CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`210867Orig1s000
`
`NON-CLINICAL REVIEW(S)
`
`
`
`
`
`
`

`

`Tertiary Pharmacology/Toxicology Review
`
`From: Timothy J. McGovern, Ph.D., ODE Associate Director for Pharmacology and
`Toxicology, OND IO
`NDA: 210867
`Agency receipt date: October 13, 2017
`Drug: Moxidectin
`Sponsor: Medicines Development for Global Health
`
`Indication: Treatment of onchocerciasis
`
`Reviewing Division: Division of Antiviral Products
`
`The pharmacology/toxicology reviewer and supervisor concluded that the nonclinical
`data support approval of ibalizumab for the indication listed above.
`
`Moxidectin is a semisynthetic derivative of a fermentation product of Streptomyces
`cyanogriseus. It is a broad spectrum endectocide that inhibits the development of
`embryos and sperm in adult filarial worms. The drug is a first-in-class new molecular
`entity and was granted both orphan drug status and breakthrough therapy designation. It
`is proposed to be administered as a single oral dose of 8 mg. The plasma half-life in
`patients (approximately 24 days) is longer than in rats (18-30 hours) and dogs (8-20
`days).
`
`The nonclinical program primarily consists of repeat-dose toxicity studies in rats (up to 3
`months) and dogs (up to one year). The only general toxicities identified were transient
`CNS-related clinical signs and anorexia.
`
`Moxidectin was negative in a battery of genotoxicity studies. A carcinogenicity
`assessment in rats and mice was conducted. While initial results appear to be negative, a
`comprehensive review requires submission of an electronic dataset for statistical
`evaluation.
`
`
`
`
`
`Moxidectin was not associated with fertility or embryo-fetal developmental effects.
`However, a pre/postnatal development study identified reduced survival and body weight
`of first generation offspring during the lactation period at a dose slightly above the
`recommended clinical dose and reduced number of live fetuses at birth at a dose
`approximating 13 times the human dose. Since the study did not evaluate physical
`development and neurological function, a new pre/postnatal development study will be
`conducted as a post-marketing requirement.
`
`Conclusion:
`I agree with the Division pharmacology/toxicology conclusion that moxidectin can be
`approved from the nonclinical perspective. I have reviewed the proposed wording for the
`nonclinical sections of the product label and agree with the Division recommendations.
`
`Reference ID: 4275285
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`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`TIMOTHY J MCGOVERN
`06/08/2018
`
`Reference ID: 4275285
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`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`
`210867
`SD #001
`10/13/2017
`10/13/2017
`Moxidectin
` Treatment of Onchocerciasis (River Blindness)
`Medicines Development for Global Health
`(MDGH)
`Division of Anti-infective Products
`Review Division:
`James S. Wild, Ph.D.
`Reviewer:
`Terry Miller, Ph.D.
`Supervisor/Team Leader:
`Sumathi Nambiar, M.D., M.P.H.
`Division Director:
`Kristine Parks, Ph.D.
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 210867 are owned by or are data for which MDGH has
`obtained a written right of reference. Any information or data necessary for approval of
`NDA 210867 that MDGH does not own or have a written right to reference constitutes
`one of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`of a previously approved application is for descriptive purposes only and is not relied
`upon for approval of NDA 210867.
`
`Reference ID: 4269698
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`NDA # 210867
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`Reviewer: James S. Wild
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 9
`1.1
`INTRODUCTION .................................................................................................... 9
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 9
`1.3 RECOMMENDATIONS .......................................................................................... 11
`2 DRUG INFORMATION .......................................................................................... 15
`2.1 DRUG ............................................................................................................... 15
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS ......................................................... 16
`2.3 DRUG FORMULATION ......................................................................................... 16
`2.4 COMMENTS ON NOVEL EXCIPIENTS ..................................................................... 17
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 17
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 22
`2.7 REGULATORY BACKGROUND .............................................................................. 22
`3 STUDIES SUBMITTED .......................................................................................... 22
`3.1
`STUDIES REVIEWED ........................................................................................... 22
`3.2
`STUDIES NOT REVIEWED ................................................................................... 25
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 26
`4 PHARMACOLOGY ................................................................................................ 26
`4.1
`PRIMARY PHARMACOLOGY ................................................................................. 26
`4.2
`SECONDARY PHARMACOLOGY ............................................................................ 26
`4.3
`SAFETY PHARMACOLOGY ................................................................................... 27
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 31
`5.1
`PK/ADME ........................................................................................................ 31
`5.2
`TOXICOKINETICS ............................................................................................... 46
`6 GENERAL TOXICOLOGY ..................................................................................... 46
`6.1
`SINGLE-DOSE TOXICITY ..................................................................................... 46
`6.2 REPEAT-DOSE TOXICITY .................................................................................... 48
`7 GENETIC TOXICOLOGY ...................................................................................... 79
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES) ....................... 79
`7.2
`IN VITRO ASSAYS IN MAMMALIAN CELLS .............................................................. 81
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY) .................. 89
`7.4 OTHER GENETIC TOXICITY STUDIES .................................................................... 92
`8 CARCINOGENICITY ............................................................................................. 92
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 114
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT ............................................. 114
`9.2
`EMBRYONIC FETAL DEVELOPMENT ................................................................... 130
`9.3
`PRENATAL AND POSTNATAL DEVELOPMENT ....................................................... 148
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`Reviewer: James S. Wild
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`SPECIAL TOXICOLOGY STUDIES ................................................................. 153
`INTEGRATED SUMMARY AND SAFETY EVALUATION ............................... 153
`APPENDIX/ATTACHMENTS ........................................................................... 159
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`NDA # 210867
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`12
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`NDA # 210867
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`Reviewer: James S. Wild
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`Table of Tables
`Table 1: Qualitative and Quantitative Composition of the Drug Product. (Applicant’s
`Table from Section 3.2.P.1 of the Electronic Submission) ............................................. 17
`Table 2: The Moxidectin Product Excipients and Comparison to Amounts Used in
`Previously Approved Products. ..................................................................................... 17
`Table 3: Specifications for the Moxidectin Drug Substance (Applicant’s Table from
`Section 3.2.S.4.1 of the Electronic Submission) ............................................................ 18
`Table 4: Qualification Information for the Moxidectin Drug Substance Impurities.
`(Applicant’s Table from Section 3.2.S.3.2 of the Electronic Submission) ...................... 19
`Table 5: Moxidectin Drug Product Impurities. (Applicant’s Table from Section 3.2.P.5.1
`of the Electronic Submission) ........................................................................................ 21
`Table 6: List of FOB Measurements for Study No.: 10SN030. (Table from the Study
`Report) .......................................................................................................................... 27
`Table 7: The Effect of Moxidectin on FOB Measurements in Study No.: 10SN030.
`(Table from the Study Report) ....................................................................................... 28
`Table 8: The Effect of Moxidectin on Locomotor Activity. (Table from the Study Report)
` ...................................................................................................................................... 29
`Table 9: Mean Toxicokientic Parameters for Plasma Moxidectin in Male Sprague-
`Dawley Rats after a Single Oral Administration of Moxidectin. (Table from the Study
`Report) .......................................................................................................................... 29
`Table 10: The Percent Inhibition of hERG Potassium Channels by Moxidectin. (Table
`from the Study Report) .................................................................................................. 30
`Table 11: Mean Male and Female Pharmacokinetic Values for Moxidectin in Mouse
`Plasma Following 14-days of Dietary Administration of 50 ppm Moxidectin. (Table from
`the Study Report) .......................................................................................................... 32
`Table 12: Male Toxicokinetic Parameters for Plasma Moxidectin Following a Single
`Oral Dose in Rats. (Table from the Study Report) ......................................................... 33
`Table 13: Calculated Doses and Serum Pharmacokinetic Values for Male and Female
`Rats Administered Dietary Moxidectin for 28 Days. (Table from the Study Report) ...... 34
`Table 14: Mean (± SD) Moxidectin Pharmacokinetic Parameters in Adult and Juvenile
`Dogs after a Single, Oral (Capsule) Dose (0.3, 1, and 3 mg/kg) of Moxidectin. (Table
`from the Study Report) .................................................................................................. 35
`Table 15: Mean (± SD) Pharmacokinetic Values for Moxidectin in the Serum of Male
`and Female Beagle Dogs Administered a Single Oral Dose of 45 ppm Dietary
`Moxidectin. (Table from the Study Report) .................................................................... 36
`Table 16: Mean Pharmacokinetic Values for Moxidectin Following 10 mg/kg Oral
`Administration to Female Pregnant Rabbits. (Table from the Study Report) ................. 36
`Table 17: Single-dose Studies for Moxidectin. (Table Adapted from a Table in Section
`2.6.6 Toxicology Written Summary in the NDA electronic submission) ......................... 47
`Table 18: Observation Schedule for the 28-Day Mouse Feeding Study ........................ 49
`Table 19: Moxidectin Dietary Dose (mg/kg/day) in the 28-Day Mouse Study. (Table from
`the Study Report) .......................................................................................................... 51
`Table 20: Moxidectin Dietary Dose (mg/kg/day) in the 28-Day Rat Study. (Table from
`the Study Report) .......................................................................................................... 55
`Table 21: Observation Schedule ................................................................................... 58
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`NDA # 210867
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`Table 22: Average Daily Intake (mg/kg/day) of Moxidectin in the 13-Week Toxicology
`Study in Rats. (Table from the Study Report) ................................................................ 60
`Table 23: Mean Absolute and Relative Testes Weights in Dogs Administered Dietary
`Moxidectin for 28 Days. ................................................................................................. 66
`Table 24: Histopathology Findings in Testes of Dogs Administered Dietary Moxidectin
`for 28 Days. (Table from the Study Report) ................................................................... 67
`Table 25: Mean Moxidectin Consumption (mg/kg/day) in Male and Female Dogs in the
`91-Day Dietary Toxicity Study in Dogs. (Table from the Study Report) ......................... 70
`Table 26: Absolute and Relative Testicular Weights in the 91-Day Toxicology Study in
`Dogs. ............................................................................................................................. 72
`Table 27: Observation Scheduled or the 1-Year Toxicology Study in Dogs .................. 74
`Table 28: Percent Body Weight Gain Over Pretreatment Values in the 1-Year
`Toxicology Study in Dogs. (Table from the Study Report) ............................................. 75
`Table 29: Mean Total Food Consumption and Standard Deviations in Grams in the 1-
`year toxicology Study in Dogs. (Table from the Study Report) ...................................... 75
`Table 30: Mean Moxidectin Consumption (mg/kg/day) on Specific Dates in Male and
`Female Dogs in the 1-Year Dietary Toxicity Study in Dogs. (Table Derived from
`Summary Data in the Study Report).............................................................................. 76
`Table 31: Absolute and Relative Ovary Weights in Female Dogs Administered Dietary
`Moxidectin for 1 year. .................................................................................................... 77
`Table 32: Absolute and Relative Testicular Weights in Male Dogs Administered Dietary
`Moxidectin for 1 year. .................................................................................................... 77
`Table 33: Study Design for the Ames Assay with Moxidectin. (Sponsor’s Table) ......... 80
`Table 34: Study Design for Trials 1 and 2 of the Mammalian Cell CHO/HGPRT
`Mutagenicity Assay. (Table from the Study Report) ...................................................... 82
`Table 35: Study Design for the Rat Chromosome Aberration Study. (Table from the
`Study Report) ................................................................................................................ 91
`Table 36: The Incidence of Corneal Opacity Observed as Clinical Signs in Mice Treated
`with Dietary Moxidectin for Two Years. (Table from the Study Report) ......................... 95
`Table 37: Mean Body Weight Gains in Male and Female Mice Administered Dietary
`Moxidectin for Two Years. (Table from the Study Report) ............................................. 97
`Table 38: Average Food Consumption for Male and Female Mice Administered Dietary
`Moxidectin for Two Years. (Table from the Study Report) ............................................. 97
`Table 39: Average Dietary Consumption of Moxidectin in Male and Female Mice. (Table
`from the Study Report) .................................................................................................. 98
`Table 40: Incidence and Statistical Analysis for Neoplasms Occurring in Male Mice.
`(Table from the Study Report) ....................................................................................... 99
`Table 41: Incidence and Statistical Analysis for Neoplasms Occurring in Female Mice.
`(Table from the Study Report) ..................................................................................... 100
`Table 42: Mean Body Weights for Control and Moxidectin-treated Male and Female
`Rats at the Start of Dosing, and in Weeks 8 and 102 of Dosing. ................................. 106
`Table 43: Dietary Compound Consumption relative to Body Weight in Male and Female
`Rats During Weeks 1-50 and Weeks 1-102 of the Study. (Table from the Study Report)
` .................................................................................................................................... 108
`Table 44: Incidence and Survival-Adjusted Statistical Analysis for Neoplasms Occurring
`in Male and Female Rats. (Table from the Study Report) ........................................... 111
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`Reviewer: James S. Wild
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`NDA # 210867
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`Table 45: Survival Adjusted Analysis of the Incidence Rates of Non-neoplastic Lesions
`with all Animals Examined Being at Risk. (Table from the Study Report) .................. 112
`Table 46: Study Design for the Pilot Fertility Study with Moxidectin. (Table from the
`Study Report) .............................................................................................................. 116
`Table 47: Mean Moxidectin Intake During the Premating Period in Male and Female
`Rats in the F1a Experiment. (Table from the Study Report) ......................................... 118
`Table 48: Mating, Pregancy, and Fertility Rates for the F1a Mating Interval. (Table from
`the Study Report) ........................................................................................................ 119
`Table 49: Pup and Litter Survival Data for the F1a Litter Group. (Table from the Study
`Report) ........................................................................................................................ 120
`Table 50: Pup Weight Data During the Lactation Period in the F1a Litter Group. (Table
`Adapted from Information in the Study Report) ........................................................... 121
`Table 51: Mating, Pregnancy, and Fertility Rates for the F1b Mating Interval. (Table from
`the Study Report) ........................................................................................................ 122
`Table 52: Pup and Litter Survival Data for the F2a Litter Group. (Table from the Study
`Report) ........................................................................................................................ 123
`Table 53: Pup Weight Data During the Lactation Period in the F1b Litter Group. (Table
`adapted from Information in the Study Report) ........................................................... 124
`Table 54: Mean Moxidectin Intake (mg/kg/day) for Males and Females During the
`Premating Period. (Adapted from Information in the Study Report) ............................ 126
`Table 55: Mating, Pregnancy and Fertility Rates for Rats Administered Dietary
`Moxidectin. (Table Adapted from Information in the Study Report) ............................. 128
`Table 56: Survival of F1 Pups and the Number of Litters with Pup Mortality. (Table
`Adapted from Information in the Study Report) ........................................................... 129
`Table 57: Mean F1 Pup Weights (Mean ± SD) During Lactation for the F1a Litter Groups.
`(Table adapted from Information in the Study Report) ................................................ 129
`Table 58: Summary of Cesarean Section Data in the Rat Embryo-Fetal Study. (Table
`from the Study Report) ................................................................................................ 133
`Table 59: Summary of Litter Data for Caesarean-Delivered Fetuses in the Rat Embryo-
`Fetal Study. (Table from the Study Report) ................................................................. 134
`Table 60: Summary of Fetal Alterations in the Rat Embryo-fetal Study. (Table from the
`Study Report) .............................................................................................................. 135
`Table 61: Summary of Fetal External Malformations in the Rat Embryo-fetal Study. .. 135
`Table 62: Summary of Fetal Soft Tissue Malformationsa in the Rat Embryo-fetal Study.
` .................................................................................................................................... 136
`Table 63: Summary of Skeletal Variations in the Rat Embryo-fetal Study. .................. 137
`Table 64: Mean Changes in Maternal Body Weight at Progressive Intervals of the
`Dosing Period. ............................................................................................................. 140
`Table 65: Mean Changes in Maternal Food Consumption in Successive Intervals of the
`Dosing Period. ............................................................................................................. 141
`Table 66: Summary Necropsy Observations in the Rabbit Embryo-Fetal Study. (Table
`from the Study Report) ................................................................................................ 142
`Table 67: Summary of the Caesarean-Section Data in Rabbits. (Table from the Study
`Report) ........................................................................................................................ 143
`Table 68: Summary of the Litter Data for F1 Offspring in the Rabbit Embryo-fetal Study
`(Table from the Study Report) ..................................................................................... 144
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`NDA # 210867
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`Table 69: Summary of Fetal Alterations in the Rabbit Embryo-Fetal Study. (Table from
`the Study Report) ........................................................................................................ 145
`Table 70: External Malformations in the Rabbit Embryo-Fetal Study. ......................... 145
`Table 71: Visceral Malformations in the Rabbit Embryo-Fetal Study. ......................... 146
`Table 72: Skeletal Malformations in the Rabbit Embryo-Fetal Study. ......................... 146
`Table 73: Visceral Variations in the Rabbit Embryo-Fetal Study. ................................ 147
`Table 74: Skeletal Variations in the Rabbit Embryo-Fetal Study. ................................ 147
`Table 75: Human Equivalent Dose (HED) and Safety Margin Calculations for CNS-
`related Clinical Signs in General Toxicology Studies with Moxidectin in Mice, Rats, and
`Dogs. ........................................................................................................................... 156
`Table 76: Plasma Cmax and AUC Values and Safety Margin Calculations for CNS-
`related Clinical Signs in General Toxicology Studies with Moxidectin in Mice, Rats, and
`Dogs. ........................................................................................................................... 156
`Table 77: Human Equivalent Dose (HED) and Safety Margin Calculations for the Mouse
`and Rat Carcinogenicity Studies. ................................................................................ 157
`Table 78: Human Equivalent Dose (HED) and Safety Margin Calculations for the
`Fertility Study in Male and Female Rats. ..................................................................... 157
`Table 79: Human Equivalent Dose (HED) and Safety Margin Calculations for the
`Embryo-fetal and Pre-postnatal Studies. ..................................................................... 158
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`NDA # 210867
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`Reviewer: James S. Wild
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`Table of Figures
`Figure 1: Distribution of Spiked Moxidectin in Lipoprotein Fractions from Plasma in Five
`Different Species. (Figure from Bassissi et al., 2004).................................................... 37
`Figure 2: Metabolic Pathway of Moxidectin in the Rat. (Figure from the Study Report) 40
`Figure 3: Proposed Metabolic Pathways for Moxidectin in Rat and Human Liver
`Microsomes. (Figure from the Study Report) ................................................................ 43
`Figure 4: Mean Body Weights in the Mouse Carcinogenicity Study with Moxidectin. aThe
`moxidectin dose for high-dose animals was reduced in Week 9 from 60 ppm to 50 ppm.
`(Figure from the Study Report) ...................................................................................... 96
`Figure 5: Adjusted Percent Survival for Male and Female Rats During 105 Weeks of
`Dosing with Moxidectin (102 Weeks are Shown). (Figure from the Study Report) ...... 105
`Figure 6: Mean Body Weights for Males and Females During 105 Weeks of Dosing with
`Moxidectin (102 weeks are shown). (Figure from the Study Report) ........................... 107
`Figure 7: Mean Maternal Body Weights in the Rabbit Embryo-fetal Study. (Figure from
`the Study Report) ........................................................................................................ 141
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`NDA # 210867
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`Reviewer: James S. Wild
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`Executive Summary
`1
`Introduction
`1.1
`Onchocerciasis is a parasitic disease caused by the helminth Onchocerca volvulus
`which is transmitted to humans by the bite of the black fly of species Simulium. Infected
`black flies deposit O. volvulus larvae (microfilariae) with each bite, some of which
`develop into mature adult worms (macrofilariae). Adult female macrofilariae live for an
`average of 11 years (up to 18 years) in the human body, and produce millions of
`microfilariae that migrate through the skin, eyes and lymph nodes. A chronic host
`response to microfilariae causes the clinical manifestations of onchocerciasis, including
`severe dermatitis, depigmentation and atrophy of the skin, lymphadenitis, and most
`significantly, visual impairment leading to blindness. The current treatment for
`onchocerciasis is ivermectin in tablet form which is administered in a single annual dose
`of 150 to 200 mcg/kg body weight. Ivermectin does not kill the adult female
`macrofilariae, but suppresses the production of microfilariae larva for a few months
`following treatment.
`
`Moxidectin is a semisynthetic derivative of a fermentation product of Streptomyces
`cyanogriseus. It is a macrocyclic lactone of the milbemycin class. Moxidectin is a broad-
`spectrum endectocide and its pharmacodynamics can be primarily described by activity
`at the glutamate-gated chloride channels (GluCls) present in nematodes and
`arthropods. GluCLs are present in the wall of the uterus and reproductive apparatus of
`female and male macrofilariae respectively, and moxidectin inhibits the development of
`embryos and sperm in adult filarial worms. Like ivermectin, moxidectin does not kill
`macrofilariae. The main action of moxidectin is to block reproduction of macrofilariae,
`leading to fewer microfilariae. Moxidectin is also active at the GABA-A receptor complex
`which may lead to somatic muscle paralysis in macrofilariae and microfilariae. The
`purported advantages of moxidectin compared to ivermectin is that moxidectin is more
`potent, minimally metabolized in vivo, more lipophilic than ivermectin, and has much
`longer plasma t1/2 (20 to 40 days) compared to ivermectin (18 hours).
`
`1.2 Brief Discussion of Nonclinical Findings
`Moxidectin will be administered clinically in a single-oral dose of 8 mg (0.133 mg/kg for
`an average 60 kg human) suggesting toxicities that occurred with repeated dosing of
`much higher doses in test animals will not be a concern in patients. However,
`moxidectin has a very long plasma t1/2 in humans, approximately 24 and 33 days in
`patients and normal subjects respectively, which is longer than in rats (18-30 hours) and
`dogs (8-20 days). Human toxicity is a possibility in cases where moxidectin is
`unintentionally overdosed or perhaps in a subpopulation of humans with increased
`sensitivity to moxidectin.
`
`The primary moxidectin-related toxicity in test animals and the toxicity with the most
`potential for clinical relevance is dose-dependent CNS toxicity. Transient CNS toxicity
`occurred with single and repeated doses in mice, rats, and dogs where CNS-related
`clinical signs included piloerection, reduced arousal, tremors, abnormal gait, irregular or
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`slowed breathing, and impaired righting reflex in rodents and lacrimation, languid
`appearance, tremors, salivation and slight ataxia in dogs. In single- and repeated-dose
`studies, CNS-related clinical signs were observed at moxidectin threshold doses of ≥ 17
`mg/kg in mice, ≥ 12.5 mg/kg in rats, and ≥ 1.5 mg/kg in dogs which are on the order of
`6-10 fold higher than the 8 mg (0.133 mg/kg) dose in humans based on body surface
`area comparison. At doses below the threshold doses in animals, CNS-related clinical
`signs were not observed suggesting relative safety at the clinical dose. Also, in test
`animals, the effects were transient and not accompanied by correlating histopathology
`even with repeated moxidectin dosing and repeated episodes of CNS toxicity
`suggesting permanent structural or functional sequelae are not expected.
`
`Moxidectin was assessed for toxicity in long-term studies with durations of 1 month
`(mice, rats, and dogs), 3 months (rats and dogs), and 1-year (dogs). In these studies,
`other than CNS-related clinical signs, moxidectin was associated with little toxicity. In all
`the test species at repeated moxidectin doses slightly lower than those associated with
`clinical signs, decreased food consumption, body-weight gain, and body weights were
`observed. However, animals resumed normal eating patterns and gained weight upon
`dosing cessation. Based on the results in nonclinical toxicology studies, the only general
`toxicities projected for doses of moxidectin in excess of the recommended clinical dose
`are transient CNS-related clinical signs, anorexia, and weight loss.
`
`In a full battery of in vitro and in vivo genotoxicity studies, moxidectin was negative for
`mutagenicity and clastogenesis. Moxidectin was also tested in 2-year carcinogenicity
`studies in mice and rats, and a preliminary review of these studies suggests moxidectin
`did not stimulate tumor formation. A comprehensive review of the carcinogenicity
`studies awaits electronic submission of accurate tumor-tabulation tables necessary for a
`new statistical analysis performed within the FDA.
`
`
`
`In a male and female fertility study in rats, moxidectin did not impair any fertility or
`pregnancy indices at doses approximately equal to the recommended human dose
`based on body surface area comparison. In embryo-fetal studies in rats and rabbits,
`moxidectin was associated with a moderate level of reduced food consumption and
`body weight gain at doses equivalent to approximately 12 times for both species the
`recommended human dose based on body surface area comparisons. In rats, one
`skeletal variation, wavy ribs was significantly increased for fetal and litter incidence and
`one malformation, cleft palate was significantly increased for fetal incidence but not litter
`incidence at a dose equivalent to approximately 15 times the recommended dose in
`humans based on body surface area comparison. In the rabbit embryo-fetal study, no
`evidence of impaired embryo-fetal development was observed at doses up to 24 times
`the recommended human dose based on body surface area comparison.
`
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`Reviewer: James S. Wild
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`NDA # 210867
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`Range-finding and d