Pegademase 375units/1.5ml solution for injection vials

PURPOSE: Metabolic detoxification with enzyme replacement therapy (ERT) promotes immune recovery in patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (ADA-SCID). Elapegademase is a PEGylated recombinant bovine ADA ERT developed to replace the now-discontinued bovine-derived pegademase. This study was a 1-way crossover from pegademase to elapegademase in 7 patients with ADA-SCID to assess efficacy and safety outcomes for elapegademase. METHODS: After once-weekly pegademase dosage was adjusted to achieve therapeutic metabolic detoxification and trough ADA activity, patients transitioned to a bioequivalent dose of elapegademase. Maintenance of metabolic detoxification and adequate ADA activity were evaluated periodically. RESULTS: One patient withdrew after 2 doses of an early elapegademase formulation due to injection-site pain caused by EDTA. The 6 remaining patients completed 71-216 weeks of elapegademase therapy with a formulation that did not contain EDTA. In these patients, elapegademase improved ADA activity compared with pegademase and maintained metabolic detoxification. Total lymphocyte counts increased for all completer patients from between 1.2- and 2.1-fold at the end of study compared with baseline. Elapegademase had a comparable safety profile to pegademase; no patient developed a severe infectious complication. Three patients had transient, non-neutralizing antibodies to pegademase, elapegademase, and/or polyethylene glycol ≤ 47 weeks of treatment without effect on trough plasma ADA activity or trough erythrocyte deoxyadenosine nucleotide levels. CONCLUSION: Elapegademase was safe, well tolerated, achieved stable trough plasma ADA activity with weekly dosing, was effective in maintaining metabolic detoxification, and was associated with maintenance or improvements in lymphocyte counts compared with pegademase therapy in patients with ADA-SCID.

Abstract licence: CC BY

INTRODUCTION: Adenosine deaminase (ADA) deficiency is an ultrarare inherited purine metabolism disorder characterized by severe combined immunodeficiency. Elapegademase-lvlr is a new pegylated recombinant bovine ADA used in enzyme-replacement therapy (ERT) for ADA deficiency. Therefore, replacement with the new drug may eliminate the infectious risks associated with the currently used bovine intestinal-derived product, pegademase. METHODS: We conducted a multicenter, single-arm, open-label, phase 3, and postmarketing clinical study of elapegademase for patients with ADA deficiency. The following biochemical markers were monitored to determine an appropriate dose of elapegademase: the trough deoxyadenosine nucleotide (dAXP) level ≤0.02 μmol/mL in erythrocytes or whole blood and the trough serum ADA activity ≥1100 U/L (equivalent to plasma levels ≥15 μmol/h/mL) indicated sufficient enzyme activity and detoxification as efficacy endpoints and monitored adverse events during the study as safety endpoints. RESULTS: A total of four patients (aged 0-25 years) were enrolled. One infant patient died of pneumonia caused by cytomegalovirus infection whereas the other three completed the study and have been observed in the study period over 3 years. The infant patient had received elapegademase at 0.4 mg/kg/week until decease and the others received elapegademase at maximum doses of 0.3 mg/kg/week for 164-169 weeks. As a result, all four patients achieved undetectable levels of dAXPs together with sufficient enzyme activity, increased T and B cell numbers, and slightly elevated and maintained IgM and IgA immunoglobulin levels. Serious adverse events occurred in three patients, all of which were assessed as unrelated to elapegademase. CONCLUSIONS: This study showed that elapegademase had comparable safety and efficacy to pegademase as ERT for ADA deficiency by demonstrating stable maintenance of sufficient ADA activity and lowering dAXP to undetectable levels, while no drug-related adverse events were reported (Trial registration: JapicCTI-163204).

Abstract licence: CC BY

Abstract Purpose The safety and tolerability of elapegademase (elapegademase-lvlr; Revcovi ® ) a PEGylated recombinant adenosine deaminase (ADA), were demonstrated in two Phase 3 clinical trials in the U.S. and Japan in patients with ADA-deficient severe combined immunodeficiency (ADA-SCID). Elapegademase replaced Adagen ® (pegademase, a PEGylated bovine ADA) in 2018. This registry study (NCT03878069) was conducted as a post-marketing requirement to bolster the limited safety and effectiveness data on elapegademase in patients with ADA-SCID and to study patients starting on enzyme replacement therapy (ERT) de novo . Methods Patients were managed by routine clinical care and treating physicians’ judgement from September 2019 to January 2023. Primary endpoints included trough plasma ADA activity and total trough erythrocyte deoxyadenosine nucleotides (dAXP). Secondary outcomes included lymphocyte counts, hospitalizations, infections, and safety outcomes. Results Thirty-two patients were grouped as ERT-naïve ( n = 7; infants and children with no prior ERT [EN]); pegademase-transitioning ( n = 21; from pegademase to elapegademase [PT]); and patients who had participated in the Phase 3 clinical trial ( n = 4; STP-2279-002; [STP]). The EN group maintained optimal plasma ADA activity, increased lymphocyte counts, had manageable infections, and had no mortality for up to 30 months while on elapegademase. The STP group and 66.7% of the PT group continued to maintain satisfactory levels of both ADA and dAXP with stable rates of infections and hospitalizations and stable lymphocyte counts for up to 48.6 months. Variability on all measures was seen, but overall, patients did not deteriorate while on elapegademase. Conclusion Effectiveness of elapegademase was maintained up to 4 years of use and with no new safety concerns.

Abstract licence: CC BY

Introduction Elapegademase (Revcovi®), a PEGylated recombinant bovine adenosine deaminase (ADA), is the only FDA-approved enzyme replacement therapy (ERT) for ADA-severe combined immunodeficiency (SCID), replacing pegademase (Adagen®) since 2018. Elapegademase is typically used from diagnosis until hematopoietic stem cell transplant (HSCT) or gene therapy (GT) can be performed, or as a bridge therapy if failed HSCT/GT or continued long term if neither option is feasible. In a phase 3 trial (NCT01420627), patients maintained metabolic detoxification, improved/stabilized lymphocyte counts, and tolerated elapegademase. Given the rarity of ADA-SCID, real-world data are crucial for evaluating its long-term effectiveness and safety. Methods This analysis included 4 patients from 4 U.S. sites who started elapegademase in the phase 3 trial (January 2014–May 2019) and continued treatment in the U.S. registry (NCT03878069; September 2019–January 2023). All 4 patients received pegademase for 13–24 years before starting elapegademase. Assessments included plasma ADA activity, erythrocyte deoxyadenosine nucleotide (dAXP) levels, and safety outcomes. Results Four patients with ADA-SCID, diagnosed in infancy (2 males) or early childhood (2 females), began ERT (pegademase) within a year of diagnosis (Table 1). Patient 1 with unsuccessful GT continued ERT. For the other 3, HSCT was not an option. Mean (range) age at elapegademase initiation was 21 years (16–31 years). Mean (standard deviation) total duration of elapegademase, including in the phase 3 trial, was 69.5 (22.6) months (range, 40.1–95.1 months). At registry end, ADA activity levels were numerically higher than at elapegademase baseline and also exceeded levels at phase 3 trial end. Additionally, all 4 patients were considered metabolically detoxified as satisfactory dAXP levels were maintained (≤ 0.02 mmol/L). Two patients required dose adjustments based on clinical assessments. Three patients experienced eight infections that resolved without sequelae and required no treatment interruption. No patients had any elapegademase-related adverse events. TABLE 1.Patient demographics, baseline characteristics, and primary effectiveness outcomes.ADA activity levels (mmol/h/L)a before and during elapegademase treatmentdAXP levels (mmol/L) b before and during elapegademase treatmentPatient (ID)SexAge at diagnosisPegademase treatment, durationAge at first elapegademase initiationDosing,mg/kg/weekLast data collectionBaselineAt end of phase 3At last visitBaselineAt end of phase 3At last visitRaceEthnicity1M4 monthsPegademase, 18 years19 years0.08–0.18Jan 12, 202310.933.74103.76<0.0020.0100.007WhiteHispanic or Latino2F∼2 yearPegademase, 13 years16 years0.3Jan 17, 202314.2646.1797.66<0.0020.0080.004WhiteOther3M∼2 monthsPegademase, 17 years18 years0.17Mar 23, 202112.3536.2565.39<0.002<0.0020WhiteOther4F∼5 yearsPegademase, 24 years31 years0.26–0.3Jan 18, 202311.3334.5557.6<0.002<0.0020.003WhiteHispanic or LatinoaOptimal trough plasma ADA activity was considered to be 30 mmol/h/L or higher.bDetoxified erythrocyte dAXP concentration was defined as 0.02 mmol/L or lower. Conclusions Long-term elapegademase was well tolerated with patients achieving stable plasma ADA and dAXP levels and maintaining metabolic detoxification for up to 8 years. This cohort received long duration of ERT for ADA-SCID to date, with up to 30 years of continuous treatment, remaining clinically stable without any new safety concerns.

Abstract licence: CC BY

Introduction Adenosine deaminase (ADA) deficiency is the second most common cause of severe combined immunodeficiency (SCID), leading to progressive T, B, and natural killer cell lymphopenia due to toxic metabolite accumulation. Early diagnosis, continuous monitoring, and timely intervention are critical to preventing irreversible complications, even in patients undergoing bone marrow transplantation (BMT). Case Presentation We present three patients with ADA-SCID managed with BMT and enzyme replacement therapy (ERT) posttransplant, demonstrating distinct therapeutic approaches and long-term outcomes. Patient 1, a 27-year-old female, underwent maternal HSCT at 1 month of age, achieving partial T cell engraftment but absent B cell recovery. Delayed initiation of ERT with elapegademase in adulthood improved biochemical markers but failed to prevent severe complications, including autoimmunity, neurocognitive decline, and adrenal insufficiency. Patient 2, a 26-year-old female, received multiple interventions including failed haploidentical HSCT and two autologous gene therapy infusions in early childhood. Due to limited engraftment, she required long-term ERT, transitioning from pegademase to elapegademase. Despite sustained deoxyadenosine nucleotide suppression, she developed chronic lung disease, metabolic dysfunction, and immune dysregulation. Patient 3, a 3-year-old female, was diagnosed through newborn screening and initiated on pretransplant ERT before undergoing matched unrelated donor HSCT at 11 months. Despite early intervention, she experienced graft failure and is currently maintained on elapegademase. Discussion This series highlights the clinical heterogeneity of ADA-SCID and underscores the critical, long-term role of ERT, not only as a bridge to definitive therapy but also as an essential ongoing treatment in cases of incomplete or failed engraftment. While early HSCT or gene therapy offers curative potential, delays or failures can result in irreversible damage. These cases emphasize the importance of universal newborn screening and sustained access to ERT, particularly in resource-limited settings.

Abstract licence: CC BY