Olivotto, Iacopo

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European Heart Journal - Cardiovascular Pharmacotherapy (2024) 0 , 1–2 https://doi.org/10.1093/ehjcvp/pvae086CORRESPONDENCE Pharmacogenetic testing to broaden patient eligibility for mavacamten Lorenz Van der Linden 1 , ∗, Lucas Van Aelst 2 , and Iacopo Olivotto 3 1 Hospital Pharmacy Department, UZ Leuven & Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; 2 Department of Cardiology, UZ Leuven & Department of Cardiovascular Sciences, KU Leuven, Leuven 3000, Belgium; and 3 Division of Cardiology, Meyer Children’s Hospital, IRCCS, Florence 50139, Italy Received 9 August 2024; revised 1 October 2024; accepted 12 November 2024; ; online publish-ahead-of-print 14 November 2024                                      doses, as well as how to manage drug-drug interactions.5 , 7 Poor metabolizers ( PMs) , who have two loss-of-function alleles ( *2/*2, *2/*3, *3/*3) , have a significantly longer t½ of mavacamten ( 533 h) compared to extensive metabolizers ( 72 h) and intermediate metabo- lizers ( 150 h) .5 , 7 Compared to non-PMs, PMs exhibit a 241% increase in total plasma exposure of mavacamten. Hence, according to EMA, PMs will achieve similar exposure with 5 mg once daily at a steady state compared to non-PMs who receive 15 mg.5 CYP2C19 status also guides drug-drug interaction management ( Figure 1 ) . Mavacamten is metabolized by both CYP3A4/5 and CYP2C19, the degree of which is determined by CYP2C19 st atus .1 , 7 Strong inhibitors can significantly increase mavacamten levels, potentially causing adverse effects such as a reduced LVEF or heart failure symptoms. Regulatory agencies classify this strength based on its impact on the exposure of selected probes, e.g. midazolam for CYP3A4.10 For mavacamten, we should be mostly concerned with CYP2C19 and/or CYP3A4/5 inhibitors that can raise mavacamten exposure by more than five-fold ( = strong) or two- to five-fold ( = moderate) .10 In CYP2C19 PMs, the focus should be on drug-drug interactions with CYP3A4/5 inhibitors and inducers, as CYP2C19 does not play a major role in these patients. Among non-PMs, interactions with both CYP2C19 and CYP3A4/5 inhibitors need consideration. If CYP2C19 status is unknown, dosing defaults to the most conservative scneario.2 Since PM status is rare in Europe, most clinically relevant interactions involve CYP2C19 inhibitors, which are less common and can be summarized in concise lists ( Figure 1 ) .5 Mavacamten presents an interesting case study for the role of pharmacogenetics. While FDA and EMA differ on dosing recommen- dations, pharmacogenetic testing does broaden patient eligibility for mavacamten in terms of allowed comedications. EMA offers spe- cific guidance on co-administering mavacamten with CYP2C19 and CYP3A4 inhibitors/inducers, depending on CYP2C19 st atus , facili- tating a more tailored and potentially safer treatment approach.2 Conversely, the FDA’s REMS program currently contraindicates the use of certain CYP2C19 and CYP3A4 inhibitors and inducers.9 In the future, if real-world data robustly confirm the favourable safety profile of mavacamten in oHCM, systematic CYP2C19 testing might still be waived given the low prevalence of PM status in Europe and the growing clinical trial and modelling data supporting the clinical and imaging-guided approach.4 , 7 Society of Cardiology.Downloaded from https://academic.oup.com/ehjcvp/advance-article/doi/10.1093/ehjcvp/pvae086/7900758 by UNIVERSITA' FIRENZE-DIP.FISIOPATOLOGIA CLINICA.SEZ.RADIOTERAPIA user on 18 DecThe European Medicines Agency ( EMA) approved mavacamten in June2023 for the treatment of symptomatic obstructive hypertrophic car-diomyopathy ( oHCM) .1 , 2 Clinical trials have demonstrated its efficacyin improving exercise capacity, reducing the left ventricular outflowtract ( LVOT) gradient, and alleviating symptoms, and decreases theneed for invasive septal reduction therapies.3 , 4 Given that pharmacists may lack access to patients’ full medicationlists, it falls on cardiologists to ensure mavacamten’s appropriate use.Pharmacogenetics affects both dosing of mavacamten and its interac-tion with other medications, a critical consideration that cardiologistsshould be aware of. We have hence summarized key pharmacokinetic( PK) information to guide prescribers on EMA-recommended dosing,particularly concerning comedications ( Figure 1 ) .2 Mavacamten has high oral bioavailability ( 90–100%) and undergoesfirst-pass metabolism ( CYP3A4/5) , resulting in an exposure of ∼85%with peak concentration at 1 h.5 It exhibits a large volume of dis-tribution ( 114–206 L) with high protein binding ( 93%) . The drug’selimination half-life ( t½) ranges from 3 to 23 days, with significantaccumulation during initiation ( up to 7.5-fold) . It is primarily me-tabolized by CYP2C19 ( 74%) , CYP3A4 ( 18%) , and CYP2C9 ( 8%)contribute minimally. Inactive metabolites are cleared renally.6 , 7 Dueto its long t½ and substantial interindividual PK/pharmacodynamicvariability, slow uptitration, and regular follow-up are recommended,including the monitoring of left ventricular ejec tion frac tion ( LVEF) forsafety and LVOT gradient for efficacy.1 , 6 Different dosing approaches have been evaluated. PIONEER-HCM( n = 21) identified a concentration-dependent effect on LVOT ob-struction, with a proposed target range of 350–700 ng/mL. Plasmaconcentrations of ≥1000 ng/mL were associated with LVEF reduc-tions ( n = 4) , which recovered after discontinuing mavacamten.8 InEXPLORER-HCM ( n = 251) , a stepped dosing approach was applied.There were no instances where mavacamten therapy was halteddue to concentrations of ≥1000 ng/mL. VALOR-HCM ( n = 108)omitted plasma monitoring altogether, focusing instead on clinical andechocardiographic follow-up.4 This has been adopted by the US Foodand Drug Agency ( FDA) as part of their Risk Evaluation and MitigationStrategies ( REMS) program for mavacamten.9 Conversely, the EMAmandates determining CYP2C19 status as part of a pharmacogeneticdosing strategy.2 CYP2C19 metabolizing status is a critical determinant of mava-camten dosing and exposure, guiding both starting and maximum∗ Corresponding author. Tel: + 003216343080, Email: lorenz.vanderlinden@uzleuven.be© The Author(s) 2024. Published by Oxford University Press on behalf of the EuropeanAll rights reserved. For permissions, please e-mail: journals.permissions@oup.com ember 20242 Letter to the EditorFigure 1 Management of drug-drug interactions with mavacamten. Abbreviations: PM, poor met abolizer ; non-PM, non-poor metabolizer. FT  LC  B  r  T  f  i  DNR                               1  ©ADownloaded from https://academic.oup.com/ehjcvp/advance-article/doi/10.1093/ehjcvp/pvae086/7900758 by UNIVERSITA' FIRENZE-unding his work was supported by a clinical research grant, provided by UZeuven ( to L.V.D.L.) . onflict of interest : L.V.D.L. reports payment to the institute byMS. L.V. A . served on a scientific advisory board for BMS. I.O. reportsesearch grants from BMS, Cytokinetics, Amicus, Genzyme, Shireakeda, Menarini International, Chiesi, Boston Scientific; personal feesrom BMS, Cytokinetics , Amicus , Genzyme, Shire Takeda, Menarininternational, Chiesi, Boston Scientific, Tenaya, Rocket Pharma, Lexeo.at a ava ila bilit y o data were generated or analysed for this article. eferences 1. Braunwald E, Saberi S, Abraham TP, Elliot t PM, Olivot to I. Mavacamten: a first-in-class myosin inhibitor for obstructive hypertrophic cardiomyopathy. Eur Heart J2023; 44 :4622–4633. 2. European Medicines Agency. Camzyos: EPAR—product information.https://www.ema.europa.eu/en/documents/product-information/camzyos-epar-product-information_en.pdf ( accessed 1 October 2024) . 3. Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, SaberiS, Lakdawala NK, Wheeler MT, Owens A, Kubanek M, Wojakowski W, Jensen MK,Gimeno-Blanes J, Afshar K, Myers J, Hegde SM, Solomon SD, Sehnert AJ, Zhang D,Li W, Bhattacharya M, Edelberg JM, Waldman CB, Lester SJ, Wang A, Ho CY, JacobyD, Bartunek J, Bondue A, Van Craenenbroeck E, Kubanek M, Zemanek D, JensenM, Mogensen J, Thune JJ, Charron P, Hagege A, Lairez O, Trochu J-N, Axthelm C,Duengen H-D, Frey N, Mitrovic V, Preusch M, Schulz-Menger J, Seidler T, Arad M,Halabi M, Katz A, Monakier D, Paz O, Viskin S, Zwas D, Olivotto I, Brunner- L a RoccaThe Author( s) 2024. Published by Oxford University Press on behalf of the European Societll rights reserved. For permissions, please e-mail: journals.permissions@oup.comDIP.FISIOPATOLOGIA CLINICA.SEZ.RADIOTERAPIA user on 18 DecHP, Michels M, Dudek D, Oko-Sarnowska Z, Oreziak A, Wojakowski W, CardimN, Pereira H, Barriales-Villa R, García Pavia P, Gimeno Blanes J, Hidalgo Urbano R,Rincón Diaz LM, Elliott P, Yousef Z, Abraham T, Afshar K, Alvarez P, Bach R, Becker R,Choudhury L, Fermin D, Jacoby D, Jefferies J, Kramer C, Lakdawala N, Lester S, MarianA, Masri A, Maurer M, Nagueh S, Owens A, Owens D, Rader F, Saberi S, Sherrid M,Shirani J, Symanski J, Turer A, Wang A, Wever-Pinzon O, Wheeler M, Wong T, YamaniM. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomy-opathy ( EXPLORER-HCM) : a randomised, double-blind, placebo-controlled, phase 3trial. Lancet 2020; 396 :759–769. 4. Desai MY, Owens A, Geske JB, Wolski K, Naidu SS, Smedira NG, Cremer PC, SchaffH, Mcerlean E, Sewell C, Li W, Sterling L, Lampl K, Edelberg JM, Sehnert AJ, Nissen SE.Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referredfor septal reduction therapy. J Am Coll Cardiol 2022; 80 :95–108. 5. European Medicines Agency. Camzyos: EPAR—Public Assessment Report.https://www.ema.europa.eu/en/documents/assessment-report/camzyos-epar-public-assessment-report_en.pdf ( accessed 1 October 2024) . 6. Merali S, Salinger DH, Palmisano M, Sehnert AJ, Thanneer N, Back H, SeroogyJD, Gretler DD, Roy A, Perera V. Recommendation of mavacamten posology bymodel-based analyses in adults with obstructive hypertrophic cardiomyopathy. CPTPharmacometrics Syst Pharmacol 2024; 13 :1448–1461. 7. Chiang M, Sychterz C, Perera V, Merali S, Palmisano M, Templeton IE, GaohuaL. Physiologically based pharmacokinetic modeling and simulation of Mavacamtenexposure with drug-drug interactions from CYP inducers and inhibitors by CYP2C19phenotype. Clin Pharmacol Ther 2023; 114 :922–932. 8. Heitner SB, Jacoby D, Lester SJ, Owens A, Wang A, Zhang D, Lambing J, Lee J,Semigran M, Sehnert AJ. Mavacamten treatment for obstructive hypertrophic car-diomyopathy: a clinical trial. Ann Intern Med 2019; 170 :741–748. 9. U.S. Food & Drug Administration. Risk evaluation and mitigation strategy forCamzyos. https://www.camzyosrems.com ( accessed 1 October 2024) . 0. European Medicines Agency. Investigation of drug interactions—scientificguideline. https://www.ema.europa.eu/en/investigation-drug-interactions-scientific-guideline ( accessed 1 October 2024) . y of Cardiology. ember 2024

Pharmacogenetic testing to broaden patient eligibility for mavacamten

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Pharmacogenetic testing to broaden patient eligibility for mavacamten

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