Adenosine deaminase (ADA), encoded by the ADA gene, is a key enzyme in the purine salvage pathway. Inborn genetic variants of ADA result in a rare and potentially fatal autosomal recessive disorder, adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) [1, 2, 3]. ADA-SCID occurs in approximately 1 in 200,000–1,000,000 newborns [2, 4], accounting for approximately 10–15% of SCID cases [5].

Variants in the ADA gene on chromosome 20q12-q13.11 cause a systemic deficiency in ADA expression, with T, B, and NK cells being the most susceptible to accumulation of purine metabolites [1, 2, 3, 6]. The types of mutations are vast, with greater than 70 causative, pathogenic mutations identified in ADA-SCID [1]. The toxic levels of deoxyadenosine nucleotides (dAXP) in these cells results in SCID and a high risk of opportunistic infections [1, 2, 3, 7, 8]. High levels of toxic metabolites can cause non-immunologic manifestations of the pulmonary, skeletal, dermatologic, gastrointestinal, and other systems [6].

The age of onset and severity of the disease are related to the type of variant and its resulting level of ADA expression [9, 10]. ADA deficiency can be further classified as early-onset (i.e. infants and small children) ADA-SCID; or less severe delayed (i.e. usually diagnosed between 1 and 10 years), or late-onset (i.e. diagnosed between 2nd to 4th decades) combined immunodeficiency (ADA-CID) [3]. Typical early onset ADA-SCID presents as a life-threatening disease in the first weeks to months of life with poor growth [3]. In countries where newborn screening is practiced and affected infants are detected early, ADA-SCID may be asymptomatic despite severe lymphopenia [3]. Less severe phenotypes of ADA-CID, which accounts for up to 20% of cases, are rarer than ADA-SCID, and typically present with infections or autoimmunity [3]. Following the inception of newborn screening in the U.S., overall survival of patients with ADA-SCID has nearly doubled [11]. Early diagnosis and prompt treatment of ADA-SCID improves survival, reduces infection risks, and enhances quality of life; if left undiagnosed and untreated, children usually die before 2 years of age [1, 2, 3].

Allogeneic hematopoietic stem cell transplant (HSCT) or autologous hematopoietic stem cell gene addition therapy (HSC-GT) are the only definitive therapies available for patients with ADA-SCID [3, 5]. Enzyme replacement therapy (ERT) is the primary treatment for ADA-SCID (1) until patients can receive HSCT or HSC-GT; (2) when transplant therapy fails to recover immune function to acceptable level [3, 12]; or (3) when definitive therapy is not an option [13, 14]. ERT serves as an exogenous source of functional ADA enzyme [15], which reduces dAXP in lymphocytes and nonimmune cells, promoting immune recovery, reducing severe infections, supporting normal growth, and preventing or reversing organ damage [3, 15, 16]. ERT does not cure the disease, and treatment must be given regularly to maintain detoxification [3].

ERT with Adagen® (pegademase), a PEGylated modified bovine ADA, started in the United States in 1990 and has been used in the EU since the early 2000s. Hundreds of patients worldwide have received pegademase to treat complications of ADA deficiency [12, 17]. Pegademase treatment rapidly increases plasma ADA activity and reduces intracellular dAXP metabolites [18]. More than 80% of ADA-SCID patients who received ADA ERT had increased T, B and/or NK cell counts, generated naïve T and B cells, and improved T cell functions [19].

To reduce the risk of bovine spongiform encephalopathy (BSE) and the dependence on bovine-derived products, elapegademase (Revcovi®, elapegademase-lvlr), a PEGylated recombinant bovine ADA replaced pegademase in 2018 [18]. Elapegademase is the only U.S. Food and Drug Administration (FDA)-approved ERT for ADA-SCID in pediatric and adult patients [15]. Compared to pegademase, elapegademase has no risk of transmitting BSE and has a prolonged stability due to its succinimidyl carbonate linker, which does not affect enzyme activity [16, 18, 20].

Due to the ultra-rare nature of ADA-SCID, there is limited clinical experience with elapegademase. In a U.S. Phase 3 clinical trial (STP-2279-002), elapegademase provided therapeutic trough plasma ADA activity, safely maintained metabolic detoxification, and maintained or improved lymphocyte counts in six patients with ADA-SCID who were previously on pegademase therapy (mean elapegademase exposure: 135.7 weeks per patient) [16]. Similarly, in a multicenter, single-arm, open‐label, Phase 3 and post-marketing clinical study of elapegademase in Japan, four patients with ADA-SCID achieved undetectable levels of dAXP, sufficient ADA activity, increased T and B cell numbers, and slightly elevated IgM and IgA immunoglobulin levels [21].

Since the clinical studies with elapegademase were in a small group of patients over a short period of time, additional data collected during patients’ routine clinical care are crucial for further understanding the effectiveness and safety. In a case series of newly diagnosed infants with ADA-SCID, all identified by newborn screening, elapegademase treatment reconstituted B and NK cells in two patients within the first month, followed by naïve T cells one month later [17]. A third patient reconstituted all lymphocyte subsets within the first month of ERT treatment. Erythrocyte dAXP levels declined by Week 17 in all patients. Another study from eight U.S. and five Canadian centers analyzed retrospective data from 17 patients’ medical charts [18]. Most patients with ADA-SCID treated for six months or more with elapegademase increased plasma ADA activity and decreased dAXP. Six ERT-naïve infants treated with elapegademase demonstrated increased CD4 + T and CD19 + B cell numbers. Treatment also resolved many clinical and lab complications of ADA deficiency such as depleted lymphocyte subset counts, low ADA activity, hypogammaglobulinemia, infections, weight loss etc. Patients that had transitioned from pegademase to elapegademase had no new adverse effects.

Here we report real-world experience from the elapegademase registry (NCT03878069), a single arm, open-label, multicenter registry study in patients with ADA-SCID who required ERT treatment with elapegademase. The registry was carried out as a post-marketing commitment [22], and started shortly after the approval of elapegademase in the U.S. by the FDA. The first patient was enrolled on 30 Sep 2019; patients were followed for at least two years or until they had undergone allogeneic HSCT. The study completed on 18 Jan 2023.