to address the full spectrum of symptomatic HCM, offering the first therapy that may directly treat the underlying disease process of HCM. The response from the HCP community at the Congress today was overwhelmingly positive. It's clear these results are resonating, and there is genuine interest in what they could mean for the future in nHCM. Since sharing the top-line results earlier this summer, we've moved swiftly to preparing a supplemental new drug application that we plan to submit to FDA later this year for aficamten in nHCM. So we're extremely proud of these results and of the exemplary execution of this clinical trial.

To that end, I'd like to express my gratitude on behalf of Cytokinetics to the patients, to the families, investigators, and the study staff who helped conduct ACACIA-HCM. We thank you for your dedication. Now with that, I'll hand it over to Dr. Masri and Dr. Maron to present the primary results from ACACIA-HCM.

Dr. Masri. Thank you, Dr. Malik, and hi, everyone here and online.

I'll present the primary results of ACACIA-HCM. All right. Everyone who's been involved in the trial. Non-obstructive HCM is a common condition. It affects a lot of patients with hypertrophic cardiomyopathy, and it leads to reduction in exercise capacity and development of progressive symptoms. There are currently no available therapies that have proven to be effective in this disease. Aficamten, which many of you are aware, is available in obstructive HCM in many jurisdictions, has favorable effects on diastolic function, as well as a whole host of other key areas that are involved in HCM pathophysiology. Aficamten has favorable pharmacological profile, which allows for rapid uptitration and dose adjustment with good tolerability. This is the design of the trial. Probably you've seen this before. Patients with symptomatic non-obstructive HCM were randomized to aficamten versus placebo.

517 total patients, 1 to 1 randomization. Aficamten dose range was 5 to 20 milligrams. All the patients were followed up to 72 weeks in a blinded fashion with a four-week withdrawal period. The study continued until the last patient crossed week 36. In terms of our study visits and assessments, they are listed up there to the left of the screen. We've conducted for the dual primary endpoint. The KCCQ assessment was done in every visit, but the peak VO2 and cardiopulmonary exercise tests were only done at baseline and at week 36. Here are our endpoints. The primary dual primary endpoint changed from baseline to week 36 in KCCQ Clinical Summary Score, as well as peak VO2.

The secondary endpoints were tested in a hierarchical fashion, going from baseline week 36 in NYHA class, Z-score, which includes both maximal and submaximal exercise metrics, NT-proBNP change, left atrial volume index, and time to first composite cardiovascular event. Safety outcomes typical of a myosin inhibitor trial, where we looked at LVEF heart failure. Something really important to note, which is unique to aficamten at this stage, is that patients who get EF between 40% and 50% due to us pushing the dose higher, they can get down titrated while staying on the drug without a drug holiday interruptions that are mandated. Per protocol, only those with EFs less than 40% have to interrupt the therapy. They can be restarted on it, but they have to interrupt the therapy. These are all baseline characteristics. Again, as I mentioned, 1 to 1 randomization, 258 aficamten, 259 placebo.

This is a really, in my opinion at least, well-conducted study. The reason behind that, if you look at how many patients had family history of hypertrophic cardiomyopathy or pathogenic, likely pathogenic variant for the disease, two-thirds of them did. This is different from when you look at any patient with LVH. This was a study conducted to enroll such patients. 75% of them were on beta blockers, and they were highly symptomatic with reduced KCCQ scores. A third of them had NYHA Class III. Biomarkers were elevated, and peak VO2 was significantly reduced. Here are the primary results. The first of the dual primary endpoint is KCCQ. The primary endpoint was aligned at week 36 for KCCQ and peak VO2. As you can see, the difference was 3 points at week 36 between aficamten and placebo in favor of aficamten with a P value of 0.021.

What you see here is that aficamten, beyond week 12, consistently improved KCCQ Clinical Summary Score. At each time point, aside from week 336, you have a difference that varies from 4.8 to 7 points, including the end of treatment, which every patient in the trial is supposed to go out at the end of the treatment from the trial, 5.6 points difference. During washout, these scores within 4 weeks were reduced back to similar to placebo without any difference. The reason behind what you see here is the fact that placebo patients had fluctuations in their benefit as it reflects on KCCQ, which you can see clearly here between, for example, week 24, 36, 48, and end of the treatment. The second dual primary endpoint was peak VO2.

Aficamten influenced positively peak VO2 with a difference of 0.67 ml per kilogram per minute with a P value of 0.003. If you look at many pre-specified subgroup analysis, the treatment effect on both KCCQ and peak VO2 was consistent. We here highlight to you some of the groups that some might feel are important, including beta blockers, intracavitary obstruction, and genotype status. As I mentioned during the presentation, I walked into the trial thinking we might end up having a super responder or a less responder group. The reality is, when you look at the pre-specified analysis here, most of these patients have derived the same degree of benefit, all in favor of aficamten.

In terms of NYHA class, which is the first of the secondary endpoints tested in a hierarchical fashion, throughout the trial, you had more in favor of aficamten improvement NYHA class by one class or more. At week 36, it was 14% difference with a P value of less than 0.001. This is the Z-score. It is a slightly complicated thing to explain, but the bottom line is it is a comprehensive exercise metric where you have one exercise metric for maximal exercise tolerance that the patient can achieve, and one is for submaximal exercise, which is what a lot of the patients do from day to day. They operate at the submaximal level, which is called ventilatory efficiency or VE/VCO2. Aficamten positively affected VE/VCO2 with minus 0.91. With VE/VCO2 slope, lower is better. With peak VO2, higher is better.

That translated obviously into a positive result on the Z-score with statistical significance. NT-proBNP was affected favorably from the first visit, follow-up visit that the patient had, continued to decline throughout the titration period, and stayed stable with the washout showing you how there is a quick rebound there. Slides are not advancing. All right. Sometimes the question come, what is the significance of having reduction in NT-proBNP or elevation in NT-proBNP? This is a recent study that we actually have been conducting for more than a decade now. It's an NIH-funded study, HCM registry or HCMR, showing that a really important predictor of outcomes in hypertrophic cardiomyopathy is NT-proBNP.