Revcovi Drug Information
Generic name: ELAPEGADEMASE-LVLR
Uses of Revcovi
is indicated for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult patients. REVCOVI is a recombinant adenosine deaminase indicated for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult patients.
Dosage & Administration of Revcovi
Side Effects of Revcovi
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. REVCOVI was administered intramuscularly in two prospective, open-label, single-arm, multi‑center studies to evaluate efficacy, safety, tolerability, and pharmacokinetics in patients with ADA-SCID: Study 1 was performed in the US and Study 2 was performed in Japan . Overall, 10 patients were treated and adverse reactions reported are summarized below. Study 1 Study 1 is a one-way crossover study, conducted in the US, to evaluate the safety, efficacy, and pharmacokinetics of REVCOVI in patients with ADA‑SCID who were receiving therapy with Adagen.
Six patients, 8 to 37 years of age enrolled in the study. Patients' exposure to REVCOVI ranged from 2 weeks to 146 weeks. 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.
The most common adverse reactions were cough (3/6 patients) and vomiting (2/6 patients). Other adverse reactions that were reported in one patient each were: abdominal pain upper, arthralgia, asthenia, cerumen impaction, conjunctivitis, convulsion, dental caries, diarrhea, ear canal irritation, ear lobe infection, epistaxis, fatigue, fungal skin infection, gait disturbance, gastrointestinal infection, groin abscess, hematochezia, haemophilus infection (pulmonary), hemoptysis, influenza, injection site discomfort, laceration, lymphadenopathy, migraine, nasal edema, nausea, nephrolithiasis, oral candidiasis, oropharyngeal pain, otitis externa, productive cough, rash, stoma site infection, swelling face, tooth abscess, tooth extraction and upper respiratory tract infection, regardless of investigator causality assessment. Study 2 Study 2 is a single-arm clinical study that was conducted to assess the safety, efficacy and pharmacokinetics of REVCOVI in patients with ADA-SCID. Four patients 3.4 months to 25 years of age, all Asian, were enrolled in the study and received REVCOVI. Three patients received REVCOVI for 21 weeks and one patient received REVCOVI for 15 weeks. 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.
Neutropenia was a serious adverse reaction reported by one of the patients. There were 22 reported adverse events for four patients. Most common adverse events were respiratory infections (2/4 patients).
Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity.
The immunogenicity results from Study 1 and Study 2 suggest that patients who previously received Adagen may present an immunologic response to REVCOVI. Therefore, monitoring for changes in ADA levels during REVCOVI treatment is recommended. The observed incidence of antibodies (including neutralizing antibodies) is dependent on assay sensitivity and specificity, assay methodology, and concomitant medications. Therefore, the comparison of the incidence of antibodies to REVCOVI with the incidence of antibodies to other products may be misleading.
Postmarketing Experience with
ADAGEN The following postmarketing adverse reactions were voluntarily reported for Adagen, the same class of enzyme replacement therapy used in the treatment of ADA-SCID, and may also be seen with REVCOVI treatment: Hematologic: hemolytic anemia, auto-immune hemolytic anemia, thrombocythemia, thrombocytopenia and autoimmune thrombocytopenia Dermatological: injection site erythema, urticaria Lymphomas Since these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Warnings & Cautions for Revcovi
Injection Site Bleeding in Patients with Thrombocytopenia
Since REVCOVI is administered by IM injection, it should be used with caution in patients with thrombocytopenia and should not be used if thrombocytopenia is severe.
Delay in Improvement of Immune Function 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.
Drug Interactions with Revcovi
The drug interaction potential of REVCOVI is not known.
Pregnancy Safety for Revcovi
Pregnancy Risk Summary Adequate and well-controlled studies with REVCOVI have not been conducted in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with REVCOVI. It is not known whether REVCOVI can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. All pregnancies have a risk of birth defect, loss, or other adverse outcomes.
In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human No pregnancy was reported for any patients receiving REVCOVI. There are two reports of confirmed cases of successful pregnancy and delivery in ADA-SCID patients treated with Adagen (the same class of enzyme replacement therapy used in the treatment of ADA-SCID). No teratogenic effects of Adagen were reported. For patients treated with REVCOVI, more frequent monitoring of the health status for both the mother during pregnancy and the development of the offspring is recommended.
Pediatric Use of Revcovi
Pediatric Use The safety and efficacy of REVCOVI have been established in pediatric patients.
Overdosage Information for Revcovi
There are no reports of administration of REVCOVI in excess of the prescribed doses. The highest weekly prescribed dose administered in the clinical studies was 0.4 mg/kg. In nonclinical studies, there was no evidence of toxicity related to study drug at doses up to 1.8-fold the clinical dose (based on mean human AUC normalized to the dose of REVCOVI administered per patient), except for a slight increase in activated partial thromboplastin time (APTT).
Clinical Studies of Revcovi
Study 1 Study 1, conducted in the US (NCT 01420627), is an
ongoing Phase 3, open-label, multicenter, single-arm, one-way crossover study of REVCOVI. The purpose of this clinical study is to evaluate the safety, efficacy, and PK of REVCOVI in 6 patients with ADA-SCID, 4 males and 2 females, who are receiving therapy with Adagen. The study treatment consists of three phases: Adagen Lead-in Phase (minimum of 3 weeks), the REVCOVI Treatment Phase (weeks 1 through 21), and followed by the REVCOVI Maintenance Phase. Six patients treated in the study were 8 to 37 years of age at the start of the study.
The starting weekly dose of REVCOVI was calculated based on the last Adagen dose received in the study. Weekly REVCOVI doses ranged from 0.188 mg/kg to 0.292 mg/kg. The efficacy endpoints assessed were as follows: Trough dAXP Level (metabolic detoxification was defined as a trough erythrocyte dAXP concentration equal to or below 0.02 mmol/L) Trough plasma ADA activity (adequate trough plasma ADA activity is defined as trough plasma ADA activity equal to or above 15 mmol/hr/L) Immune status (lymphocyte and B-, T-, and NK-lymphocyte subset counts as well as quantitative immunoglobulin concentration ) A PK assessment was performed during Week 9 of the REVCOVI Treatment phase . Five of six patients reached the 21-week endpoint of the Treatment Phase, and three of six patients received treatment with REVCOVI (elapegademase-lvlr) for over 135 weeks.
These patients (except for one value in a patient at Treatment Week 47) had erythrocyte dAXP concentration equal to or below 0.02 mmol/L. These patients had trough plasma ADA activity equal to or above 15 mmol/hr/L at 88/89 timepoints and maintained metabolic detoxification for at least 2 years under REVCOVI treatment. Patients achieved trough plasma ADA activity above 30 mmol/hr/L by week 5, except for one patient who achieved this level at week 1. The mean trough plasma ADA activity for patients receiving REVCOVI at a normalized dose of 0.2 mg/kg/week were 34.3 ± 6.6 mmol/hr/L. The same patients had a mean trough plasma ADA activity of 14.2 ± 5.1 mmol/hr/L when treated with Adagen at a normalized dose of 30 U/kg/week during the Lead-in Phase of the study. Lymphocyte and subset counts during REVCOVI treatment increased above levels observed during the Adagen Lead-in Phase (i.e., PK day 1 or before the start of REVCOVI treatment): maximum increases of approximately 3-fold at Weeks 60-73 for one patient, maximum increases of approximately 2- to 3-fold at Weeks 73-99 for one patient and approximately 1.5- to 3-fold for the third patient at several timepoints.
For these three patients who completed the primary endpoint (21 weeks of treatment) and received REVCOVI for over 135 weeks, a positive trend between high trough plasma ADA activity and increased total lymphocyte counts was observed. Observations for the other three patients in the study, indicate that these patients also achieved complete detoxification based on trough dAXP level and trough plasma ADA activity, and show stable or slightly increased lymphocyte counts during REVCOVI treatment relative to values recorded during the Adagen Lead-in Phase.
Study 2 Study 2, conducted in Japan, is a single-arm clinical study
that assessed the safety, efficacy and PK of REVCOVI in patients with ADA-SCID. The study includes two phases: 1) Evaluation, consisting of a Dose Adjustment Period (5 weeks) and a Dose Maintenance Period (16 weeks); and 2) Continuous Administration (Extension) Phase, to be continued until the end of the study. A total of four patients were enrolled in the study: two males (age 25 years and 3.4 months) and two females (age 16 years and 4.3 months). Two patients, who were on Adagen treatment within 4 weeks before entering the study, received a first dose of REVCOVI that was calculated to be equivalent to the last Adagen dose received. One patient, who did not receive Adagen within four weeks prior to entering the study, was given the first dose of REVCOVI at 0.1 mg/kg body weight, followed by second and third doses at 0.133 mg/kg body weight and weekly thereafter.
Over the dose adjustment phase of the study, the dose was titrated to meet criteria for dAXP level (equal to or below 0.02 mmol/L) and adequate trough ADA activity (equal to or above 15 mmol/hr/L). These three patients received REVCOVI for at least 21 weeks (having completed the 5-week Dosage Adjustment Period and the 16-week Maintenance Period) before entering the Extension Phase. The fourth patient (newly diagnosed Adagen-naïve patient with CMV pneumonia ) was dosed with REVCOVI at 0.4 mg/kg weekly (divided into two IM administrations) for 16 weeks. All four of the patients in Study 2 achieved and maintained detoxification (trough dAXP ≤0.02 mmol/L) throughout their participation in the Treatment Phase of 21 weeks (Dose Adjustment and Dose Maintenance). Serum ADA activity increased after administering REVCOVI for all four patients, with three patients achieving activity level over 15 mmol/hr/L during the Dose Maintenance Period.
Total lymphocyte counts and B-/T-/NK-lymphocyte subset counts for three patients increased from screening to Day 15 during dose adjustment and were stable or increasing during the Maintenance Period.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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