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.
The effect of elapegademase on the QT interval is not known.
The pharmacokinetics (PK) of elapegademase 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. The PK results are summarized in Table 1.
Table 1. Individual Estimates of Steady State Plasma Pharmacokinetic Parameters of Elapegademase 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 |
|---|---|---|---|---|---|---|
| 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 |
a PK data calculated over the dosing interval after weekly IM administration of elapegademase at a stable elapegademase dose for at least five consecutive weeks
b Dose-normalized (DN) AUC0-168hr and Cmax estimates based on mg/kg/week dose of elapegademase
c Non-dose normalized steady state Ctrough 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 elapegademase. 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.
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