SYNRIBO Powder for solution for injection Ref.[10354] Active ingredients: Omacetaxine mepesuccinate

Cardiac Electrophysiology

In an uncontrolled pharmacokinetic study there were no reports of QTcF >480 ms or ΔQTcF >60 ms in 21 treated patients who received omacetaxine mepesuccinate 1.25 mg/m² BID for 14 consecutive days. There was no evidence for concentration-dependent increases in QTc for omacetaxine mepesuccinate or 4'-DMHHT. Although the mean effect on QTc was 4.2 ms (upper 95% CI: 9.5 ms), QTc effects less than 10 ms cannot be verified due to the absence of a placebo and positive controls.

The dose proportionality of omacetaxine mepesuccinate is unknown. A 90% increase in systemic exposure to omacetaxine mepesuccinate was observed between the first dose and steady state.

Absorption

The absolute bioavailability of omacetaxine mepesuccinate has not been determined. Omacetaxine mepesuccinate is absorbed following subcutaneous administration, and maximum concentrations are achieved after approximately 30 minutes.

Distribution

The steady-state (mean ± SD) volume of distribution of omacetaxine mepesuccinate is approximately 141 ± 93.4 L following subcutaneous administration of 1.25 mg/m² twice daily for 11 days. The plasma protein binding of omacetaxine mepesuccinate is less than or equal to 50%.

Elimination

The terminal elimination half-life of omacetaxine mepesuccinate in plasma is 14.6 hours.

Metabolism

Omacetaxine mepesuccinate is primarily hydrolyzed to 4′-DMHHT via plasma esterases with little hepatic microsomal oxidative and/or esterase-mediated metabolism in vitro.

Excretion

Following a single subcutaneous dose of radiolabeled omacetaxine mepesuccinate, the mean total recovery of radioactivity in excreta was approximately 81% of the radioactive dose. Approximately 37% of the radioactivity was recovered in urine and approximately 44% in feces.

Drug Interaction Studies

Cytochrome P450 (CYP) Enzymes

Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit major CYP enzymes in vitro at concentrations that can be expected clinically. The potential for omacetaxine mepesuccinate or 4′-DMHHT to induce CYP enzymes has not been determined.

Transporter Systems

Omacetaxine mepesuccinate is a P-glycoprotein (P-gp) substrate in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit P-gp mediated efflux of loperamide in vitro at concentrations that can be expected clinically.

No carcinogenicity studies have been conducted with omacetaxine mepesuccinate.

Omacetaxine mepesuccinate was genotoxic in an in vitro chromosomal aberration test system in Chinese hamster ovary (CHO) cells, but was not mutagenic when tested in an in vitro bacterial cell assay (Ames test), and it did not induce genetic damage using an in vivo mouse micronucleus assay.

SYNRIBO may impair male fertility. Studies in mice demonstrated adverse effects on male reproductive organs. Bilateral degeneration of the seminiferous tubular epithelium in testes and hypospermia/aspermia in the epididymides were reported in the highest dose group (2.33 mg/kg/day reduced to 1.67 mg/kg/day; 7 to 5 mg/m²/day) following subcutaneous injection of omacetaxine mepesuccinate for six cycles over six months. The doses used in the mice were approximately two to three times the recommended daily human dose based on body surface area.

The efficacy of SYNRIBO was evaluated using a combined cohort of adult patients with CML from two trials. The combined cohort consisted of patients who had received 2 or more approved TKIs and had, at a minimum, documented evidence of resistance or intolerance to dasatinib and/or nilotinib. Resistance was defined as one of the following: no complete hematologic response (CHR) by 12 weeks (whether lost or never achieved); or no cytogenetic response by 24 weeks (i.e., 100% Ph positive [Ph+]) (whether lost or never achieved); or no major cytogenetic response (MCyR) by 52 weeks (i.e., ≥35% Ph+) (whether lost or never achieved); or progressive leukocytosis. Intolerance was defined as one of the following: 1) Grade 3-4 non-hematologic toxicity that does not resolve with adequate intervention; or 2) Grade 4 hematologic toxicity lasting more than 7 days; or 3) any Grade ≥ 2 toxicity that is unacceptable to the patient. Patients with NYHA class III or IV heart disease, active ischemia or other uncontrolled cardiac conditions were excluded.

Patients were treated with omacetaxine mepesuccinate at a dose of 1.25 mg/m² administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and twice daily schedule for 7 consecutive days every 28 days (maintenance cycle). Patients were allowed to continue to receive maintenance treatment for up to 24 months. Responses were adjudicated by an independent Data Monitoring Committee (DMC).

Chronic Phase CML (CP CML)

A total of 76 patients with chronic phase CML were included in the efficacy analysis. The demographics were: median age 59 years, 62% were male, 30% were 65 years of age or older, 80% were Caucasian, 5% were African-American, 4% were Asian and 4% were Hispanic. Thirty-six (47%) patients had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (54%), interferon (30%), and/or cytarabine (29%). The efficacy endpoint was based on MCyR (adjudicated by a DMC).

Table 5: Efficacy Results Evaluated by DMC for Patients with CP CML

Cytogenetic response evaluation is based on standard cytogenetic analysis (at least 20 metaphases).
Complete: 0% Ph+ cells, Partial >0% to 35% Ph+ cells

The mean time to MCyR onset in the 14 patients was 3.5 months. The median duration of MCyR for the 14 patients was 12.5 months (Kaplan-Meier estimate).

Accelerated Phase CML (AP CML)

A total of 35 patients with accelerated phase CML were included in the efficacy analysis. The demographics were: median age was 63 years, 57% were male, 46% were 65 years of age or older, 68% were Caucasian, 23% were African-American, 3% were Asian and 3% were Hispanic. Twenty-two (63%) of 35 patients with accelerated phase had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (43%), interferon (31%), and/or cytarabine (29%). The efficacy endpoint was assessed based on MCyR and MaHR (complete hematologic response [CHR] or no evidence of leukemia [NEL]). The efficacy results for the patients with accelerated phase as adjudicated by the DMC are shown in Table 6.

Table 6. Efficacy Results Evaluated by DMC for Patients with AP CML:

MaHR is defined as complete hematologic response (CHR) or no evidence of leukemia (NEL): CHR – absolute neutrophil count ≥1.5 × 10⁹/liter, platelets ≥100 × 10⁹/liter, no blood blasts, bone marrow blasts <5%, no extramedullary disease; NEL – Morphologic leukemia-free state, defined as <5% bone marrow blasts.

The mean time to response onset in the 5 patients was 2.3 months. The median duration of MaHR for the 5 patients was 4.7 months (Kaplan-Meier estimate).