1. Basic introduction of Elapegademase
Elapegademase, is a PEGylated recombinant adenosine deaminase. It can be defined molecularly as a genetically modified bovine adenosine deaminase with a modification in cysteine 74 for serine and with about 13 methoxy polyethylene glycol chains bound via carbonyl group in alanine and lysine residues. Elapegademase is generated in E.coli, developed by Leadiant Biosciences and FDA approved on October 5, 2018. Originally a targeted Enzyme Replacement Therapy (ERT) product, it is composed of the dimeric group Recombinant Adenosine Deaminase (rADA) and Polyethylene Glycol (PEG). PEGylation is a method to enhance the therapeutic effect of drugs by lowering the metabolic rate and enhancing the pharmacokinetics of drugs. In Elapegademase, rADA acts as a core component that accelerates adenosine metabolism, thereby improving immune function in patients with severe congenital immunodeficiency disease (SCID).
2. Clinical application and research progress
Elapegademase was approved by the U.S. Food and Drug Administration (FDA) in 1990 for the treatment of patients with SCID. SCID is a rare but serious congenital immune deficiency in which the immune system cannot repair damaged cells, leading to susceptibility to infections, allergies, and even death. In patients with SCID, the lack of ADA(Adenosine Deaminase), a key enzyme, leads to the accumulation of adenosine diphosphate (ADP) and adenosine receptors, which seriously impair the function of the T and B cell immune system. Elapegademase is used to replace the function of ADA and accelerate the metabolism of adenosine metabolites, thereby improving the function of the patient's immune system.
The efficacy and safety of Elapegademase have been confirmed by FDA-approved clinical trials and multiple large-scale clinical studies. Today, Elapegademase has become a common treatment option for SCID patients and is widely used in clinical practice.
In addition, Elapegademase is also used to treat other diseases caused by ADA deficiency, such as ADA deficiency caused by sexual inheritance or pheochromocytoma complicated by ADA deficiency. Because these diseases all cause the same ADA deficiency, this alternative enzyme therapy is also feasible in their treatment.
The application of Elapegademase has also been further extended to the treatment of diseases related to uric acid metabolisms, such as gout and related uric acid crystal disease. Gout is a disorder caused by an imbalance in uric acid metabolism, with symptoms including pain, redness, and elevated local temperature. Some recent studies have shown that the new ADA agent Elapegademase can accelerate the metabolism of uric acid in the body, thereby reducing uric acid levels and improving the condition of gout patients.
In terms of efficacy, several clinical studies have shown that Elapegademase can significantly reduce pain, redness, and other related symptoms in patients, reduce uric acid levels, improve kidney function, and is well tolerated and safe. This means that Elapegademase has great potential in the treatment of gout and may become a new gout treatment.
3. Problems and prospects
Due to the special nature of its ERT, Elapegademase has some potential safety risks and limitations. For example, because Elapegademase is given to patients by injection, allergic reactions and local irritation reactions may occur. In addition, Elapegademase requires regular infusions to maintain the patient's immune system function and stable efficacy. This makes the use of Elapegademase subject to certain restrictions and regulations.
It should be noted that Elapegademase is still in the early stage of clinical research in the treatment of gout, and the study sample is relatively small. Its efficacy, safety, and tolerability need further research and validation. If successful in the future, this novel ADA formulation has the potential to become an important tool in the field of gout treatment, and will also provide new ideas and hope for the treatment of related uric acid crystal disease.
However, despite some limitations and safety risks, Elapegademase has still considered an effective SCID treatment and is widely used in many clinical practices. Ongoing research and clinical trials will continue to further explore the potential, efficacy, and safety of Elapegademase to provide more effective treatments for future clinical applications.
References
- Bhutani P, Joshi G, et al.. U.S. FDA Approved Drugs from 2015-June 2020: A Perspective. J Med Chem. 2021 Mar 11;64(5):2339-2381.
- Luis M, Sneha S, et al.. Long-Term Immune Reconstitution in ADA-Deficient Patients Treated With Elapegademase: A Real-World Experience, The Journal of Allergy and Clinical Immunology: In Practice, Volume 11, Issue 6, 2023, 1725-1733.
- Dorsey M, Rubinstein A, et al. PEGylated Recombinant Adenosine Deaminase Maintains Detoxification and Lymphocyte Counts in Patients with ADA-SCID. J Clin Immunol 43, 951–964 (2023).
