What is Revcovi?1
Revcovi is a new enzyme replacement therapy (ERT) indicated for the treatment of patients with adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult patients. Revcovi is a PEGylated recombinant adenosine deaminase (rADA) enzyme pegylated using a succinimidyl carbamate (SC) linker.
How does Revcovi differ from pegademase bovine?
Revcovi is the product of recombinant technology, thus eliminating the need to source the ADA enzyme from animals. Leadiant developed it to replace the ADA (nADA) that is used in the manufacture of pegademase bovine injection. The succinimidyl carbamate (SC) linker used in Revcovi is more stable than the succinimidyl succinate (SS) linker used in pegademase bovine injection, reducing spontaneous dePEGylation and improving shelf-life. Recombinant technology eliminates exogenous proteases and the need for animal-sourced proteins, thus maintaining consistent supply.
Why is a recombinant version of pegademase bovine needed?
Revcovi is the product of recombinant technology, thus eliminating the need to source the adenosine deaminase (ADA) enzyme from animals. In addition, Revcovi™ combines the recombinant ADA enzyme with a more stable linker, reducing spontaneous PEGylation and improving shelf-life.
Pegademase bovine was produced by obtaining the enzyme adenosine deaminase (ADA) from cow intestine. The naturally derived bovine ADA (nADA) was then purified and PEGylated to produce the treatment. The bovine derived nADA used to manufacture pegademase bovine is no longer available in the market. Therefore, to maintain continuity of supply of PEGylated ADA for the treatment of ADA-SCID, a new source of the enzyme was needed.
What is ADA-SCID?
ADA-SCID is an acronym for adenosine deaminase severe combined immune deficiency. It is an ultra-rare, inherited genetic disorder, caused by a deficiency in the adenosine deaminase (ADA) enzyme, that is often fatal if left untreated.2, 3
ADA-SCID is a primary immune deficiency (PID) disease, a group of more than 350 rare, chronic disorders in which part of the body’s immune system is missing or functions improperly. These diseases are usually caused by hereditary or genetic defects (mutations).4
In SCID, the term “severe” is used because the extent of the defect can lead to death from infections in infancy or early childhood that a normal immune system would manage more effectively. The term “combined” is due to the presence of defects in both cell-mediated (T-lymphocytes) immunity and humoral-antibody production (defects in B- lymphocytes).5
What causes ADA-SCID?3
ADA-SCID results from defects in the adenosine deaminase (ADA) gene, which provides instructions for producing the ADA enzyme. This enzyme is found throughout the body but is most active in lymphocytes. When functioning properly, the ADA eliminates adenosine and deoxyadenosine, which are toxic at high concentrations to lymphocytes. If the enzyme is reduced or absent then these toxic metabolites damage lymphocytes and render the immune system deficient risking life threatening infections.3
How is the ADA enzyme affected by mutations in the ADA gene?
Adenosine deaminase converts adenosine to inosine and deoxyadenosine to deoxyinosine, molecules that do not harm lymphocytes. However, mutations in the ADA gene reduce or eliminate the activity of adenosine deaminase, allowing the buildup of adenosine and deoxyadenosine to toxic levels.3 These toxic levels cause T-cells and B-cells to accumulate biologic chemicals that would normally be processed by ADA. The buildup of these biologic byproducts in excess of normal causes the T-cells and B-cells to die, leaving affected individuals with insufficient immune defense and increasing their risk of infection.3
How is ADA activity assessed?
ADA is typically assessed by measuring activity of the ADA enzyme in plasma or serum.
How is Erythrocyte dAXP assessed?
Red blood cells (RBCs) are assayed for levels of deoxyadenosine nucleotides (dAXP, the sum of adenosine mono/di/tri phosphate [dAMP+dADP+dATP]) or dATP alone in RBCs. RBC dAXP is a surrogate marker for dAXP concentrations in immune cells.3
What is the rationale for enzyme replacement therapy (ERT) to treat ADA-SCID?
Once ADA is supplemented in the plasma by ERT, it breaks down plasma adenosine and deoxyadenosine rapidly, allowing for an outward movement of adenosine and deoxyadenosine from inside the cell into the plasma. Diffusion of adenosine into the plasma leaves it less available for the formation of the toxic metabolites dAXP, especially dATP.3,6
ERT with ADA mostly corrects the metabolic abnormalities associated with adenosine accumulation (due to the absence of ADA) and reduces toxic levels of adenosine metabolites from accumulating in immune cells. Improvement in immune cell number and function and diminished frequency of opportunistic infections occurs only after correction of the metabolic abnormalities.3,6
The metabolic detoxification afforded by ERT allows clinical stabilization of patients.8 By maintaining metabolic detoxification, increasing plasma ADA levels, and improving lymphocyte counts to normal or near normal, ERT may improve clinical outcomes for patients with ADA-SCID.3,6
How common is ADA-SCID?
ADA-SCID is an ultra-rare disease. It is estimated to occur in approximately 1 in 200,000 to 1 in 1 million newborns around the world.3
About how many people with SCID have the ADA-SCID variant?
ADA-SCID accounts for ~15% of SCID cases.3
At what age is ADA-SCID diagnosed?
ADA-SCID is typically diagnosed within the first few months of life.3 However, with the addition of SCID to the newborn screening panel in the U.S., the average age of diagnosis may become lower.
Why is early diagnosis important?
Without early diagnosis and effective treatment, babies with ADA-SCID usually die from infections before they reach two years of age. The disease is typically diagnosed within the first few months of life. In all 50 states, the District of Columbia, and Puerto Rico, newborn screening for SCID allows for timely detection of ADA-SCID in newborns and early initiation of enzyme replacement therapy.3,7
Is there a screening test for ADA-SCID? Is it required in the U.S.?
If the mutation leading to SCID in a family is known, an at-risk fetus can be tested using DNA sequencing. However, SCID is so rare that prenatal testing of a baby with no family history is probably not justified because the test is so expensive.3,7
A new test known as T-cell Receptor Excision Circles (TREC) can be done at birth to identify babies with SCID and intervene with supportive care. This test is part of the newborn screening panel performed on dried blood spots. Babies found to screen positive for SCID can have assays (enzyme tests) and genetic testing for ADA to determine whether they have ADA deficiency before symptoms or illness develop.3,7
All 50 states, the District of Columbia, and Puerto Rico are currently screening newborns for SCID, reaching a total of 3,968,667 newborns screened per year (100%), including screening in the Navajo population in Arizona.8
- Revcovi® (elapegademase-lvlr) Injection prescribing information. Leadiant Biosciences, Inc.; 2018.
- Whitmore KV, Gaspar HB. Adenosine deaminase deficiency – more than just an immunodeficiency. Front Immunol. 2016; 7:314. doi: 10.3389/fimmu.2016.00314.
- Hershfield M. Adenosine deaminase deficiency. Gene Reviews [Internet]. Initially posted October 2006; updated March 2017. Available at https://www.ncbi.nlm.nih.gov/books/NBK1483/. Accessed January 8, 2019
- About Primary Immune Deficiencies. Immune Deficiency Foundation. https://primaryimmune.org/about-primary-immunodeficiencies. Accessed January 9, 2019.
- Severe Combined Immune Deficiency and Combined Immune Deficiency. Immune Deficiency Foundation. https://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/severe-combined-immune-deficiency-and-combined-immune-deficiency. Accessed January 9, 2019.
- Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, Grunebaum E. Consensus Approach for the Management of Severe Combined Immune Deficiency Cuased by Adenosine Deaminase Deficiency. J Clin Allergy Immunol. 2018 5 pii: S0091-6749(18)31268-5. doi: 10.1016/j.jaci.2018.08.024
- Kwan A, Puck JM. History and Current Status of Newborn Screenning for Severe Combined Immunodeficiency. Semin. Perinatol 2015;39(3):194-205
- IDF SCID Newborn Screening Campaign. Immune Deficiency Foundation. https://primaryimmune.org/idf-advocacy-center/idf-scid-newborn-screening-campaign. Accessed January 9, 2019.
Revcovi (elapegademase-lvlr) is indicated for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult patients.
Important safety information
Warnings and precautions:
- Injection site bleeding in patients with thrombocytopenia: Increased risk of local bleeding in patients with thrombocytopenia; should not be used if thrombocytopenia is severe.
- Delay in improvement of immune function: Protect immune deficient patients from infections until improvement in immune function.
The most commonly reported adverse reactions were cough and vomiting.
In addition, the following post-marketing reports for the same class of enzyme replacement therapy used in the treatment of ADA-SCID, may also be seen with Revcovi treatment:
- Hematologic events: hemolytic anemia, autoimmune hemolytic anemia, thrombocythemia, thrombocytopenia and autoimmune thrombocytopenia
- Dermatological events: injection site erythema, urticaria
Important monitoring information:
Treatment with Revcovi should be monitored by measuring trough plasma ADA activity and trough dAXP levels for maintenance of therapeutic targets. If a persistent decline in plasma ADA activity occurs, immune function and clinical status should be monitored closely, and precautions should be taken to minimize the risk of infection.
Please refer to Revcovi’s Full Prescribing Information.