Moxidectin (Page 4 of 5)

12.4 Microbiology

Mechanism of Action

The mechanism by which moxidectin exhibits its effect against O. volvulus is not known. Studies with other nematodes suggest that moxidectin binds to glutamate-gated chloride channels (GluCl), gamma-aminobutyric acid (GABA) receptors and/or ATP-binding cassette (ABC) transporters. This leads to increased permeability, influx of chloride ions, hyperpolarization and muscle paralysis. Additionally, there is a reduction in motility of all stages of the parasite, excretion of immunomodulatory proteins, and the fertility of both male and female adult worms.

Antimicrobial activity

Moxidectin is active against the microfilariae of O. volvulus [see Clinical Studies ( 14)].

Studies suggest that moxidectin is not effective in killing the adult worms, however, it inhibits intra-uterine embryogenesis and release of microfilariae from the adult worms.

Resistance

Studies in vitro and in infected animals suggest a potential for development of resistance to moxidectin and cross-resistance with other macrocyclic lactones, such as ivermectin. However, the clinical relevance of these findings is not known.

The mechanism of resistance may be multifactorial that include alteration in the target GluCl, GABA receptors and/or ABC transporters.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies in mice and rats were conducted with moxidectin. Mice were administered a mean dietary dose of 8.7 mg/kg/day moxidectin which is approximately equivalent to 5 times the recommended human dose based on body surface area comparison. Rats were administered a mean dietary dose of 6.1 mg/kg/day moxidectin which is approximately equivalent to 7 times the recommended human dose based on body surface area comparison. There was no evidence of tumorigenicity in either study.

Mutagenesis

Moxidectin was shown to be negative for genotoxicity in a battery of in vitro assays including a bacterial mutagenicity assay, mouse lymphoma cell mutagenicity assay, unscheduled DNA synthesis assay, and a chromosome aberration assay, as well as in vivo in a micronucleus assay in mice and a chromosome aberration assay in rats.

Impairment of Fertility

In fertility evaluations, male and female mating and fertility indices were not inhibited by oral-dietary moxidectin doses of approximately 0.86 mg/kg/day which is approximately equivalent to the recommended human dose based on body surface area comparison.

13.2 Animal Toxicology and/or Pharmacology

Moxidectin was associated with transient CNS-related clinical signs. In rats, a single dose of 20 mg/kg (equivalent to approximately 24 times the recommended human dose based on body surface area comparison) moxidectin was associated with piloerection, reduced arousal and body tone, abnormal gait, slowed breathing, and impaired righting reflex. In dogs, repeated doses of 1.6 mg/kg/day moxidectin (equivalent to approximately 7 times the recommended human dose based on body surface area comparison) was associated with lacrimation, languid appearance, tremors, slight salivation, and slight ataxia.

14 CLINICAL STUDIES

The assessment of the safety and efficacy of Moxidectin Tablets 8 mg in the treatment of onchocerciasis is based on data from two randomized, double-blind, active-controlled trials in patients with O . volvulus infection, Trial 1 in 1472 patients (NCT 00790998), and Trial 2, a dose-ranging trial (NCT 00300768). Patients in the trials received a single oral dose of moxidectin or ivermectin, the active control medication.

Efficacy was assessed by skin microfilarial density (microfilariae/mg skin) from the mean of 4 skin snips per person per time point up to 18 months post-treatment.

Trial 1 recruited adult and adolescent patients ≥ 12 years with a body weight ≥ 30 kg and ≥ 10 microfilariae/mg skin. Mean (± SD) age was 42.5 (± 16.3) years, height 1.59 (± 0.09) meters, weight 51.6 (± 8.2) kg; 36.1% were female and 100% were black. Mean (± SD) pretreatment skin microfilarial density was 39.5 (± 30.7) microfilariae/mg skin, 69.6% had ≥ 20 microfilariae/mg skin and 39.7% had at least one ocular microfilaria.

Patients who were not previously exposed to ivermectin community directed treatment programs were recruited from the sub-Saharan African region (Democratic Republic of Congo, Liberia, and Ghana). Table 5 reports mean skin microfilarial density and the proportion of patients with undetectable skin microfilariae at Months 1, 6, and 12.

Table 5: Mean Microfilarial Density and Percentage of Undetectable Microfilariae in Skin of O. volvulus Patients (12 Years of Age and Older) at Months 1, 6, and 12 in Trial 1

Endpoint	Moxidectin N = 977	Ivermectin N = 495	Difference (95% Confidence Interval)
1 month
Mean Microfilarial Density a	0.10	2.30	-2.20 (-2.83, -1.58) p < 0.0001
% Undetectable Microfilariae b	83.4%	42.9%	40.5% (35.7, 45.3) p < 0.0001
6 months
Mean Microfilarial Density a	0.14	3.71	-3.57(-4.11, -3.03) p < 0.0001
% Undetectable Microfilariae b	91.0%	11.5%	79.6% (76.3, 82.9) p < 0.0001
12 months
Mean Microfilarial Density a	1.79	9.83	-8.04 (-9.11, -6.98) p < 0.0001
% Undetectable Microfilariae b	45.9%	5.4%	40.4% (36.7, 44.1) p < 0.0001

^a Mean microfilarial density in skin is the average microfilarial density (microfilariae count/mg skin) over skin snips from four sites.

^b Proportion of subjects undetectable (defined as a mean skin microfilariae density of zero across all 4 skin snips).

Additionally, safety and efficacy was assessed in a smaller single ascending dose trial (Trial 2, NCT 00300768) comparing 2 mg (n = 44), 4 mg (n = 45) (2 mg and 4 mg are not approved doses) and 8 mg (n = 38) single doses of moxidectin to ivermectin. Trial 2 was conducted in Ghana in adults aged ≥ 18 to ≤ 60 years with O. volvulus infection. Analysis of the baseline-to-12-month change in skin microfilarial density for the proposed moxidectin 8 mg dose showed statistically significant superiority to ivermectin, p < 0.001.