Injection Site Reactions with Long-Term Pegcetacoplan Use in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Brief Report.

INTRODUCTION: Pegcetacoplan is a targeted complement component 3 (C3) therapy approved for adults with paroxysmal nocturnal hemoglobinuria (PNH; US) or PNH plus anemia despite C5-targeted therapy for ≥ 3 months (EU). Patients with PNH receiving pegcetacoplan in the phase 3 PEGASUS trial who experienced injection site reactions (ISRs) mostly experienced mild events. We evaluated ISR incidence and severity with longer-term treatment in the PEGASUS cohort of the Study 307 open-label extension (307 OLE). METHODS: Patients from PEGASUS enrolled in the 307 OLE continued pegcetacoplan subcutaneous self-administration twice or three times weekly or every 3 days for an additional 48 weeks. ISRs were coded as adverse events (AEs) or treatment-emergent AEs (TEAEs) and summarized by MedDRA System Organ Class and Preferred Term. RESULTS: As of August 27, 2021, 58/64 patients from PEGASUS completed an additional 48 weeks of treatment in the 307 OLE (median treatment duration 337.0 [range 55-344] days); 95.3% (61/64) of patients achieved compliance ≥ 80%. ISRs occurred in 9/64 (14.1%) patients in the 307 OLE, which was lower than observed at PEGASUS completion (20/77; 26.0%). Most patients with ISRs in the 307 OLE had events with a maximum severity of mild (7/9 patients; 77.8%). Injection site erythema and induration were the most common overall (4/64 patients each; 6.3%) and pegcetacoplan-related (3/64 patients each; 4.7%) ISRs. The exposure-adjusted rates of these events were each 6.5 per 100 patient-years. No ISRs were classified as severe or serious TEAEs or led to drug discontinuation. CONCLUSION: Though ISRs were common, most were mild, and the percentage of patients reporting ISRs declined from PEGASUS through the 307 OLE. Patient compliance remained high, and no patients discontinued because of ISRs, suggesting that ISRs do not pose a barrier to long-term pegcetacoplan treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03500549 (PEGASUS) and NCT03531255 (307 OLE).

Management of CLN1 Disease: International Clinical Consensus.

BACKGROUND: CLN1 disease (neuronal ceroid lipofuscinosis type 1) is a rare, genetic, neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase 1 (PPT1) enzyme deficiency. Clinical features include developmental delay, psychomotor regression, seizures, ataxia, movement disorders, visual impairment, and early death. In general, the later the age at symptom onset, the more protracted the disease course. We sought to evaluate current evidence and to develop expert practice consensus to support clinicians who have not previously encountered patients with this rare disease. METHODS: We searched the literature for guidelines and evidence to support clinical practice recommendations. We surveyed CLN1 disease experts and caregivers regarding their experiences and recommendations, and a meeting of experts was conducted to ascertain points of consensus and clinical practice differences. RESULTS: We found a limited evidence base for treatment and no clinical management guidelines specific to CLN1 disease. Fifteen CLN1 disease experts and 39 caregivers responded to the surveys, and 14 experts met to develop consensus-based recommendations. The resulting management recommendations are uniquely informed by family perspectives, due to the inclusion of caregiver and advocate perspectives. A family-centered approach is supported, and individualized, multidisciplinary care is emphasized in the recommendations. Ascertainment of the specific CLN1 disease phenotype (infantile-, late infantile-, juvenile-, or adult-onset) is of key importance in informing the anticipated clinical course, prognosis, and care needs. Goals and strategies should be periodically reevaluated and adapted to patients' current needs, with a primary aim of optimizing patient and family quality of life.

Management Strategies for CLN2 Disease.

CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, autosomal recessive, pediatric-onset, rapidly progressive neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 (TPP1) enzyme deficiency, and is characterized by language delay, seizures, rapid cognitive and motor decline, blindness, and early death. No management guidelines exist and there is a paucity of published disease-specific evidence to inform clinical practice, which currently draws upon experience from the field of childhood neurodisability. Twenty-four disease experts were surveyed on CLN2 disease management and a subset met to discuss current practice. Management goals and strategies are consistent among experts globally and are guided by the principles of pediatric palliative care. Goals and interventions evolve as the disease progresses, with a shift in focus from maintenance of function early in the disease to maintenance of quality of life. A multidisciplinary approach is critical for optimal patient care. This work represents an initial step toward the development of consensus-based management guidelines for CLN2 disease.