Promising tests––but no immediate hope for female nonsurgical sterilants

From ANIMAL PEOPLE,  July-August 2013:

PORTLAND,  Oregon––“I think we will get a single-injection contraceptive product for dogs and cats,  but when,  and at what cost?” rhetorically asked Linda Rhodes,  DVM from the plenary podium at the June 20-23,  2013 Alliance for Contraception in Cats & Dogs conference in Portland,  Oregon. 

That was what most of the audience of about 150 researchers,  animal advocates,  and news media had come to find out.  

Rhodes,  an ACC&D founding board member and member of the Scientific Advisory Board of the Michelson Prize & Grants in Reproductive Biology,  had already reviewed 38 years of scientific studies of immunocontraception, one of the newest major approaches to developing an injectable dog and cat contraceptive.  

Only approaches based on genetic engineering are newer in theoretical basis.  Studies of hormonal contraceptives and chemosterilants began more than 70 years ago.

But where are we now?  

The most optimistic trajectory Rhodes could offer,  after describing the most promising present approaches,  included another five years of scientific research,  at cost of $10 million,  followed by another five years of product development to put a contraceptive on the market. This would cost an additional $15 million.

The $25 million Michelson Prize for a single-dose dog and cat contraceptive,  posted in 2008 by medical inventor Gary Michelson,  might just about cover the research and development costs to make the product easily accessible.

Reported the June 2002 edition of ANIMAL PEOPLE,  “A commercialized alternative to surgical castration or ovario-hysterectomy for either dogs or cats  may still be 10 years away,  Linda Rhodes,  DVM,  told the 2002 International Symposium on Nonsurgical Methods for Pet Population Control,  held April 19-21,  2002 in Atlanta.”

Rhodes’ considerations in 2013 were essentially the same as in 2002.  Getting a single-injection contraceptive for dogs and cats through the regulatory process will be difficult.  But before that even begins,  more research is necessary to perfect such a contraceptive enough to interest major pharmaceutical manufacturers in funding the pursuit of regulatory approval.  Only major pharmaceutical manufacturers are believed to have access to the investment capital that will be necessary to bring a successful dog and cat contraceptive to market.  

There are two possible regulatory approaches to approval of a dog and cat contraceptive in the U.S.,  of which the most advantageous would be to obtain Food & Drug Administration recognition of the product as a veterinary pharmaceutical.  This,  however,  would be much slower and more expensive than obtaining Environmental Protection Agency authorization of the product for use as a “pesticide.”  

The drawback to pursuing the EPA route would be that the animals for whom the contraceptive is meant would be thereby legally defined as pests,  potentially exposed to indiscriminate extermination.  Further,  while EPA registration would make a contraceptive product available to nuisance wildlife control agencies,  the product would not be accessible to veterinarians for use in pets.

GonaCon

This is more than just a theoretical concern.  GonaCon,  an immunocontraceptive already on the market for use in wildlife and hooved species,  was developed by the National Wildlife Research Center,  under the umbrella of USDA Wildlife Services.  Effective in ground squirrels, deer,  and wild horses,  GonaCon also appears to suppress conception in cats and dogs.  USDA Animal & Plant Health Inspection Service veterinarian Luis Lecuona at the 2013 ACC&D conference presented results from an experiment in Mexico which combined rabies vaccination of street dogs with applications of GonaCon.  Members of another research team offered similar findings from use of GonaCon in connection with rabies vaccination in the city of Sauraha,  Nepal.

Spay First coordinator Ruth Steinberger,  of Bristow,  Oklahoma,  hoped to attend  the 2013 ACC&D conference to share preliminary information about a two-year test of GonaCon due to start on two remote Native American reservations in September 2013.  Steinberger was obliged to cancel attending the conference at the last minute,  she told ANIMAL PEOPLE,  after twisters hitting Oklahoma caused logistic complications for the Spay First conventional surgical sterilization program.  

“The $60,000 contraceptive study will be conducted by the National Wildlife Research Center and Spay First,”   summarized Associated Press writer Sue Manning.  “Veterinarians plan to catch and inject 300 wild female dogs,”  who will be  “microchipped,  tattooed,  collared, injected and released.  After a year,  researchers will round up as many as they can and do blood tests to measure reaction to the vaccine. The Petco Foundation donated about half the money for the study.”

Steinberger told ANIMAL PEOPLE that she is aware of concerns about how GonaCon is registered,  by whom,  and what legal precedents that might create,  but pointed out that feral dogs on Native American reservations are often shot or poisoned now,  so bringing them under the indirect jurisdiction of USDA Wildlife Services by using GonaCon is in her view unlikely to change the dogs’ status in any harmful way.

Julie Levy,  DVM,  director of the Maddie’s Shelter Medicine Program at the University of Florida,  told the 2013 ACC&D conference about her findings concerning the use of GonaCon in cats.  Levy has found that both the onset and duration of each cat’s immune response are unpredictable,  and that some cats have injection site reactions which may suggest later development of tumors.  Some of these problems may be avoided or reduced by reformulating GonaCon specifically for use in cats.

Deslorelin  

Judith Samson-French,  DVM presented findings about her use of Deslorelin to control the dog populations on the Tsuu T’ina and Siksika First Nations reserves in the southern Alberta foothills.  Deslorelin,  long used in zoo animals,  is a hormone analog,  modeled on a natural hormone that turns reproductive processes on and off in the brains of both male and female animals.  

Samson-French and Calgary Zoo senior animal health technologist Lori Rogers began their work on the First Nations reserves in 2009. Among the drawbacks to Deslorelin is that administration requires careful timing,  since it can sometimes stimulate dogs to produce a litter before the contraceptive effect begins.  Also,  because it is administered as an implant,  it is not permanent.  To achieve lifelong contraception, each dog must be recaptured every couple of years for reimplantation.

ChemSpay

The 2013 ACC&D conference did not hear an update from SenesTech,  the Arizona company whose product ChemSpay was field-tested in 2006 at the Navajo Nation,  at the junction of Arizona,  Nevada,  Colorado,  and Utah.  Funded by ACC&D,  the experiment was unsuccessful. Based on the industrial chemical 4-vinylcyclohexene diepoxide,  which is a carcinogen with other known damaging effects on the human reproductive system,  ChemSpay would in any event have been extremely difficult to register for use in dogs and cats.

The ChemSpay approach was initially developed to model human menopause in laboratory mice.  SenesTech has focused since 2006 on developing a similar product,  ContraPest,  licensed as a rodenticide.  In March 2013 SeneTech and the New York City Metropolitan Transportation Authority began researching baits for possible use in a test of ContraPest in the New York City subway tunnels.   “SenesTech already is running tests in Indonesia,  Laos,  the Philippines,  Australia,  and New Zealand,  mostly to keep rodents from ruining crops such as wheat and rice,”  reported Caroline Winter of Bloomburg BusinessWeek.  

Alex Pacheco,  who cofounded People for the Ethical Treatment of Animals in 1981,  but left PETA in 1998,  in 2009 formed an organization called 600 Million Stray Dogs Need You to raise funds for developing a “Super Birth Control Pill for Dogs” which appeared to be ChemSpay.  600 Million and SenesTech in December 2010 announced a partnership,  but in April 2011 SenesTech ended the relationship.  600 Million has continued to raise funds in the name of contraceptive research,  most recently to develop contraceptive pet foods––an approach which has little chance of winning licensure in the present regulatory environment.

Several contraceptive pet foods were briefly marketed between 1963 and 1978,  but all required repeated dosing to sustain the contraceptive effect,  and sustained use led often to pyometra.  Two products from this generation of animal contraceptives are still available by prescription––Ovaban,  for dogs,  and Feral-Stat,  for cats.  But neither is actually a sterilant.  The  birth control pet food  introduced with the greatest fanfare,  Mibolerone,  was a progestin product closely related to the post-coital human contraceptive RU-486.  It had the same issues as the rest,  however,  and the active ingredient was banned in the U.S. as an abortificant from 1988 to 2000.

Testicular injectibles

Other contraceptives for dogs and cats are under study.  Meanwhile,  the only injectable contraceptive now available to any U.S. veterinarian is Zeuterin,  a zinc-based chemosterilant made to be injected into the testicles of male dogs,  originally marketed as Neutersol and sold abroad as Esterisol.  Similar products are produced in Brazil and Thailand.  Zeuterin has only just been brought back to market by Ark Sciences Inc.,  several years after the Neutersol manufacturer quit production.

The zinc-based chemosterilants relatively inexpensively induce sterility in male dogs and cats.  But they have been slow to gain favor, because sterilizing males is usually of secondary concern in reducing stray populations and because zinc injections are not seen as effective in bringing about the changes in male animal behavior that follow surgical castration.

Testicular injections of calcium chloride to sterilize male dogs have been tested in India,  Italy,  and Nepal,  encouraged since 2011 by the San Francisco-based Parsemus Foundation.

An Alliance for Contraception in Cats & Dogs position paper acknowledges that “While no direct comparison has been performed,  the available evidence suggests that calcium chloride sterilization of male dogs may reduce testosterone concentrations more than Esterisol and Zeuterin;  this is a feature of interest to those who desire a greater testosterone reduction.”

Calcium chloride is inexpensive and available for other pharmaceutical uses worldwide.  But as the Alliance for Contraception in Cats & Dogs position paper summarizes,  “To our knowledge,  calcium chloride as not been reviewed or approved by any regulatory agencies for use as an animal sterilant.”   Parsemus Foundation director Elaine Lissner explained to the Portland audience that her foundation does not have nearly the resources that would be needed to win FDA approval for contraceptive use of calcium chloride.  The Parsemus Foundation is funding projects,  however, which may help to perfect the calcium chloride method for use wherever the regulatory environment might allow it but Esterisol or Zeuterin is inaccessible,  and may move calcium chloride closer to winning U.S. approval if and when a larger foundation takes it up.

Because calcium chloride is already in common use for other purposes and therefore cannot be patented,  and because it is so cheap as to offer little possibility of making a profit from selling it,  Lissner does not anticipate commercial interest in advancing it.

Michelson Prize

The $25 million Michelson Prize in Reproductive Biology is to be awarded for the development of a single-dose nonsurgical sterilant, preferably to be administered by injection,  that will be effective and safe in both male and female dogs and cats for 10 to 20 years,  “ablates presence or action of sex steroids,”  can be easily made at a reasonable cost ($5.00 to $30 per animal treated),  is “suitable for administration in a field setting,”  and has a “reasonable pathway to regulatory approval.”

Progress toward developing such a product is supported by the $50 million Michelson Grants in Reproductive Biology.  This program provides funding of up to $250,000 per year for up to three years to researchers who have already presented “proof of concept studies in vitro, in rodent models,  in target species (dogs and cats),  in one gender or one species.”  

The Michelson program requires that “Research animals must be placed in adoptive homes if terminal studies are not essential.”  

Terminal studies might be required to meet the regulatory requirements for licensing products which might be ingested or inhaled,  by humans––even if the human exposure results from deliberate misuse. Michelson Prize & Grants in Reproductive Biology director of scientific research Shirley D. Johnston told the ACC&D conference that in the five years since the funding was made available,  the trustees have committed $11.3 million in grants to 23 research groups,  after reviewing 83 research proposals and receiving 234 letters of intent to apply for funding.  Several proposals are still under consideration.  About $38.7 million remains uncommitted.  

Among the funded approaches,  13 are investigating “targeted delivery of cytotoxins,”  the method including chemosterilants;  seven are investigating immunocontraception,  which seeks to use the animals’ immune systems to prevent conception;  and five are investigating genetic methods,  including gene silencing and gene therapy.

The Michelson Prize and grants have been publicized to more than 10,000 neuroscientists,  oncologists,  pharmaceutical chemists, immunologists,  virologists,  molecular biologists,  and reproductive physiologists,  Johnson said,  via booths at 43 scientific conferences and ads in 78 professional publications.  

The availability of the funding has stimulated scientific interest.  But it has not produced any current hope that anyone will soon hit the jackpot.