Adenosine deaminase is an ultra-rare and inherited disorder that is detrimental to the immune system and causes severe combined immune deficiency.
On October 5, 2018, the FDA approved Revcovi (elapegademase-lvlr) for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult patients. The drug is an enzyme replacement therapy developed by Leadiant Biosciences.1
“This is a great day for people living with ADA-SCID and their families as the approval of Revcovi gives them a path forward,” said John Boyle, president and chief executive officer of the Immune Deficiency Foundation. “We commend Leadiant Biosciences for bringing this innovative enzyme replacement therapy to market and for helping to advance scientific understanding of ADA-SCID.”2
ADA is an ultra-rare and inherited disorder that is detrimental to the immune system and causes SCID. ADA-SCID is estimated to occur in 1 in 200,000 to 1 in 1 million newborns in the world.3
Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life. Without treatment, these babies usually do not survive passed age 2. In about 10% to 15% of cases, onset of immune deficiency is delayed to between 6 and 24 months of age (delayed onset) or even until adulthood (late onset).
Patients with SCID lack immune protection from pathogens and are prone to repeated infections that can be fatal. These infections are often caused by opportunistic organisms that ordinarily do not cause illness in people with a normal immune system. 4
"For decades, physicians, patients, and their families have relied upon enzyme replacement therapy as a life-saving treatment for adenosine deaminase severe combined immunodeficiency, a disease in which the buildup of toxic metabolites can cripple children's immune systems," Morna Dorsey, MD, MMSc, professor of pediatrics at the University of California, San Francisco, said in the news release. "Individuals with ADA-SCID are at an increased risk of severe and recurrent infections and often fail to thrive. By providing specific and direct replacement of the adenosine deaminase enzyme, Revcovi can reduce patients' risk of potentially serious, life-threatening infections and their debilitating complications."
Leadiant is working with physicians, payers, and policymakers to bring elapegademase-lvlr to patients in need. The company offers comprehensive treatment support, from disease state education to navigating reimbursement and patient assistance programs.
The company’s post-marketing commitment includes a clinical study, which will record information about the health status of patients using elapegademase-lvlr. This initiative will help Leadiant better understand and track information about elapegademase-lvlr following approval as well as provide critical information about the efficacy and safety of elapegademase-lvlr, especially in newly diagnosed patients.
Mechanism of Action
ADA enzyme is involved in purine metabolism, catalyzing the irreversible hydrolytic deamination of adenosine or deoxyadenosine to inosine or deoxyinosine, respectively, as well as several naturally occurring methylated adenosine compounds. Maintaining a low level of 2’-deoxyadenosine and adenosine is crucial for a proper number and function of immune cells as well as decreasing the frequency of opportunistic infections.
Elevated adenosine levels, as occurring in ADA deficiency, contribute to apoptosis and a block in the differentiation of thymocytes, causing severe T-lymphopenia. Elapegademase-lvlr provides an exogenous source of ADA enzyme that is associated with a decrease in toxic adenosine and deoxyadenosine nucleotides levels as well as an increase in lymphocyte numbers.
Elapegademase-lvlr is for intramuscular (IM) injection only. Follow sterile IM administration technique guidelines appropriate to the patient’s age and anatomy (ie choice of needle gauge and length, site of administration). Take precautions not to inject into or near an artery or nerve. Alternate the injection site periodically.
The starting weekly dose of IM injection is 0.4 mg/kg based on ideal body weight, divided into 2 doses (0.2 mg/kg twice a week), intramuscularly for a minimum of 12 to 24 weeks until immune reconstitution is achieved. After that, the dose may be gradually adjusted down to maintain through ADA activity more than 30 mmol/hr/L, trough dAXP level under 0.02 mmol/L and/or to maintain adequate immune reconstitution based on clinical assessment of the patient.
The optimal long-term dose and schedule of administration should be established by the treating physician for each patient individually and may be adjusted on the laboratory values for trough ADA activity, trough dAXP level, and/or on the treating physician’s medical assessment of the patient’s clinical status.
Patients transitioning from Pegademase Bovine (Adagen) to Elapegademase-lvlr
If a patient’s weekly pegademase bovine dose is unknown or a patient’s weekly dose is at or lower than 30 U/kg, the recommended minimum starting dose of elapegademase-lvlr is 0.2 mg/kg, intramuscularly, once a week. If a patient’s weekly pegademase bovine dose is above 30 U/kg, an equivalent weekly elapegademase-lvlr dose (mg/kg) should be calculated using the following conversion formula: elapegademase-lvlr dose in mg/kg = (pegademase bovine dose in U/kg) / (150).
Subsequent doses may be increased by increments of 0.033 mg/kg weekly if trough ADA activity is under 30 mmol/hr/L, trough deoxyadenosine nucleotides (dAXP) are above 0.02 mmol/L, and/or the immune reconstitution is inadequate based on the clinical assessment of the patient. The total weekly dose may be divided into multiple intramuscular administrations during a week.
Elapegademase-lvlr is for IM injection only. Follow sterile IM administration technique guidelines appropriate to the patient’s age and anatomy. Take precautions not to inject into or near an artery or neve. Alternate injection site periodically.
Preparation of Injection Procedure Instructions
Elapegademase-lvlr was administered intramuscularly in 2 prospective, open-label, single-arm, multi-center studies to evaluate the efficacy, safety, tolerability, and pharmacokinetics in patients with ADA-SCID. Overall, 10 patients were treated.
Study 1 is a 1-way crossover study conducted in the United States to evaluate the safety, efficacy, and pharmacokinetics of elapegademase-lvlr in patients with ADA-SCID who were receiving therapy with pegademase bovine. Six patients, 8 to 37 years of age enrolled in the study. Patients’ exposure to elapegademase-lvlr ranged from 2 weeks to 146 weeks. The study treatment consists of 3 phases: Adagen Lead-in Phase (minimum of 3 weeks), the REVCOVI Treatment Phase (weeks 1 through 21) and followed by the REVCOVI Maintenance Phase.
The efficacy endpoints assessed were as follows:
No deaths were reported and one patient discontinued treatment due to injection site pain associated with an earlier drug product formulation that was consequently modified.
Study 2 is a single-arm clinical study that was conducted to assess the safety, efficacy, and pharmacokinetics of elapegademase-lvlr in patients with ADA-SCID in Japan. Four patients aged 3.4 months to 25 years, all Asian, were enrolled in the study. Three patients received elapegademase-lvlr for 21 weeks and 1 patient received it for 15 weeks. The study includes 2 phases:
1) Evaluation, consisting of a dose adjustment period (5 weeks) and a dose maintenance period (16 weeks).
2) Continuous Administration (Extension) Phase, to be continued until the end of the study.
One death due to CMV pneumonitis and respiratory failure was observed in an infant who had also experienced pulmonary hemorrhage, respiratory failure, and upper respiratory tract infection that represented serious adverse events.
Warnings and Precautions
Since elapegademase-lvlr is administered by IM injection, it should be used with caution in patients with thrombocytopenia and should not be used if thrombocytopenia is severe.
Maintain precautions to protect immune deficient patients from infections until improvement in immune function has been achieved. The timing and degree of improvement in immune function may vary from patient to patient.
Use in Specific Populations
Adequate and well-controlled studies with elapegademase-lvlr have not been conducted in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with elapegademase-lvlr. It is not known whether elapegademase-lvlr can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. No pregnancy was reported for any patients receiving elapegademase-lvlr.
Human or animal lactation studies have not been conducted to assess the presence of elapegademase-lvlr in breast milk, the effects on the breastfed infant, or the effects on milk production for the mother.
The safety and efficacy of elapegademase-lvlr have been established in pediatric patients.
Revcovi was not studied in patients 65 years and older.
The drug interaction potential of elapegademase-lvlr is not known.
In study 1, the most common adverse reactions were cough (3 of 6 patients) and vomiting (2 of 6 patients).
In study 2, the most common adverse events were respiratory infections (2 of 4 patients).
Storage and Handling
Store Revcovi in the refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or shake. Elapegademase-lvlr should not be used if there are any indications that it may have been frozen.
About the Author
Christa Eans earned her Bachelor of Science in Pharmaceutical Sciences and Doctor of Pharmacy degrees from the University of Pittsburgh. She most recently earned her Master of Science in Pharmacy Business Administration (MSPBA) at the University of Pittsburgh, a 12-month, executive-style graduate education program designed for working professionals striving to be tomorrow’s leaders in the business of medicines. Christa has spent the last 5 years working in Specialty Pharmacy, initially as a clinical pharmacist and most recently as the Manager of Clinical Programs. Christa is credentialed as a HIV Pharmacist (AAHIVP) through the American Academy of HIV Medicine and a Certified Specialty Pharmacist through the Specialty Pharmacy Certification Board.