Synribo

CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism of action of
omacetaxine mepesuccinate has not been fully elucidated but includes inhibition
of protein synthesis and is independent of direct Bcr-Abl binding. Omacetaxine
mepesuccinate binds to the A-site cleft in the peptidyl-transferase center of
the large ribosomal subunit from a strain of archaeabacteria. In vitro,
omacetaxine mepesuccinate reduced protein levels of the Bcr-Abl oncoprotein and
Mcl-1, an anti-apoptotic Bcl-2 family member. Omacetaxine mepesuccinate showed
activity in mouse models of wild-type and T315I mutated Bcr-Abl CML.

Pharmacokinetics

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/m²twice daily
for 11 days. The plasma protein binding of omacetaxine mepesuccinate is less
than or equal to 50%.

Metabolism

Elimination

The major elimination route of
omacetaxine mepesuccinate is unknown. The mean percentage of omacetaxine
mepesuccinate excreted unchanged in the urine is less than 15%. The mean
half-life of omacetaxine mepesuccinate following subcutaneous administration is
approximately 6 hours.

Drug Interactions

Cytochrome P450 Enzymes (CYPs): Omacetaxine
mepesuccinate is not a substrate of CYP450 enzymes in vitro. Omacetaxine mepesuccinate and 4'-DMHHT do not inhibit
major CYPs in vitro at concentrations that can be expected clinically. The
potential for omacetaxine mepesuccinate or 4'-DMHHT
to induce CYP450 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.

Assessment For Risk Of QT Prolongation

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/m²BID 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.

Clinical Studies

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/m²administered
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).

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 5.