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Unproven Upside Potential For MyoKardia's Mavacamten

May 04, 2020 12:34 PM ETMyoKardia, Inc. (MYOK)3 Comments
WS BioPharma Wolf profile picture
WS BioPharma Wolf


  • Mavacamten’s Phase III trial in obstructive hypertrophic cardiomyopathy (oHCM) is likely to meet its primary endpoint, but we believe the market has priced in most of it.
  • The result of Mavacamten’s Phase II trial in non-obstructive HCM, the MAVERICK, is something we actually see as negative.
  • Mavacamten’s potential in non-oHCM, and the further “heart failure with preserved ejection function”, or HFpEF population is unproven.

Hypertrophic cardiomyopathy ("HCM") is a genetic heart disease mostly caused by mutations in one of the many sarcomeric genes. The most prevalent mutations include genes encoding myosin heavy chain (~30% of the HCM patients), myosin-binding protein C (~20% of the HCM patients), and cardiac troponin T (~20%). The exact mechanism of how these mutations lead to HCM still remains unclear, but pathological pathways may include increased sarcomeric contractility, altered calcium cycling and sarcomeric calcium sensitivity, disturbed biomechanical stress sensing, and impaired cardiac energy homeostasis. Those impacted pathways lead to establishment of clinical manifestation including left ventricular ("LV") hypertrophy, deranged cardiomyocyte energetics, diastolic dysfunction, microvascular ischaemia, enhanced myocardial fibrosis, and multifactorial arrhythmias, which further result in physiological symptoms such as dyspnea, fatigue, chest pain, limited exercise capacity and increased rate of sudden cardiac death ("SCD"). Current or potential targets of pharmacologic therapies for HCM cover wide range of those pathways (Fig. 1), with each having their own limitations.

Figure 1. Targets of pharmacologic therapies for HCM. (Source: Internet)

Being a monogenic, autosomal-dominant genetic disease, HCM is the most common hereditary heart disease with an estimated prevalence of 1:500 in US, resulting in a 700k affected population. However, only a small portion (15%~20%) of HCM patients are clinically diagnosed, with vast majority lacking clear or self-aware symptoms. Current diagnostic methods include echocardiography (ECG), cardiac catheterization, cardiac MRI, genetic testing and trace of family history of HCM. HCM also has a high degree of phenotypic heterogenicity. In fact, it is further classified into two subgroups: obstructive HCM (oHCM) and non-obstructive HCM. Obstructive HCM is usually defined by HCM patients who have a resting or provoked peak left ventricular outflow track gradient (LVOT) of at least 30 mm Hg. Obstructive HCM takes about 70% of all HCM cases.

Myokardia’s leading asset, mavacamten is an allosteric

This article was written by

WS BioPharma Wolf profile picture
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Comments (3)

"Mavacamten’s Phase III trial in obstructive hypertrophic cardiomyopathy (oHCM) is likely to meet its primary endpoint, but we believe the market has priced in most of it."

Looks like Mr Market doesn't agree. I'm closing out my position as I don't see additional upside catalysts anytime soon.
WS BioPharma Wolf profile picture
Thanks for the comment. The outcome is much better than expected - almost a best case scenario, which I gave a price estimate of $95/share in the article. There was no EF related drop out. In addition, all secondary endpoints were met. Big congrats to Myokardia's management team.
However, I still think such a near-perfect oHCM readout does not necessarily translate to non-oHCM or HFpEF potential. Further, I suspect a possible dilution could be in the near term. Closing out position now may indeed be a wise move.
Bernardo Garcês profile picture
Interesting perspective.

I have, however, found it lacking in the extent to which you neglected to mention certain data points crucial for an informed decision on Myokardia's so-called "unproven upside potential".

Most gravely, you failed to address the results reported from both the PIONEER and the OLE studies hinting at a fundamental change in the heart's structure over time, essentially bringing it back to a "normal state" (as measured by several parameters). Furthermore, the clinical benefit provided by mava is nothing short of ground-breaking compared to that of the current SoC by any measure - the purported proven effect of BBs is far more tenuous than the article would lead us to believe (as hinted at by the 18-patient study cited).

On the safety front, I can see you have taken some liberties in your analysis of the available data. Specifically, your claims surrounding the effect on AF (5 patients' worth, in a dosing-ranging study no less), coupled with the suggestion of a boxed warning, are particularly amusing taken in the context of mava's pristine safety record in several studies to date (namely the OLE study, whose dosing is similar to EXPLORER's) and data on mava's effect on LA vol index (a predictor of AF), for example.

In the spirit of keeping it breezy, I shall lastly mention that MAVERICK did show a statistically significant improvement in NT-proBNP in all patients, which extended to other efficacy measures in pre-specified patient populations - which is consistent with the company's precision medicine approach. A far cry from a failure, I would argue.

Having said this, I certainly appreciate the use of a quantitative model to justify your perspective on the company's current valuation; and the commentary on BMI variability.

I thoroughly enjoyed reading your article.
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