VIN News Service archive/Photo courtesy of Ark Sciences

This dog is shown three months after being sterilized with Zeuterin. The injectable drug has become difficult to obtain due to company financial troubles.

Ark Sciences Inc., purveyor of the only federally approved drug to sterilize male dogs, is in disarray due to poor sales of Zeuterin, an alternative to surgical castration.

The New York-based company, which began selling Zeuterin in the United States in early 2014, has for several months not answered telephone or email inquiries, including those from veterinarians wishing to learn more about the product or place an order.

Ark Sciences founder and board member Joe Tosini told the VIN News Service today that the company is "in the final stages of restructuring" and expects to roll out an updated website and telephone system soon, as well as resume sales, which are suspended due to a hitch in distribution.

Tosini said he is in the process of arranging funding to keep the company functional.

"There's a lot of things that I have going on," he said. "It's like we're in the middle of an operation, and you're saying, 'Hey, can you tell us what's going on?' "

Ark Sciences closed its office in Irvington, New York, in October, according to Vincent Garritano, operations manager at G.S. Garritano & Associates, an accounting and consulting firm. The firm is contracted to serve as Ark Sciences' chief financial officer.

"It has been a rough transition," Garritano acknowledged. "Very rough."

Garritano attributed the company's difficulties to poor acceptance from the veterinary community and "something wrong with the marketing."

"We got a lot of pushback from people who preferred to do the surgery rather than the injection," he said.

Tosini said, "It's fear of the unknown, and that's very costly."

Using Zeuterin to sterilize a male dog is significantly different from standard neutering, which involves removing the testicles.

The procedure with Zeuterin entails injecting a solution of zinc gluconate and L-arginine into each testicle to kill existing sperm and stimulate a buildup of scar tissue that blocks new sperm from traveling through feeder tubes, thereby making the patient infertile.

The injection requires no general anesthesia and takes only moments to complete. However, the idea of piercing testes with a needle can induce squeamishness, even among veterinarians. On a message board of the Veterinary Information Network, an online community for the profession, practitioners discussing the concept several years ago called it "cringe-worthy" and "barbaric."

The standard practice of surgically removing the testicles is not a trivial procedure, of course, but it's well-accepted, Garritano observed: "Everybody can understand what happens when you do a surgical castration, but with an injection, people are like, 'What am I putting in my dog, and what are the possible side effects?' "

Testicles usually swell mildly a day or two after injection with Zeuterin, according to Ark Sciences' client information sheet. Some testes remain enlarged for several months, but they tend to atrophy over time.

Dogs are said to feel little to no pain from the injection itself, if done correctly, but may feel pain for a few days afterward. Adverse reactions include scrotal irritation, inflammation or infection.

The U.S. Food and Drug Administration received five reports of adverse events with Zeuterin in 2014 and 2015. (Exactly how many dogs were sterilized with Zeuterin in the same period is unclear; Tosini said he did not have a precise figure at hand but that it was in the "thousands.")

Among the five cases, the clinical signs were: vocalization (indicating pain), general pain, injection-site edema, injection-site inflammation, injection-site lesion, injection-site necrosis, lethargy, muscle tremor, hypertension, tachycardia (abnormally rapid heart rate) and death.

Dr. Byron Maas, Ark Sciences' chief medical officer, said the dog who died was sterilized with Zeuterin after being picked up by a rescue organization in Southern California. "The dog developed an abscess and was not quickly treated because it was in a rescue with limited funds," he said. "Eventually, it began to deteriorate and had surgery for castration and, I believe, scrotal ablation …."

Maas said the dog died a few days later. "To be fair, I believe the Zeuterin may have been part of the reason for this dog's death," he said, "however, its prior extremely poor health played a more significant role in failure to respond to traditional therapy."

Veterinarians show support, reluctance

To minimize chances of negative side effects, Ark Sciences requires training for veterinarians wishing to use Zeuterin. Among those trained to "Zeuter" are Dr. Kathy Kocher, owner of State College Veterinary Hospital in Pennsylvania, and her associate.

Kocher said she supports the alternative approach because of the potential health benefits of retaining some level of sex hormones. Recent research suggests that removing dogs' reproductive organs may have long-term medical implications, especially if done before adulthood. A study that garnered widespread attention in 2013 found that surgically sterilized golden retrievers had an elevated risk of cruciate ligament injuries, hip dysplasia and some cancers.

Dogs treated with Zeuterin retain about half their normal levels of testosterone, according to Ark Sciences. Surgical castration reduces it to near zero.

Kocher and her associate treated seven dogs with Zeuterin during their training in July 2014. Since then, she said, they've Zeutered only four. "I have a hard time selling the product, although I believe in it," she said.

One issue is that many patients come to her already surgically sterilized by shelters. Kocher approached the local humane society and other shelters in the area, hoping to stimulate their interest in Zeuterin. "They're adamantly opposed to it," she reported.

Her impression is that the shelters prefer to sterilize dogs as early as possible "and they don't want any returns for behavioral issues."

Surgical castration, in addition to preventing male dogs from reproducing, is associated with reducing behaviors such as aggression, marking territory with urine, and roaming, although to what degree is variable.

Dr. Susan Powell, director of shelter medicine at Woods Humane Society in San Luis Obispo, California, cited dogs' sex drive in explaining her perspective on Zeuterin. "I really don't think this product has any place in the shelter world," she told the VIN News Service by email. "Dogs come into the shelter because they were roaming, intact males following their testosterone drive with one thing on their mind. It's quick and easy and not that expensive to remove the source of that testosterone completely."

Still, what deterred Powell from trying Zeuterin was not her preference for surgical castration but the cost of training. "My big problem with this product was that they were going to charge me a large amount of money (at one point I was told $1,000) to train me to use a product I could only buy from them," she said.

She added, "I would only have considered using it if they provided the training for free. And even then, not in shelter dogs, but potentially as an option for public neuters."

Occasionally, the type of sterilization offered through Zeuterin is exactly what a pet owner is after. Last fall, one of Kocher's clients inquired about neutering a purebred samoyed who had retired from a show career. The dog's owner wanted to avoid surgical castration because of the potential health consequences.

Zeuterin seemed a good solution. However, in the United States, Zeuterin is labeled for use only in puppies between 3 months and 10 months of age; the samoyed is 4 years old. Kocher thought the drug would be safe to use in an older dog — it's been deployed in other countries on pups and adults alike — but she wanted to be certain. (Doctors may prescribe drugs for purposes other than their labeled indications; the application is known as off-label or extra-label use.)

Kocher said, "I reached out in every single way I knew to try to contact the people from Ark about what data they had on using it on older animals ... and got no response back."

Her client tried to reach the company, as well. At last, frustrated by the dog's "oversexed attitude," the client opted to have him neutered the usual way, Kocher said.

The experience left the veterinarian shaking her head. "It would have been nice if they'd given you the courtesy of a reply, even an automated reply, to emails and phone calls," she said.

Dr. Jennifer Niemczyk had the same reaction. A practitioner in Appleton, Wisconsin, Niemczyk was interested in using Zeuterin to sterilize a puppy who is considered a poor risk for anesthesia because he has a major heart condition, subaortic stenosis.

But Niemczyk could not reach the company. She was dismayed to learn through a VIN message board that sales were suspended. "It would have been courteous for the company to modify their website, email or voice message to reflect that the product would not be available," she said.

Tosini acknowledged that was a problem. "That's been a real burr in our saddle. We're getting this resolved," he promised.

Déjà vu

Ark Sciences is not the first company to flounder in an attempt to bring zinc neutering to the U.S. pet market.

Pet Healthcare International, which originated the zinc gluconate-arginine formula, received FDA approval for the product in 2003, and marketed it in partnership with Addison Biological Laboratory Inc. under the name Neutersol. Neutersol was available only briefly before trouble arose.

Ark Sciences recounts on its website: "Addison Labs, the exclusive distributor of Neutersol, overestimated the growth in demand and created too much inventory on credit. The excess inventory expired in two years and the manufacturer went unpaid, shutting down production." Neutersol went off the market in 2005.

Tosini was a minority investor in Pet Healthcare International. He acquired rights to the drug and founded Ark Sciences, which brought the product, renamed Esterilsol, to Mexico and other countries in Latin America. (Esterilsol is not currently commercially available, according to Tosini.)

Ark Sciences obtained FDA approval and reintroduced the drug to the United States in 2014 under the name Zeuterin.

Like its predecessor, Ark Sciences has had trouble matching demand to supply.

"They sold a very small amount," said Joe Marquard, who distributed Zeuterin through his company, Saddle River Marketing Concepts Inc., in Paramus, New Jersey. Marquard estimated that Ark Sciences sold 1,000 units or fewer. Each unit contains enough solution to sterilize two or three dogs, depending on their testicle size.

Saddle River no longer serves as a distributor but instead is acting as a third-party logistics provider, Marquard said, due to recent changes in law affecting distributors of drugs for human patients. The upshot is that Ark Sciences no longer has a distributor, and therefore cannot move inventory into the hands of willing buyers.

"The product they have expires in August or September," Marquard said. "It's still in my warehouse."

Tosini drew a distinction between Ark Sciences's and Pet Healthcare International's experiences. "The difference with us, we went through a painstaking process of developing a training protocol, going to vet schools, getting CE [continuing education] credits [for practitioners who underwent training]. All these things have been foundational work that don't bring you a lot of immediate sales," he said.

Moreover, some veterinarians encountered resistance when they tried to bring the procedure to their clinics, Tosini said, "Let's say a veterinarian gets certified. You have this training, you have a webinar, people fall in love [with the product]. Then they go back to their organizations, and because they're not the decision-maker," he said, referring mainly to those working for nonprofit organizations, "all of a sudden, there's a lag time and it doesn't happen. So you wind up training hundreds of veterinarians and you get 50 doing it."

Maas, a private practitioner in Oregon who initially was paid to be Ark Sciences' chief medical officer but is no longer paid, said he continues as a volunteer to conduct veterinarian training in order to promote non-surgical sterilization.

He returned recently from a session at St. George's University School of Veterinary Medicine in Grenada; the university covered the airfare, he said. That was followed by a training session via Skype with a group near Toronto.

But the fact that veterinarians cannot get their hands on the product is a hindrance, to say the least. "It makes a huge challenge," said Maas, who has a page on his practice website devoted to Zeuterin. "I get a lot of calls from people who are looking for the product. I've got [my own] clinic here in Bend, and I happen to have some stock that I'm using and hopefully was going to get it replaced. I don't know if I can ...

"Definitely Ark Sciences is struggling, no question about it," he said. "… it's come down to, if Ark Sciences doesn't raise a significant amount of money, it may not be able to continue."

Few substitutes for surgical castration

If Zeuterin were to be withdrawn, no FDA-approved options to surgical castration would exist for male dogs in the United States.

According to the Alliance for Contraception in Cats & Dogs, two categories of drugs are available as compounded drugs, which are not approved by the FDA:

• Progestin contraceptives. These usually are used to suppress estrus in females, but have some effect in males, too. "In the U.S., they are typically not recommended at all, or not for more than one cycle, given concern about side effects," the ACC&D reports.
• Injectable calcium chloride and ethyl alcohol. The drug "should be considered experimental," the ACC&D cautions in a position paper.

An implant designed to prevent fertility and suppress libido in male dogs, called Suprelorin, is available in New Zealand, Australia and the European Union, but not the United States, according to the ACC&D.

In light of the scarce options, Joyce Briggs, president of the ACC&D, said she hopes the owners of Zeuterin don't go out of business.

"In this age of increasingly personalized medical options for dogs, Zeuterin creates choice for veterinarians, pet owners and animal shelters, with a number of benefits not provided by surgery," Briggs said. "I would be very disappointed if it cannot be sustained as an option for dog fertility control."

She's also concerned that if Zeuterin fails, the prospects for approaches in the research-and-development pipeline will darken. "There's a lot of different things that are being worked on, but there's nothing imminent," Briggs said. "[Zeuterin] is the first one out there … and I would hate for it to not succeed as part of setting the stage for new options to come."

Sandeep Manchanda, who until six months ago was Ark Sciences' chief operating officer, said Zeuterin's problems are strictly business. "The discussion was on funding and marketing strategy," he said, explaining that he left the company following a disagreement with the board on how to proceed.

As for Zeuterin itself, Manchanda said, "I have complete faith and trust in the product. That was never the issue."

In fact, a few weeks ago — mindful of studies of Zeuterin in other species and the option to use drugs off-label — he enlisted a veterinarian friend to Zeuter his pet cat and mouse. "That worked really well," he reported