Tash-Roby KU-AS-272 Final

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Presented by Dr. Joseph Tash and Dr. Kathy Roby at the Alliance for Contraception in Cats & Dogs’ 4th International Symposium on Non-Surgical Contraceptive Methods of Pet Population Control, April 8-10, 2010, in Dallas, Texas, U.S.

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KU-AS-272 as a Potential Single-Dose Non-hormonal Male and Female Sterilant for Dogs and Cats : 

KU-AS-272 as a Potential Single-Dose Non-hormonal Male and Female Sterilant for Dogs and Cats Joseph S. Tash, PhD & Katherine F. Roby, PhD Interdisciplinary Center for Male Contraceptive Research & Drug Development, Center for Reproductive Sciences, University of Kansas Medical Center 1

Overview of KU-AS-272 Drug Development Plan : 

Overview of KU-AS-272 Drug Development Plan 2

Meeting the Goal of a Single Agent for Sterilization of Males and Females by Targeting Somatic Components in Testis and Ovaries : 

Meeting the Goal of a Single Agent for Sterilization of Males and Females by Targeting Somatic Components in Testis and Ovaries Support of gametogenesis by KU-AS-272 target cells in ovary and testis: same agent can be used in males and females Target cells are in pubertal and pre-pubertal animals: potential for treatment of wide age ranges (ideal for companion and feral populations) Non-hormonal method Single dose efficacy (thus far, all hormonal methods require multiple doses) Does not require access behind blood-testis barrier (male) 3

KU-AS-272 Related Chemical Structures* : 

KU-AS-272 Related Chemical Structures* *US Patent 7,514,463 and CIP of 7,514,463 Lonidamine (LND) KU-AS-110* KU-AS-272* 4 *We have a series of alternative agents available to test if these leads fail testing.

Implementation Advantages for KU-AS-272 : 

Implementation Advantages for KU-AS-272 Patent protection already in place by KU, licensing can be negotiated directly without need for 3rd party approvals Small molecule with 5-6 step synthesis optimized for large commercial scale production Formulation for multiple field-use routes of administration including SQ, IM, and oral already accomplished Our studies will provide initial efficacy and safety data to promote filing, establish GLP/GMP protocols, and approval process with FDA CVM (Center for Veterinary Medicine) 5

Project Timeline for KU-AS-272 as Single Dose Non-Hormonal Sterilant for Male & Female Dogs & Cats : 

Project Timeline for KU-AS-272 as Single Dose Non-Hormonal Sterilant for Male & Female Dogs & Cats 6

Key Go-No Go Efficacy Decision Points in Rats Before Starting Studies in Male Dogs and Cats : 

Key Go-No Go Efficacy Decision Points in Rats Before Starting Studies in Male Dogs and Cats Establish SQ sterilizing dose in adult (60d old) rats (based on 9wk and 6mo post-dose outcome measures) Establish SQ sterilizing dose in pre-pubertal (30d old) rats, based on 30d+9wk and 6mo post-dose outcome measures (age match to adults at end-of-study analysis) 7

Key Go-No Go Safety Decision Points Before Starting Studies in Male & Female Dogs and Cats : 

Key Go-No Go Safety Decision Points Before Starting Studies in Male & Female Dogs and Cats Use rats first to obtain FDA-style safety and efficacy data: maximize efficacy and minimize negative side-effects when starting trials in dogs and cats Safety toxicology in rats (FDA standardized methods): Determine maximum tolerated SQ dose (MTD): this will establish the upper limit of the safety window Determine 7-day Repeated Dose (DRF) and toxicokinetics (TK): An FDA standard to determine worst case scenario side effects of the compound and establish range of side-effects to monitor in dogs and cats 8

Order of Initial Proof-of-Principal Studies in Dogs and Cats : 

Order of Initial Proof-of-Principal Studies in Dogs and Cats Males will be ready to test before females Adult dogs (beagle) Pre-pubertal dogs Adult cats (domestic short hair) Pre-pubertal cats 9

Sequence of Trials in Dogs and Cats* : 

Sequence of Trials in Dogs and Cats* Pharmacokinetics and bioavailability (IM and SQ with IV reference) Single dose-finding efficacy and safety Long term safety and efficacy (up to 2yrs after adult dose, ~2½yrs after pre-pubertal dose for age matching at end-of-study) 10 *To maximize reduction (fewest animal possible) animals will be carried from A to B to C, rather than starting new cats and dogs for each phase of the study.

Plans for End-of-Study Outcomes : 

Plans for End-of-Study Outcomes All study cats and dogs will be pre-selected from vendor for good temperament for humanization and handling Daily enrichment by dedicated enrichment personnel for duration of study, especially training to be adopted pets at the end of study Scientific staff will be different from enrichment personnel Dedicated secure outdoor exercise/play/training area Spay/neuter of all animals at end-of-study Standard vaccination series Adoption agencies already with agreements to find homes for all dogs and cats at end-of-study 11

Female Proof-of-Concept and Study Design : 

Female Proof-of-Concept and Study Design 12

KU-AS-272 Single Dose Reduces Ovarian Weight and Progesterone Production, and Follicle Atresia in Mice : 

KU-AS-272 Single Dose Reduces Ovarian Weight and Progesterone Production, and Follicle Atresia in Mice 13

Female Sterilization by Targeting Oogenesis via Disruption of Granulosa Cell/Oocyte Junctions : 

Female Sterilization by Targeting Oogenesis via Disruption of Granulosa Cell/Oocyte Junctions 14

Infertility Endpoint Markers to Assess Sterilization in Female Rats, Dogs and Cats : 

Infertility Endpoint Markers to Assess Sterilization in Female Rats, Dogs and Cats 15

Male Proof-of-Concept and Study Design : 

Male Proof-of-Concept and Study Design 16

Single High Dose of KU-AS-272 Induces Loss of Spermatogenic Cells in Rats, Rabbits and Mice* : 

Single High Dose of KU-AS-272 Induces Loss of Spermatogenic Cells in Rats, Rabbits and Mice* 17 *Mouse not at same magnification

Rapid Changes in Testis Histology After Single Dose of KU-AS-272* : 

Rapid Changes in Testis Histology After Single Dose of KU-AS-272* *Single oral dose at 6mg/kg 18

Summary of KU-AS-272 Rat Pharmacokinetics : 

Summary of KU-AS-272 Rat Pharmacokinetics 100% Orally Bioavailable Rapid Absorption Terminal Half-life of 5 Hours Low Clearance Drug May be Dose-proportional 19

Rat Mating Study: Single 6 mg/kg Oral Dose of KU-AS-272 or KU-AS-110 : 

Rat Mating Study: Single 6 mg/kg Oral Dose of KU-AS-272 or KU-AS-110 Results (6 rats per group): 100% infertility 60% reversibility/ 40% Sterility FSH, LH and testosterone normal Normal # of normal conceptuses in recovered fertile males Toxicology is promising NIH, BIOQUAL 20

Male Sterilization by Disruption of Sertoli cell-Spermatogenic cell Junctions : 

Male Sterilization by Disruption of Sertoli cell-Spermatogenic cell Junctions 21

Infertility Endpoint Markers to Assess Sterilization in Male Rats, Dogs, and Cats : 

Infertility Endpoint Markers to Assess Sterilization in Male Rats, Dogs, and Cats 22

General Considerations for Field Implementation of KU-AS-272 as a Single Dose Sterilant : 

General Considerations for Field Implementation of KU-AS-272 as a Single Dose Sterilant 23

Essential Considerations for Field and Clinical Trials : 

Essential Considerations for Field and Clinical Trials Likely dosing scenarios In the veterinary clinic: SQ (subcutaneous) IM (intramuscular) PO (oral) (unlikely) In the field: IM (jab stick and dart gun) 24

Essential Considerations for Field and Clinical Trials : 

Essential Considerations for Field and Clinical Trials 25 ~2.5 lbs (Chihuahua) ~175 lbs (Great Dane) (English Mastiff = ~225lbs)

Relationship Between Observed Dose Effect and Linear Dose Based on 6mg/kg of KU-AS-272 versus Body Mass : 

Relationship Between Observed Dose Effect and Linear Dose Based on 6mg/kg of KU-AS-272 versus Body Mass 26

Effective Doses Across Animal Species Appear to be Best Predicted Based on Body Surface Area rather than Body Weight : 

Effective Doses Across Animal Species Appear to be Best Predicted Based on Body Surface Area rather than Body Weight Effective Single Dose Body Surface Area Safety Limit (>100mg/kg) 27

Single Dose Rat Mating Trials Predict Sterilizing Dose at 12mg/kg : 

Single Dose Rat Mating Trials Predict Sterilizing Dose at 12mg/kg 28 Single dose given (mg/kg) Probability of effect

Essential Toxicology: KU-AS-272 and KU-AS-110 are hERG Negative : 

Essential Toxicology: KU-AS-272 and KU-AS-110 are hERG Negative 29

Essential Considerations for Field and Clinical Trials : 

Essential Considerations for Field and Clinical Trials Will chemical sterilization affect/alter social/mating behavior? If so, will there be a difference between pre-pubertal-treated and adult-treated animals? This data will be obtained in our long-term post dosing phase of the studies. 30

Long Term Efficacy/Safety Veterinary Clinical Trials : 

Long Term Efficacy/Safety Veterinary Clinical Trials Expand trials to multiple sites: veterinary teaching hospitals, large veterinary practices, select animal control facilities, a limited number of ASPCA, HSUS, other AW test sites Determine age and dose-finding range of pre-pubertal cats and dogs that can be treated safely and effectively Determine safety and efficacy dose range in different breeds and size of dogs and cats: One dose fits all? Dose range increments based on weight/size? 31

Long Term Health Considerations in Male and Female Dogs and Cats : 

Long Term Health Considerations in Male and Female Dogs and Cats Male Canine prostatitis (Mean onset 8.4-8.9y) Canine prostatic cancer (Mean onset 9.9y) Female Canine pyometra (Mean onset 9.4y) Feline mammary cancer (Mean onset 11y) 32 Will KU-AS-272 sterilization be associated with changes in the frequency or mean time of onset?

Slide 33: 

www.KCAnimalHealth.com 33 We are part of the federally designated Animal Health Corridor.

Industry Concentration : 

Industry Concentration 34 “Kansas City has the largest single concentration of animal health companies in the world.” Brakke Consulting 32% of the $19 billion global animal health industry is based in Kansas City

Animal Health Companies in KC Region : 

Animal Health Companies in KC Region 35

Industry Leadership : 

Industry Leadership 36 Four of the 10 largest global animal health companies Bayer Boehringer Ingelheim Vetmedica CEVA/Biomune Intervet/Schering-Plough Animal Health Three of the 5 largest global animal nutrition companies Mars Petcare Nestle/Purina Hill’s Pet Nutrition

Animal Health Project Activity : 

Animal Health Project Activity 37 Since the Corridor’s Launch in 2006: Worked with 80 animal health companies evaluating new locations in region With partners, recruited or expanded 16 animal health companies into the KC area Companies will create: 1,249 new jobs $60 million in new payroll $935 million in new capital investment Currently working with 12 animal health prospects

Acknowledgements : 

Acknowledgements Gunda Georg, PhD (Dept. Medicinal Chemistry, U. Minn) Nathan Culley, DVM (KUMC Lab Animal Resources) Melinda Broward, Project Manager (KU Institute for Advanced Medical Innovation, IAMI) Roger Rajewski, PhD (KU Biotechnology Innovation and Optimization Center (BIOC)) Matt Mayo, PhD (KUMC Institute for Biostatistics) Scott J. Weir, PharmD, PhD (KU IAMI) National Institutes of Health KUMC Administration ACC-D and Found Animals Foundation 38

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