Bristol Myers Squibb statement on ICER mavacamten evidence report

Bristol Myers Squibb today released the below statement following the issuance of a report from the Institute for Clinical and Economic Review (ICER), which examined the clinical effectiveness of mavacamten in its determination of pricing recommendations:

Mavacamten is an investigational first-in-class myosin inhibitor that, if FDA approved, will fill a critical unmet need for patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) by targeting the underlying cause of the disease.

The Institute for Clinical and Economic Review’s assessment of mavacamten is premature and its inappropriate choice of treatment comparators and omission of critical public data undermine the credibility of the evidence report. ICER’s incomplete and misleading assessment of this medicine’s value to patients and the health care system is evidenced by the following:

• The Institute for Clinical and Economic Review’s assessment of mavacamten is premature given the rapidly-evolving body of scientific evidence for mavacamten, as the MAVA-LTE,¹ PIONEER-OLE,² and VALOR-HCM³ clinical studies are still ongoing.
• Even within the specified criteria of this review, ICER’s methods remain fundamentally flawed, as it compares later-line treatments, disopyramide and septal reduction therapies, to mavacamten. ICER disregarded current American Heart Association/American College of Cardiology (AHA/ACC)⁴ and European Society of Cardiology (ESC)⁵ guideline recommendations to generally reserve invasive therapies for patients with higher symptom burden (New York Heart Association functional classes III/IV) and overlooked the absence of data necessary for a methodologically rigorous comparative assessment of these therapies.
• Furthermore, the review ignores well-documented epidemiological evidence on mortality and disease progression in obstructive HCM.*

BMS, along with other external stakeholders, asked that these shortcomings and limitations be addressed.

At BMS, we establish the value of our medicines using a holistic, evidence-based approach that incorporates patient priorities, total health system benefit, multi-stakeholder input and the most up-to-date clinical evidence.

* - As seen in the literature, mortality risk increases with higher NYHA functional class in HCM and obstructive HCM.^6-14 The ICER base case model assumed there is no difference in mortality risk by NYHA class. While ICER’s scenario analysis attempted to account for this difference in mortality risk, the hazard ratio was based on a study where the majority of patients had non-obstructive disease.⁸ It is well-known that the mortality risks are different for obstructive and non-obstructive HCM.^4,8,13 BMS had previously shared with ICER mortality data by NYHA class in obstructive HCM from BMS-sponsored research in partnership with the Sarcomeric Human Cardiomyopathy Registry (SHaRe); this mortality data was not included in the ICER scenario analysis.¹⁵ Additionally, ICER did not account for the natural disease progression of obstructive HCM that will likely continue over the lifetime of the patient population in the model, particularly if the patients are treated on standard first-line pharmacologic therapy alone.^4,13

BMS provided a public response statement to ICER at its October 22, 2021, California Technology Assessment Forum (CTAF) meeting.
The statement can be found here.

BMS provided a written summary to ICER for its Final Evidence Report and Meeting Summary. The BMS summary can be found here.

On February 16, 2022, data was released from VALOR-HCM, the Phase 3 randomized, double-blind, placebo-controlled study evaluating mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy (obstructive HCM) who are eligible for septal reduction therapy (SRT), showing it met its primary endpoint at Week 16. 

• On April 2, data was released from the Phase 3 VALOR-HCM study, which showed the addition of mavacamten, an investigational, first-in-class cardiac myosin inhibitor, significantly reduced the need for septal reduction therapy (SRT) in patients with severely symptomatic obstructive hypertrophic cardiomyopathy (obstructive HCM) who had been appropriate for SRT per the 2011 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines at baseline. Study participants were on maximally tolerated background regimens when they entered the trial and remained on them through the duration of the study
• On April 3, data was released from the EXPLORER-LTE cohort of the MAVA-LTE study (NCT03723655), the largest and longest evaluation of mavacamten, an investigational, first-in-class cardiac myosin inhibitor, in patients with symptomatic obstructive hypertrophic cardiomyopathy (obstructive HCM). These data showed sustained improvements in cardiovascular outcomes at 48 and 84 weeks.

References

1. Clinicaltrials.gov. A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed MAVERICK-HCM or EXPLORER-HCM. Accessed September 15, 2021. https://clinicaltrials.gov/ct2/show/NCT03723655
2. Clinicaltrials.gov. Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER (PIONEER-OLE). Accessed September 15, 2021. https://clinicaltrials.gov/ct2/show/NCT03496168
3. Clinicaltrials.gov. A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy (VALOR-HCM). Accessed September 15, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04349072
4. Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. Dec 22 2020;76(25):e159-e240. doi:10.1016/j.jacc.2020.08.045
5. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. Oct 14 2014;35(39):2733-79. doi:10.1093/eurheartj/ehu284
6. Elliott PM, Gimeno JR, Tomé MT, et al. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J. Aug 2006;27(16):1933-41. doi:10.1093/eurheartj/ehl041
7. Coats CJ, Rantell K, Bartnik A, et al. Cardiopulmonary Exercise Testing and Prognosis in Hypertrophic Cardiomyopathy. Circ Heart Fail. Nov 2015;8(6):1022-31. doi:10.1161/circheartfailure.114.002248
8. Liu Q, Li D, Berger AE, Johns RA, Gao L. Survival and prognostic factors in hypertrophic cardiomyopathy: a meta-analysis. Sci Rep. Sep 20 2017;7(1):11957. doi:10.1038/s41598-017-12289-4
9. Ntusi NA, Shaboodien G, Badri M, Gumedze F, Mayosi BM. Clinical features, spectrum of causal genetic mutations and outcome of hypertrophic cardiomyopathy in South Africans. Cardiovasc J Afr. May/Jun 2016;27(3):152-158. doi:10.5830/CVJA-2015-075
10. Nasermoaddeli A, Miura K, Matsumori A, et al. Prognosis and prognostic factors in patients with hypertrophic cardiomyopathy in Japan: results from a nationwide study. Heart. Jun 2007;93(6):711-5. doi:10.1136/hrt.2006.095232
11. Spirito P, Autore C, Rapezzi C, et al. Syncope and risk of sudden death in hypertrophic cardiomyopathy. Circulation. Apr 7 2009;119(13):1703-10. doi:10.1161/CIRCULATIONAHA.108.798314
12. Xiao Y, Yang KQ, Yang YK, et al. Clinical Characteristics and Prognosis of End-stage Hypertrophic Cardiomyopathy. Chin Med J (Engl). Jun 5 2015;128(11):1483-9. doi:10.4103/0366-6999.157656
13. Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. Jan 23 2003;348(4):295-303. doi:10.1056/NEJMoa021332
14. Cui H, Schaff HV, Geske JB, et al. Early septal reduction therapy for patients with obstructive hypertrophic cardiomyopathy. J Thorac Cardiovasc Surg. Oct 28 2020;doi:10.1016/j.jtcvs.2020.10.062
15. Lakdawala N, Saberi S, Day S. New York Heart Association Functional Class and Mortality in Obstructive Hypertrophic Cardiomyopathy. 2021:

Updated April 2022