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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  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.
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.
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.
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.
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 baseline
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.
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.
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.
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.
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.
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.
This study was sponsored by Array BioPharma Inc., (Boulder, Colorado, USA) which was acquired by Pfizer (New York, NY, USA) in July 2019. Medical writing support was provided by Caitlin Watson, PhD, of Engage Scientific Solutions and funded by Pfizer (New York, NY, USA). Pfizer contributed to the study design and management, and collection of data. In their role as authors, employees of Pfizer were involved in the interpretation of data, preparation, review, and approval of the manuscript and the decision to submit it for publication, along with their co-authors. The study sponsor approved the manuscript from an intellectual property perspective but had no right to veto the publication.