REVCOVI Solution for injection Ref.[10276] Active ingredients: Elapegademase

The effect of REVCOVI on the QT interval is not known.

The pharmacokinetics (PK) of REVCOVI were evaluated based on steady state plasma ADA activity in six patients with ADA-SCID (five adults and one pediatric) from two studies (Study 1 and Study 2) who received weekly IM injections at doses ranging from 4.99 to 19.6 mg [see Clinical Studies (14)]. The PK results are summarized in Table 1.

Table 1. Individual Estimates of Steady State Plasma Pharmacokinetic Parameters of REVCOVI Following Weekly IM Administration in ADA-SCID Patients:

^a PK data calculated over the dosing interval after weekly IM administration of REVCOVI at a stable REVCOVI dose for at least five consecutive weeks
^b Dose-normalized (DN) AUC_0-168hr and C_max estimates based on mg/kg/week dose of REVCOVI
^c Non-dose normalized steady state C_trough ADA activity in plasma at Day 7 prior to administration of next weekly dose

In Study 1, steady state ADA activity levels were reached following seven consecutive once weekly IM doses of REVCOVI. In addition, dAXP activity levels in all patients at the majority of all sampling timepoints in Study 1 were less than 0.02 mmol/L.

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential and impairment of fertility have not been performed with REVCOVI.

14.1 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 [see Dosage and Administration (2.1)].

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 [Ig] concentration [IgG, IgA, IgM])

A PK assessment was performed during Week 9 of the REVCOVI Treatment phase [see Clinical Pharmacology (12.3)].

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.

14.2 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 [see Adverse Reactions (6.1)]) 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 [erythrocyte or blood] ≤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.