Marty the cat

Photo by Kelly Watson

After Marty nearly died from congestive heart failure, his veterinarian in Australia prescribed him Rapamune, a formulation of rapamycin labeled for use in humans. In the United States, cats with subclinical hypertrophic cardiomyopathy soon will have access to a new form of rapamycin developed specifically for cats.

Shmitty the cat had been a patient of Dr. Kourtney Morrissette for three years by the time his owner saw him fall onto his side for more than a minute, breathing through his mouth — which is unusual for a cat — and paddling the air with his paws. What Morrissette detected years earlier as a faint heart murmur was the first hint that Shmitty had a condition known as hypertrophic cardiomyopathy, or HCM.

Though Shmitty survived this incident, Morrissette explained to her client that Shmitty's prognosis was poor. Characterized by a thickened heart muscle, HCM can result in congestive heart failure, clots to the legs or sudden death. For many cats, HCM will remain subclinical, or asymptomatic, for their entire lives. In others, an HCM diagnosis is terminal.

It is the most common heart condition in domestic cats, affecting an estimated 15%, and no treatment specific for HCM has been approved in the United States — until now.

Last month, the U.S. Food and Drug Administration granted conditional approval to Felycin-CA1, a delayed-release tablet that contains the active ingredient rapamycin. The product's developer, Ireland's TriviumVet, has not yet announced when Felycin will be available to prescribe.

Notably, the drug is intended only for cats with subclinical HCM. In other words, it's not for patients that are ill from the disease.

Rapamycin, also known as sirolimus, already is used off-label by some pet owners around the world to treat feline HCM. Rapamycin was first approved by the FDA in 1999 as an immunosuppressant for organ transplant in human patients. The drug also is being explored experimentally for its apparent anti-aging properties.

Shmitty's owner had asked about rapamycin, having read about the drug in a Facebook group page. Could Shmitty get a prescription? For Morrissette, prescribing a drug without knowing its side effects, efficacy or dosage for cats felt like rolling the dice.

"I told the client that I really could not recommend it at this time," Morrissette told the VIN News Service by email.

Other veterinarians also had been fielding questions about rapamycin prior to Felycin's conditional approval, judging from message board posts on the Veterinary Information Network, an online community for the profession and parent of VIN News.

One veterinarian, Dr. Melissa Jones, was asked by a client to prescribe rapamycin for her sphynx cat. Jones initially was uneasy.

"I just don't hesitate to say, 'Hey, this is something new, this is not something we've experienced a lot, do you mind if I take a couple of days to look into it a little bit more and talk with my colleagues and consult the literature?' " she recounted, adding, "It's my license on the line if something doesn't go right."

After consulting with colleagues and discussing the ample unknowns with her client, Jones agreed to write the prescription. The biggest factor in her decision was that the client was a physician, so Jones was able to thoroughly and scientifically discuss with her the knowns and unknowns about rapamycin in cats.

Felycin's conditional approval is based on the results of a pilot study that involved fewer than 50 cats with subclinical HCM. Cats that received the drug did better than those on a placebo. And strikingly, cats given a lower dose of the drug did better than cats given a higher dose. Researchers gauged the cats' response to the drug by measuring the thickness of their left ventricle, a chamber of the heart.

The FDA can elect to grant conditional approval to a drug shown to be safe and that has a "reasonable expectation of effectiveness," enabling the drugmaker to market the drug while it gathers more evidence that the medication is effective. The status lasts for a year, with the potential to renew for up to five years. TriviumVet is embarking on a large clinical trial, with the goal of securing full approval. Fully approved drugs are those demonstrated to be both safe and effective.

Jones believes she'll probably prescribe Felycin to her patients but might hold out until more evidence comes in.

"I was a little bit uneasy with the situation because that's one study," she said. "It's a good study, but we'll probably need more."

What is rapamycin?

Rapa Nui — or Easter Island — in the southeastern Pacific Ocean is known globally for its awe-inspiring moai, gigantic, centuries-old stone statues.

A lesser-known attribute of the island is its unique soil. In 1965, a Canadian research team collected a sample that they found to have potent antifungal activity. Ten years later, the antifungal component was identified as rapamycin, according to an account in The Enzymes, a book published on ScienceDirect.

Rapamycin works by interacting with receptors for an enzyme called mTOR that helps regulate various cell processes, including growth. Much remains unknown about the drug, which also is being investigated as a cancer treatment. The Dog Aging Project, an initiative based at Texas A&M University and the University of Washington, is studying its ability to delay cell aging, potentially extending lifespans in canines.

Rapamycin has amassed a following among pet owners who wonder if it can help their pets.

Kelly Watson is an administrator in Australia of the Facebook group "Rapamycin (sirolimus) for cats and all pets." After her 3-year-old cat, Marty, nearly died of congestive heart failure and respiratory distress, Watson said she started reading everything she could about his condition. After learning that no approved treatment could delay progression of his disease, she began reading up on rapamycin.

Watson was intrigued, even with the dearth of evidence in cats.

"I felt the risk was worth trying," she said.

At Watson's request, Marty's veterinarian wrote a prescription for Rapamune, a formulation of rapamycin for human patients made by Pfizer. Whether it's working is to be determined. A few months in, Marty hasn't yet had a follow-up appointment.

The Facebook group, started last year, has more than 600 members around the world. They share information about rapamycin and post updates on their cats' health. Some cite difficulties getting a prescription from their regular veterinarian, due to the practitioner's lack of experience with the drug.

Watson said the group's goal is to help members learn about rapamycin so they can have a conversation with their veterinarian. Members share names of prescribing practitioners they trust, such as Dr. Letrisa Miller.

Miller has a feline-only practice in Connecticut. Due to HCM's prevalence in cats, Miller followed the Felycin trial study with interest. Once preliminary results started coming out, Miller began prescribing rapamycin to some feline patients, using information from the trial as a guide. Miller said it's important to be transparent with clients about what is known and unknown about the drug.

"With new drugs, I always tell people, 'This is how long this drug has been available. This is what we know,' " Miller said, "so that they can make an informed decision."

Miller plans to prescribe Felycin once it becomes available. (Off-label, or extralabel, use of human drugs such as Rapamune is legal in the U.S. for veterinary patients unless there is an approved, clinically effective drug available with the same active ingredient and in the dosage form and concentration needed for treatment. Extralabel use of conditionally approved drugs is not allowed.)

"It's heartbreaking to see cats that no matter what we do, we see progression," Miller said. "Anything that is at all effective is going to be so helpful."

What the pilot study showed

Amid the optimism surrounding rapamycin, Felycin is entering what Dr. Joshua Stern, a veterinary cardiologist and lead researcher on the Felycin studies, calls a "drug desert" because there's nothing else available to treat feline HCM.

"There are zero approved compounds for the treatment of feline hypertrophic cardiomyopathy," said Stern, who is associate dean of research and graduate studies at North Carolina State University College of Veterinary Medicine. "So this is an area where there's a clear need for us to have something to do, and so that has been the focus of my research and academic mission for many, many years now."

The trial study of Felycin was conducted on 43 cats with subclinical HCM. The test subjects were divided into three groups. One received a placebo, one received a lower dose, and one received a higher dose. The cats were followed via echocardiography for six months to see if their left ventricles would thicken further. At the end of the study, left ventricular thickness in the lower-dose group was significantly lower than that of the placebo group, whereas no statistically significant difference was found between the higher-dose group and the placebo group.

Three out of 12 cats in the higher-dose group experienced progression or death related to progressive heart disease and congestive heart failure. One cat in the lower-dose group developed diabetic ketoacidosis and died, suggesting to the researchers that caution is warranted when giving rapamycin to cats with risk factors for diabetes (as this one had). Other adverse effects included loss of appetite, vomiting, diarrhea and lethargy. There was no statistically significant difference in the number of adverse reactions among the three groups.

Given that a lower dose of the drug achieved better outcomes than a higher dose, the results illustrate the importance of understanding dosing and structure, Stern said. Blindly administering rapamycin to a cat is not recommended.

Stern is aware of how many pet owners want to try rapamycin on their cats. He worries that conditional approval will make it harder to recruit subjects for the expanded study needed for full approval because the medication will be more readily available through veterinarians. At the same time, conditional approval is the best way to quickly provide access to patients to a regulated rapamycin treatment.

"People are desperate to get access to this medication," Stern said. "I'm very happy that the conditional approval has gone through so that at least cat owners have the opportunity to use the compound formulated in a way that we know is safe and believe to be effective."

A more extensive study to examine the effects of the lower dose of Felycin on 300 cats is now underway. Still in the process of enrolling subjects, the study must show results within the five years before conditional approval expires.

Stern emphasized that the treatment is not for every cat — for now, the research is focused on cats in the subclinical phase, not already in heart failure or with other complications such as diabetes.

"We simply don't have data on the use of this compound in cats that are already in congestive heart failure, and I know that's very disappointing for a lot of cat owners," he said.

It's also unclear what the long-term effects of rapamycin are on cats. Still, Stern is optimistic that more will be understood about the drug as veterinarians start prescribing it to a growing number of patients.

"I'm just excited to have the opportunity to allow myself to imagine a time where I can have a cat owner say, 'What can I do?' and actually be able to give them an answer."