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

Open AccessPublished:September 13, 2022DOI:https://doi.org/10.1016/j.amjcard.2022.08.001
      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)

      Introduction

      Lamin A/C gene (LMNA)-related dilated cardiomyopathy (DCM) is a rare and life-threatening condition with a high unmet need.
      • Hasselberg 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.
      ,
      • Taylor 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.
      Variants in LMNA, which encodes nuclear envelope proteins lamin A and lamin C, account for approximately 6% of idiopathic DCM cases.
      • Hasselberg 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.
      • Taylor 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.
      • Hershberger RE
      • Hedges DJ
      • Morales A.
      Dilated cardiomyopathy: the complexity of a diverse genetic architecture.
      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.
      • Taylor 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.
      ,
      • Arbustini 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.
      • Bécane 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.
      • Meune 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.
      • van 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?.
      • Escobar-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.
      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.
      • Muchir 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.
      ,
      • Wu 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.
      ARRY-371797 (PF-07265803) is a potent, selective, oral, small-molecule inhibitor of the p38 MAPK pathway
      • Muchir 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.
      ,
      • Romero-Becerra R
      • Santamans AM
      • Folgueira C
      • Sabio G.
      p38 MAPK pathway in the heart: new insights in health and disease.
      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.
      • Judge 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.

      Methods

      The methods of the phase 2 study have been previously published.
      • Judge 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.
      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.
      Figure 1
      Figure 1Study design. Patients assigned to 100 mg bid could escalate to 400 mg bid at week 24 or later if the 6MWT distance had not improved by ≥10% and there were no grade 3/4 adverse events. * Patients were assigned to ARRY-371797 (PF-07265803) 100 or 400 mg in an alternating manner. Dose reductions to 200 mg bid for poor tolerability were allowed in the 400 mg bid group; further reduction was allowed to 100 mg bid for poor tolerability at 200 mg bid. bid = twice a day.
      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.

      Results

      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 baseline
      Sex, age (yrs)6MWT distance (m)Contrast-enhanced LVEF (%)RVFA (%)Concomitant therapy for heart failure
      ACEIs or ARBsBeta-blocking agents
      Selective beta-blockers, nonselective beta-blockers, and alpha-and beta-blockers.
      Aldosterone antagonistICD
      Female, 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.
      low asterisk Selective beta-blockers, nonselective beta-blockers, and alpha-and beta-blockers.
      Measured without contrast.
      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 events
      Patient sex, age (yrs)Treatment-emergent adverse events
      Related to study treatment
      All were considered mild/grade 1 and not serious.
      Leading to study discontinuation
      None were considered related to study medication.
      Female, 55Heart transplant
      Male, 50
      Male, 42
      Female, 61Stomatitis, onychoclasis
      Female, 61
      Female, 52High liver function tests
      Male, 56
      Male, 31Congestive heart failure
      low asterisk All were considered mild/grade 1 and not serious.
      None were considered related to study medication.
      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.
      Figure 2
      Figure 2(A) 6MWT distance in individual patients; all visits, including early termination visits, are plotted until week 144. (B) Mean change from phase 2 study baseline in 6MWT distance over time with ARRY-371797 (PF-07265803) treatment; early termination visits are not included. The #n represents unique subjects. Dose reduction in the LTE 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. 80% CI of the mean 6MWT distance is included for each time point. bid = twice a day; CI = confidence interval.
      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).
      Figure 3
      Figure 3(A) NT-proBNP concentration in individual patients; all visits, including early termination visits, are plotted until week 144. (B) Median, twenty-fifth, and seventy-fifth percentile change from phase 2 study baseline in NT-proBNP concentration over time with ARRY-371797 (PF-07265803) treatment; early termination visits are not included. The #n represents unique subjects. Dose reduction in the LTE 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. Week 48 NT-proBNP values for 1 patient with a protocol deviation (visit outside protocol window as the patient enrolled 7 days after completion of the phase 2 study at the week 48 visit) were missing. bid = twice a day.
      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).

      Discussion

      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.
      • Fry M
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      • Heo S
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      Quality of life in patients with heart failure: ask the patients.
      • Sabbag 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.
      The 6MWT is an inexpensive and reproducible method to measure exercise tolerance as an estimate of functional capacity.
      • Guyatt 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.
      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.
      • Giannitsi S
      • Bougiakli M
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      6-minute walking test: a useful tool in the management of heart failure patients.
      • Passantino A
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      Short-term change in distance walked in 6 min is an indicator of outcome in patients with chronic heart failure in clinical practice.
      • Awwad O
      • El-Zahwy SS
      • Shawky A
      • Attia S.
      Short-term statin treatment in idiopathic dilated cardiomyopathy.
      • Bittner 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.
      • Han 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.
      This study demonstrated significant and durable improvements in 6MWT distance, suggesting a signal toward a clinically significant improvement associated with the administration of ARRY-371797 (PF-07265803). Furthermore, treatment was well tolerated.
      The number of patients in this study is small but relevant for a rare disease. Although the data from this study are encouraging, the lack of a control arm limits robust understanding of the intervention effect on disease progression and safety.
      The results of the Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation represent one of the first investigations in a molecularly distinct subset of HF with reduced ejection fraction, and prompted the further investigation in an ongoing, formally powered, randomized, double-blind, placebo-controlled, multicenter phase 3 study in adults (REALM-DCM [NCT03439514]). This study uses 6MWT distance as a primary registrational end point.
      In conclusion, treatment with ARRY-371797 (PF-07265803) was associated with preserved exercise capacity over 144 weeks and was generally well tolerated over a median drug exposure duration of around 3 years.

      Acknowledgment

      This study was sponsored by Array BioPharma Inc., which was acquired by Pfizer in July 2019. Medical writing support was provided by Caitlin Watson, PhD, of Engage Scientific Solutions and funded by Pfizer.

      Disclosures

      This study was sponsored by Pfizer, which also provided financial support for the trial. Daniel P. Judge reports receiving consultancy fees from 4D Molecular Therapeutics, ADRx, Inc., Cytokinetics, MyoKardia, Pfizer, and Tenaya Therapeutics. Neal K. Lakdawala reports consulting fees from MyoKardia, Bristol Myers Squibb, Tenaya Therapeutics, Array BioPharma, and Pfizer. Matthew R.G. Taylor has consulted for Array BioPharma, Rocket Pharmaceuticals, and 4D Molecular Therapeutics. Luisa Mestroni reports consulting for Array BioPharma and Pfizer. Huihua Li, Colleen Oliver, Franca S. Angeli, and Patrice A. Lee are full-time employees of Pfizer and hold stock and/or stock options. Calum A. MacRae reports consulting for Affinia, Array BioPharma, AstraZeneca, Bayer, Bristol Myers Squibb, Design Therapeutics, Dewpoint, DiNAQOR, Merck, MyoKardia, Novartis, and Pfizer and has received grant support from Bayer, Merck, Novartis, and Sanofi.

      Data Availability

      Upon request and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

      Appendix. Supplementary materials

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