Long-Term Efficacy and Safety of ARRY-371797 (PF-07265803) in Patients With Lamin A/C–Related Dilated Cardiomyopathy

Abstract

Dilated cardiomyopathy associated with lamin A/C (LMNA) gene variants (LMNA-related dilated cardiomyopathy [DCM]) is a life-threatening condition with a high unmet need, accounting for approximately 6% of idiopathic DCM cases. Currently, no disease-specific treatments target the underlying disease mechanism. ARRY-371797 (PF-07265803), a potent, selective, oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase pathway, improved 6-minute walk test (6MWT) distance in 12 patients with symptomatic LMNA-related DCM in a 48-week, open-label, phase 2 study. This long-term extension study examined the safety and efficacy of ARRY-371797 in patients from the phase 2 study. 6MWT, N-terminal pro-B-type natriuretic peptide concentration, and 12-item Kansas City Cardiomyopathy Questionnaire score were assessed at weeks 48, 72, 96, 120, and 144 from phase 2 study baseline. Eight patients enrolled (mean [SD] age, 51 [10] years, 4 male). Mean 6MWT increased by >30 m (>10%) from phase 2 study baseline up to week 120. The decrease in N-terminal pro-B-type natriuretic peptide observed in the phase 2 study was maintained throughout the present study. Twelve-item Kansas City Cardiomyopathy Questionnaire Physical Limitation increased from baseline at all visits except week 96 (range: −0.8 [week 96] to 13.8 [week 120]); results for other domains were variable. Treatment was generally well tolerated; 2 patients discontinued because of causes not considered treatment-related. There were no deaths. ARRY-371797 was generally well tolerated over median (range) 155.7 (61 to 327)-week exposure; evidence suggested preserved exercise capacity over the study period. The ongoing, pivotal, phase 3, randomized, placebo-controlled study REALM-DCM investigates the efficacy and safety of ARRY-371797 (PF-07265803) in LMNA-related DCM. (ClinicalTrials.gov Identifier: NCT02351856) Dilated cardiomyopathy associated with lamin A/C (LMNA) gene variants (LMNA-related dilated cardiomyopathy [DCM]) is a life-threatening condition with a high unmet need, accounting for approximately 6% of idiopathic DCM cases. Currently, no disease-specific treatments target the underlying disease mechanism. ARRY-371797 (PF-07265803), a potent, selective, oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase pathway, improved 6-minute walk test (6MWT) distance in 12 patients with symptomatic LMNA-related DCM in a 48-week, open-label, phase 2 study. This long-term extension study examined the safety and efficacy of ARRY-371797 in patients from the phase 2 study. 6MWT, N-terminal pro-B-type natriuretic peptide concentration, and 12-item Kansas City Cardiomyopathy Questionnaire score were assessed at weeks 48, 72, 96, 120, and 144 from phase 2 study baseline. Eight patients enrolled (mean [SD] age, 51 [10] years, 4 male). Mean 6MWT increased by >30 m (>10%) from phase 2 study baseline up to week 120. The decrease in N-terminal pro-B-type natriuretic peptide observed in the phase 2 study was maintained throughout the present study. Twelve-item Kansas City Cardiomyopathy Questionnaire Physical Limitation increased from baseline at all visits except week 96 (range: −0.8 [week 96] to 13.8 [week 120]); results for other domains were variable. Treatment was generally well tolerated; 2 patients discontinued because of causes not considered treatment-related. There were no deaths. ARRY-371797 was generally well tolerated over median (range) 155.7 (61 to 327)-week exposure; evidence suggested preserved exercise capacity over the study period. The ongoing, pivotal, phase 3, randomized, placebo-controlled study REALM-DCM investigates the efficacy and safety of ARRY-371797 (PF-07265803) in LMNA-related DCM. (ClinicalTrials.gov Identifier: NCT02351856) Lamin A/C gene (LMNA)-related dilated cardiomyopathy (DCM) is a rare and life-threatening condition with a high unmet need.1Hasselberg NE Haland TF Saberniak J Brekke PH Berge KE Leren TP Edvardsen T Haugaa KH. Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation.Eur Heart J. 2018; 39: 853-860Crossref PubMed Scopus (162) Google Scholar,2Taylor MR Fain PR Sinagra G Robinson ML Robertson AD Carniel E Di Lenarda A Bohlmeyer TJ Ferguson DA Brodsky GL Boucek MM Lascor J Moss AC Li WL Stetler GL Muntoni F Bristow MR Mestroni L Familial Dilated Cardiomyopathy Registry Research Group. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.J Am Coll Cardiol. 2003; 41 (Published correction appears in J Am Coll Cardiol 2003;42:590): 771-780Crossref PubMed Scopus (374) Google Scholar Variants in LMNA, which encodes nuclear envelope proteins lamin A and lamin C, account for approximately 6% of idiopathic DCM cases.1Hasselberg NE Haland TF Saberniak J Brekke PH Berge KE Leren TP Edvardsen T Haugaa KH. Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation.Eur Heart J. 2018; 39: 853-860Crossref PubMed Scopus (162) Google Scholar, 2Taylor MR Fain PR Sinagra G Robinson ML Robertson AD Carniel E Di Lenarda A Bohlmeyer TJ Ferguson DA Brodsky GL Boucek MM Lascor J Moss AC Li WL Stetler GL Muntoni F Bristow MR Mestroni L Familial Dilated Cardiomyopathy Registry Research Group. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.J Am Coll Cardiol. 2003; 41 (Published correction appears in J Am Coll Cardiol 2003;42:590): 771-780Crossref PubMed Scopus (374) Google Scholar, 3Hershberger RE Hedges DJ Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture.Nat Rev Cardiol. 2013; 10: 531-547Crossref PubMed Scopus (660) Google Scholar Almost 70% of LMNA variant carriers experience cardiac death, heart transplant, or a major cardiac event by age 45 years, which is corroborated by evidence suggesting LMNA-related DCM has a malignant course despite conventional therapies.2Taylor MR Fain PR Sinagra G Robinson ML Robertson AD Carniel E Di Lenarda A Bohlmeyer TJ Ferguson DA Brodsky GL Boucek MM Lascor J Moss AC Li WL Stetler GL Muntoni F Bristow MR Mestroni L Familial Dilated Cardiomyopathy Registry Research Group. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.J Am Coll Cardiol. 2003; 41 (Published correction appears in J Am Coll Cardiol 2003;42:590): 771-780Crossref PubMed Scopus (374) Google Scholar,4Arbustini E Pilotto A Repetto A Grasso M Negri A Diegoli M Campana C Scelsi L Baldini E Gavazzi A Tavazzi L. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease.J Am Coll Cardiol. 2002; 39: 981-990Crossref PubMed Scopus (293) Google Scholar, 5Bécane HM Bonne G Varnous S Muchir A Ortega V Hammouda EH Urtizberea JA Lavergne T Fardeau M Eymard B Weber S Schwartz K Duboc D. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation.Pacing Clin Electrophysiol. 2000; 23: 1661-1666Crossref PubMed Scopus (225) Google Scholar, 6Meune C Van Berlo JH Anselme F Bonne G Pinto YM Duboc D. Primary prevention of sudden death in patients with lamin A/C gene mutations.N Engl J Med. 2006; 354: 209-210Crossref PubMed Scopus (314) Google Scholar, 7van Berlo JH de Voogt WG van der Kooi AJ van Tintelen JP Bonne G Yaou RB Duboc D Rossenbacker T Heidbüchel H de Visser M Crijns HJ Pinto YM. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death?.J Mol Med (Berl). 2005; 83: 79-83Crossref PubMed Scopus (377) Google Scholar, 8Escobar-Lopez L Ochoa JP Mirelis JG MÁ Espinosa Navarro M Gallego-Delgado M Barriales-Villa R Robles-Mezcua A Barsurte-Elorz MT Gutiérrez García-Moreno L Climent V Jiménez-Jaimez J Mogollón-Jiménez MV Lopez J Peña-Peña ML García-Álvarez A Brion M Ripoll-Vera T Palomino-Doza J Tirón C Idiazabal U Brögger MN García-Hernández S Restrepo-Córdoba MA Gonzalez-Lopez E Méndez I Sabater M Villacorta E Larrañaga-Moreira JM Abecia A Fernández AI García-Pinilla JM Rodríguez-Palomares JF Gimeno-Blanes JR Bayes-Genis A Lara-Pezzi E Domínguez F Garcia-Pavia P Association of genetic variants with outcomes in patients with nonischemic dilated cardiomyopathy.J Am Coll Cardiol. 2021; 78: 1682-1699Crossref PubMed Scopus (45) Google Scholar Currently, no disease-specific treatments target the underlying mechanism of LMNA-related DCM. Activation of the p38α mitogen-activated protein kinase (MAPK) pathway has been observed in both animal models and biopsies from the hearts of patients with LMNA‑related DCM. Evidence from animal models suggests that inhibition of p38α MAPK may be a useful treatment mechanism.9Muchir A Wu W Choi JC Iwata S Morrow J Homma S Worman HJ. Abnormal p38α mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation.Hum Mol Genet. 2012; 21: 4325-4333Crossref PubMed Scopus (98) Google Scholar,10Wu W Iwata S Homma S Worman HJ Muchir A. Depletion of extracellular signal-regulated kinase 1 in mice with cardiomyopathy caused by lamin A/C gene mutation partially prevents pathology before isoenzyme activation.Hum Mol Genet. 2014; 23: 1-11Crossref PubMed Scopus (26) Google Scholar ARRY-371797 (PF-07265803) is a potent, selective, oral, small-molecule inhibitor of the p38 MAPK pathway9Muchir A Wu W Choi JC Iwata S Morrow J Homma S Worman HJ. Abnormal p38α mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation.Hum Mol Genet. 2012; 21: 4325-4333Crossref PubMed Scopus (98) Google Scholar,11Romero-Becerra R Santamans AM Folgueira C Sabio G. p38 MAPK pathway in the heart: new insights in health and disease.Int J Mol Sci. 2020; 21: 7412Crossref Scopus (58) Google Scholar with improved selectivity for p38α MAPK. This open-label, long-term extension (LTE) study (NCT02351856) was designed to examine the safety and durability of the efficacy of ARRY-371797 (PF-07265803) in patients with symptomatic LMNA-related DCM who previously participated in the phase 2 study.12Judge DP Lakdawala NK Taylor MRG Mestroni L Li H Oliver C Angeli FS Lee PA MacRae CA. Long-term efficacy and safety of ARRY-371797 (PF-0765803) in an open-label rollover study in patients with dilated cardiomyopathy due to a lamin A/C gene mutation.Circulation. 2021; 144: A12210Crossref Google Scholar The methods of the phase 2 study have been previously published.12Judge DP Lakdawala NK Taylor MRG Mestroni L Li H Oliver C Angeli FS Lee PA MacRae CA. Long-term efficacy and safety of ARRY-371797 (PF-0765803) in an open-label rollover study in patients with dilated cardiomyopathy due to a lamin A/C gene mutation.Circulation. 2021; 144: A12210Crossref Google Scholar The study protocol was approved by each institutional review board and/or ethics committee and performed per the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines established by the International Council for Harmonisation and local regulatory requirements. All patients provided written informed consent. In the present LTE study, eligible patients continued to receive the same dose and schedule administered at the conclusion of the phase 2 study (Figure 1). Assessments were performed at weeks 48, 72, 96, 120, and 144 from treatment initiation in the phase 2 study. Assessments included: 6-minute walk test (6MWT) distance (and change from phase 2 study predose baseline); 6MWT response (defined as ≥10% increase in 6MWT distance from phase 2 study predose baseline, by visit); and N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentration (and change from phase 2 study predose baseline). Echocardiographic measurements of left and right ventricular function were determined by a central core laboratory, and patient-reported outcomes were assessed using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). The incidence of adverse events was used to evaluate safety. The safety population included all enrolled patients who received ≥1 dose of ARRY-371797 (PF-07265803), and the efficacy population included all patients who had ≥1 assessment after baseline efficacy. Efficacy data up to week 144 are reported. All safety data up to study closure, including those after week 144, are reported. Eight patients from the phase 2 study were enrolled. Patient-level demographics and clinical characteristics are listed in Table 1. Summary data are presented in Supplementary Table 1. Mean (SD) age was 51 (10) years, and 50% (n = 4) of the patients were male. The median (range) duration of exposure was 155.7 (61 to 327) weeks from the start of phase 2.Table 1Individual patient demographics and baseline characteristics at the LTE baselineSex, age (yrs)6MWT distance (m)Contrast-enhanced LVEF (%)RVFA (%)Concomitant therapy for heart failureACEIs or ARBsBeta-blocking agents*Selective beta-blockers, nonselective beta-blockers, and alpha-and beta-blockers.Aldosterone antagonistICDFemale, 554063022.5××××Male, 503933028.1××××Male, 423484638.9××Female, 6129848NA××Female, 613625222.7×××Female, 523603646.3××Male, 564573233.7××××Male, 3137429†Measured without contrast.18.6××××6MWT = 6-minute walk test; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ICD = implantable cardioverter-defibrillator; LTE = long-term extension; LVEF = left ventricular ejection fraction; NA = not available; RVFA = right ventricular fractional area. Selective beta-blockers, nonselective beta-blockers, and alpha-and beta-blockers.† Measured without contrast. Open table in a new tab 6MWT = 6-minute walk test; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ICD = implantable cardioverter-defibrillator; LTE = long-term extension; LVEF = left ventricular ejection fraction; NA = not available; RVFA = right ventricular fractional area. Two patients discontinued treatment early because of causes not considered treatment-related: 1 instance each of heart transplant and congestive heart failure (Table 2; Supplementary Table 2)Table 2Treatment-emergent adverse eventsPatient sex, age (yrs)Treatment-emergent adverse eventsRelated to study treatment*All were considered mild/grade 1 and not serious.Leading to study discontinuation†None were considered related to study medication.Female, 55–Heart transplantMale, 50––Male, 42––Female, 61Stomatitis, onychoclasis–Female, 61––Female, 52High liver function tests–Male, 56––Male, 31–Congestive heart failure All were considered mild/grade 1 and not serious.† None were considered related to study medication. Open table in a new tab Dose reduction occurred in 2 patients: 1 at LTE day 88 (from 400 to 200 mg bid) and 1 at LTE day 165 (from 200 to 100 mg bid). No patients were dose-escalated. Data on 6MWT distance from individual patients are shown in Figure 2. Overall, there were mean changes of >30 m and >10% in 6MWT distance from the phase 2 study baseline (319.5 m, 80% confidence interval 297.5 to 341.5) at all time points up to week 120 (Figure 2). Mean percentage (80% confidence interval) increases from baseline were 19.0% (10.4 to 27.6), 10.8% (0.7 to 20.8), 17.0% (4.2 to 29.8), 13.0% (−0.1 to 26.1), and 3.7% (−15.2 to 22.7), respectively. Response (≥10% increase in 6MWT distance from phase 2 study baseline) was observed in 5 (62.5%) patients at week 48, 2 (25.0%) patients at both weeks 72 and 96, and 3 (37.5%) patients at both weeks 120 and 144. Data on NT-proBNP concentration from individual patients are shown in Figure 3. Overall, the decrease observed in mean and median NT-proBNP concentration in the phase 2 study was maintained, with a reduction from baseline in median concentration seen at all study visits (Figure 3). Mean (SD) left ventricular ejection fraction was 36.5% (10.4) at phase 2 baseline and 33.5% (8.0) at week 144, and the mean (SD) right ventricular fractional area was 22.1% (6.9) at baseline and 25.8% (7.7) at week 144 (Supplementary Figure 1). Mean KCCQ-12 Physical Limitation score had increased from phase 2 baseline at all visits except week 96, ranging from −0.8 (week 96) to 13.8 (week 120), whereas results for other domains of the KCCQ-12 were variable during the course of the study (Supplementary Table 3). Treatment with ARRY-371797 (PF-07265803) was generally well tolerated. There were no deaths. A summary of adverse events can be found in Supplementary Table 2. The most common treatment-emergent adverse events were ventricular tachycardia (n = 5 patients) and accidental overdose (n = 4). This phase 2 LTE study examined the safety and efficacy of ARRY-371797 (PF-07265803) for up to 144 weeks in patients with symptomatic LMNA-related DCM. Despite the progressive nature of this disease, our results show mean increases of >30 m and >10% in 6MWT distance from phase 2 study baseline for an extended treatment period, up to week 120. Preserved exercise capacity was mirrored by favorable trends in NT-proBNP concentration. Genetic cardiomyopathies, such as LMNA-related DCM, are an important cause of chronic heart failure (HF). Chronic HF is not only associated with substantial morbidity and mortality, but also has a major impact on how patients feel and function, which is associated with impaired quality of life and ability to perform activities of daily living.13Fry M McLachlan S Purdy S Sanders T Kadam UT Chew-Graham CA. The implications of living with heart failure; the impact on everyday life, family support, co-morbidities and access to healthcare: a secondary qualitative analysis.BMC Fam Pract. 2016; 17: 139Crossref PubMed Scopus (32) Google Scholar, 14Heo S Lennie TA Okoli C Moser DK. Quality of life in patients with heart failure: ask the patients.Heart Lung. 2009; 38: 100-108Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 15Sabbag A Mazin I Rott D Hay I Gang N Tzur B Goldkorn R Goldenberg I Klempfner R Israel A. The prognostic significance of improvement in exercise capacity in heart failure patients who participate in cardiac rehabilitation programme.Eur J Prev Cardiol. 2018; 25: 354-361Crossref PubMed Scopus (33) Google Scholar The 6MWT is an inexpensive and reproducible method to measure exercise tolerance as an estimate of functional capacity.16Guyatt GH Sullivan MJ Thompson PJ Fallen EL Pugsley SO Taylor DW Berman LB. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure.Can Med Assoc J. 1985; 132: 919-923PubMed Google Scholar Improvement in 6MWT distance is a direct measure of a favorable therapeutic intervention and is associated with reduced morbidity and mortality in patients with HF in general, and in patients with DCM.17Giannitsi S Bougiakli M Bechlioulis A Kotsia A Michalis LK Naka KK. 6-minute walking test: a useful tool in the management of heart failure patients.Ther Adv Cardiovasc Dis. 2019; 131753944719870084Crossref PubMed Scopus (128) Google Scholar, 18Passantino A Lagioia R Mastropasqua F Scrutinio D. Short-term change in distance walked in 6 min is an indicator of outcome in patients with chronic heart failure in clinical practice.J Am Coll Cardiol. 2006; 48: 99-105Crossref PubMed Scopus (69) Google Scholar, 19Awwad O El-Zahwy SS Shawky A Attia S. Short-term statin treatment in idiopathic dilated cardiomyopathy.Egypt Heart J. 2012; 64: 15-20Abstract Full Text Full Text PDF Scopus (4) Google Scholar, 20Bittner V Weiner DH Yusuf S Rogers WJ McIntyre KM Bangdiwala SI Kronenberg MW Kostis JB Kohn RM Guillotte M et al.Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. SOLVD investigators.JAMA. 1993; 270: 1702-1707Crossref PubMed Scopus (750) Google Scholar, 21Han LN Guo SL Lin XM Shi XM Zang CB Yang LM Ding GL. Torasemide reduces dilated cardiomyopathy, complication of arrhythmia, and progression to heart failure.Genet Mol 2014; PubMed Scopus Google Scholar This study and in 6MWT suggesting a a improvement associated with the of ARRY-371797 treatment was well tolerated. The of patients in this study is but for a rare the data from this study are the of a of the intervention on disease progression and safety. The results of the of ARRY-371797 (PF-07265803) in Dilated Cardiomyopathy to a Lamin A/C of the in a of HF with reduced ejection and the in an ongoing, randomized, phase 3 study in This study 6MWT distance as a In treatment with ARRY-371797 (PF-07265803) was associated with preserved exercise capacity over 144 weeks and was generally well tolerated over a median exposure duration of 3 This study was by which was by in was provided by of and by This study was by which also provided for the from and Lakdawala from and Taylor has for and Mestroni for and S. and A. Lee are of and and/or A. MacRae for and and has received from and and to the data that the of this study. to and may also access to the related individual for with

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