12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

SCID associated with a deficiency of ADA enzyme is a rare, inherited, and often fatal disease. 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 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 number [see Clinical Studies (14)].

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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
Study	Patient's Age (yrs), Sex, Race	Weekly Dose (mg) [mg/kg]	Tmax (hr)	DN AUC0-168hr (hr*mmol/hr/L)/ (mg/kg)b	DN Cmax (mmol/hr/L)/ (mg/kg)b	Ctrough (mmol/hr/L)c
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) AUC0-168hr and Cmax estimates based on mg/kg/week dose of REVCOVI c Non-dose normalized steady state Ctrough ADA activity in plasma at Day 7 prior to administration of next weekly dose
Study 1a	19, Male, Hispanic/Latino	10.0 [0.188]	47.7	32710	237	29.0
	21, Male, Hispanic/Latino	10.2 [0.224]	71.9	31343	219	37.7
	37, Male, Black/African American	19.6 [0.2]	48.2	42400	292	46.2
	30, Female, White/Caucasian	10.0 [0.209]	72.0	24564	166	23.5
Study 2a	25, Male, Asian	10.0 [0.167]	48.0	37605	251	33.5
	16, Female, Asian	4.99 [0.233]	27.2	19013	150	20.2

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.