Background: Hereditary pyruvate kinase (PK) deficiency results in lifelong hemolytic anemia and several significant comorbidities, the epidemiology of which are not well characterized. Among these is reduced bone mineral density (BMD), which can result in premature osteopenia, osteoporosis, and fractures. To better characterize the bone density abnormalities in patients with PK deficiency, this study evaluated pooled pre-treatment baseline data from 3 clinical trials involving patients with PK deficiency investigating mitapivat, an allosteric activator of PK: DRIVE-PK (NCT02476916), ACTIVATE (NCT03548220), and ACTIVATE-T (NCT03559699). This is the first large PK deficiency cohort in which dual-energy x-ray absorptiometry (DXA) scores were systematically and consistently assessed.

Methods: DRIVE-PK is a completed phase 2, global, randomized, open-label study. ACTIVATE is an ongoing phase 3, global, randomized, double-blind, placebo-controlled study. ACTIVATE-T is an ongoing phase 3, global, open-label, single-arm study. In all 3 studies, patients ≥ 18 years of age with a confirmed diagnosis of PK deficiency were eligible to participate. Patients were eligible to participate in DRIVE-PK and in ACTIVATE if they were not regularly transfused (DRIVE-PK: ≤ 3 units of red blood cells in the prior 12 months; no transfusions in the prior 4 months; ACTIVATE: ≤ 4 transfusion episodes in the previous year; no transfusions in the prior 3 months) and in ACTIVATE-T if they were regularly transfused (≥ 6 transfusion episodes in the previous year). BMD was measured using DXA scans at baseline; scans were obtained locally for all 3 studies. Scans were interpreted locally for DRIVE-PK and centrally for ACTIVATE and ACTIVATE-T. Osteopenia and osteoporosis were identified on DXA scanning according to standard definitions, and the prevalence of each was compared to the prevalence ascertained via medical history.

Results: Full demographics and characteristics of patients at baseline are shown in the Table. Of 159 patients evaluated (DRIVE-PK, n = 52; ACTIVATE, n = 80; ACTIVATE-T, n = 27), the median age was 34 years (range, 18-78) and the majority were female (n = 88; 55.3%). Of 155 patients who had baseline T-scores for total femur, spine, and femoral neck, 38 (24.5%) had a T-score of ≥ -1.0 at all locations, indicating normal BMD; 91 (58.7%) had a T-score of < -1.0 to > -2.5 at 1 or more locations, indicating osteopenia; and 26 (16.8%) had a T-score of ≤ -2.5 at 1 or more locations, indicating osteoporosis. The proportion of patients in each T-score range for each of the 3 locations is shown in the Figure. In contrast to the DXA scan findings, only 28 (17.6%) patients had a known medical history of osteopenia and 23 (14.5%) had a known medical history of osteoporosis.

Taking together DXA scan results and medical history for all 159 patients, 85 patients (53.5%) had osteopenia and 33 patients (20.8%) had osteoporosis. The median age for patients with either osteopenia or osteoporosis (n = 118) was 36 years (range, 18-78). Of these, 20 patients (16.9%) were regularly transfused and 98 patients (83.1%) were not regularly transfused.

Conclusions: In this large cohort, universal DXA scanning revealed that over three-quarters of adults with PK deficiency had osteopenia or osteoporosis, irrespective of transfusion requirements. Given the young median age of the cohort (34 years), these findings have considerable significance and implications for the screening and care of patients with PK deficiency throughout their adult lives. Early monitoring of these patients with DXA scans in order to ensure a prompt diagnosis of bone density abnormalities and indicated treatment may be warranted.

Disclosures

Al-Samkari:Argenx: Consultancy; Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Rigel: Consultancy; Amgen: Research Funding. Grace:Novartis: Research Funding; Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Glenthoej:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexicon: Research Funding; Novo Nordisk: Honoraria. Barcellini:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding; Novartis: Honoraria, Other: invited speaker , Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Kuo:Bluebird Bio: Consultancy; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy; Celgene: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding. Layton:Cerus: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morado:Sanofi Genzyme: Honoraria, Other: Grants. Viprakasit:BMS, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios Pharmaceuticals, Ionis Pharmaceuticals, La Jolla Pharmaceuticals, Protagonist Therapeutics, Vifor Pharma: Consultancy, Research Funding. Dong:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Tai:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Hawkins:Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Infinity Pharmaceuticals: Current equity holder in publicly-traded company; Jazz Pharmaceuticals: Current equity holder in publicly-traded company. Gheuens:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Bowden:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Porter:Silence Therapeutics: Honoraria; La Jolla Pharmaceuticals: Honoraria; Vifor Pharmaceuticals: Honoraria; Protagonist Therapeutics: Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria; BMS: Consultancy, Honoraria. van Beers:Novartis: Research Funding; Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.