Pegademase 375units/1.5ml solution for injection vials

PurposeMetabolic 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.MethodsAfter 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.ResultsOne 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.ConclusionElapegademase 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

Adenosine deaminase deficiency (ADA) is a rare, inherited disorder of purine metabolism characterized by immunodeficiency, failure to thrive and metabolic abnormalities. A lack of the enzyme ADA allows accumulation of toxic metabolites causing defects of both cell mediated and humoral immunity leading to ADA severe combined immune deficiency (SCID), a condition that can be fatal in early infancy if left untreated. Hematopoietic stem cell transplant is curative but is dependent on a good donor match. Other therapeutic options include enzyme replacement therapy (ERT) with pegademase bovine (PEG-ADA) and more recently gene therapy. PEG-ADA has been used in over 150 patients worldwide and has allowed stabilization of patients awaiting more definitive treatment with hematopoietic stem cell transplant. It affords both metabolic detoxification and protective immune function with patients remaining clinically well, but immune reconstitution is often suboptimal and may not be long lived. We discuss the pharmacokinetics, immune reconstitution, effects on systemic disease and side effects of treatment with PEG-ADA. We also review the long-term outcome of patients receiving ERT and discuss the role of PEG-ADA in the management of infants and children with ADA-SCID, alongside other therapeutic options.

Abstract licence: CC BY-NC 3.0

PurposeThe 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.MethodsPatients 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.ResultsThirty-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.ConclusionEffectiveness 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 4.0

This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study designed to assess the efficacy and safety of a cryopreserved formulation of OTL-101 (autologous CD34+ hematopoietic stem/progenitor cells transduced ex vivo with EFS (Elongation Factor 1α Short form) Lentiviral Vector (LV) encoding for the human ADA gene) administered to ADA-SCID subjects between the ages of 30 days and 17 years of age, who are not eligible for an Human Leukocyte Antigen (HLA) matched sibling/family donor and meeting the inclusion/exclusion criteria. The OTL-101 product is infused after a minimal interval of at least 24 hours following the completion of reduced intensity conditioning. For subjects who successfully receive the OTL-101 product, pegademase bovine (PEG-ADA) Enzyme Replacement Therapy (ERT) is discontinued at Day+30 (-3/+15) after the transplant. After their discharge from hospital, the subjects will be seen at regular intervals to review their history, perform examinations and draw blood samples to assess immunity and safety. Conditions: Severe Combined Immunodeficiency Due to ADA Deficiency. Interventions: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101), busulfan, PEG-ADA ERT.

Source: ClinicalTrials.gov (public domain)