Journalism, Monoclonal Antibodies, and Adverse Outcomes

The Wall Street Journal report on adverse outcomes caused a drop in Zoetis' stock price. But what does it mean for our patients and pets?

The Wall Street Journal published a report on April 13th of this year, questioning the safety of the relatively recently approved canine drug Librela (bedinvetmab injection) and its feline counterpart Solensia (frunevetmab injection).

Both Librela and Solensia work by targeting Nerve Growth Factor (NGF), a mediator of pain and inflammation in osteoarthritis (OA). These treatments utilize monoclonal antibodies that bind to NGF, effectively blocking its action and thereby reducing pain and inflammation associated with arthritis. This mechanism provides a targeted approach to pain relief, which is intended to be safer and more specific compared to traditional NSAIDs that have broader effects and can lead to various side effects.

The marketing materials for these treatments enthusiastically note their minimal side effects. It’s believed that because the drugs are eliminated in the same way as naturally occurring proteins, with little to no liver or kidney involvement, they are thought to be particularly suitable for long-term management of OA without the typical risks associated with NSAIDs, such as gastrointestinal, renal, or hepatic issues.

As ever, there is a lot of empty space between what media reports, what a corporation’s public relations provides, and what’s likely happening on the ground. And such swaths of my own ignorance make my brain itch.

I’m going to break down the WSJ report piece by piece and try to put it in the context of some of the scientific research and my experience as a practicing veterinarian.

Adverse Events

There are several adverse events reported by veterinarians and pet owners in the article.

1. Patient: “Daisy” Jordan, 12yo mixed breed, female (presumed spayed)

   1. Presenting Complaint: “stiff right rear hip”

   2. Outcome:

      1. “about two weeks after the first injection in January, however, Daisy wobbled on both hips and limped”

      2. “A week after her second dose, the dog couldn’t walk, became lethargic, and lost her appetite.”

      3. “She gained some mobility back, but her kidney function plunged.”

      4. “In March, the Jordan family euthanized their dog.”

2. Patient: “Max” Stover, 16yo DSH, male (presumed neutered)

   1. Presenting Complaint: “suspected arthritis”

   2. Outcome:

      1. “appeared lethargic, wobbled his head and was barely able to move after getting Solensia injection in December.”

      2. “issues lasted for two months”

      3. “The cat’s kidneys eventually failed.”

      4. “He died …in February.”

3. Patient: “Soren” Boyd, unknown age, male (unknown)

   1. Outcome:

      1. “dog struggled to walk, became weak and anxious and had a fever for three days after his first Librela injection in January.”

      2. “a joint tap…showed… immune-mediated polyarthritis.”

      3. “put down her dog Soren last week”

         1. Roughly three months following initial injection.

   2. Of note: Pet located in San Marcos, Texas.

GPT-4; essay as prompt; pills everywhere? The mouse on the wrong side? These images often seem to have a vaguely unsettling wrongness element

Response

My initial response to these reports, and reports like them, is to note the overall vagueness of the reporting as well as the easily imagined possible comorbidities. I don’t know if it’s because there was an absence of good medicine or because such details were beyond the scope of the Journal’s reporting, and it’s wrong to assume either.

Daisy

In the case of Daisy, described as a mixed-breed rescue dog, one could conclude that the administration of a Librela injection caused the subsequent clinical signs. From the limited amount of information provided, that conclusion is sound - or it would be, if that was all the information there was. But our patients do not exist in so simple a system and do assume such would disappoint professors of mathematics and logic the world over.

Daisy could have had osteoarthritis in her “stiff right hip,” or she could’ve been afflicted with another fairly common condition, degenerative myelopathy, perhaps. Degenerative myelopathy is an inherited neurologic disease typically affecting dogs around eight years of age or older. It causes gradual muscle wasting and incoordination in the hind limbs before progressing to an inability to walk over six to twelve months. I strongly suspect its progression would have been accelerated by the administration of a long-acting anti-NGF medication.

Or she could’ve been afflicted with any of dozens of other pathologies that present with similarly vague clinical signs.

I don’t have enough information to conclude one thing or another. My strong desire for clarity doesn’t give me the logical license to invent facts in order to reach a conclusion. Yes, the medication could have caused horrible side effects, but those side effects could be much more significant if the medication was administered inappropriately.

Max

Let’s take Max, the 16yo DSH, who was treated for suspected arthritis. NGF isn’t just for nerves, it can influence the function of non-neuronal tissues as well. NGF is involved in the normal functioning and repair of, among others, renal tissue. Blocking the NGF can disrupt these processes, potentially leading to impaired kidney function.

What makes me think that Max might have had impaired kidney function? 30-40% of cats over 12 years of age have elevated renal biomarkers. In the Solensia Prescribing Information, an insert included in the package of the drug, it’s noted that renal insufficiency, specifically a worsening of existing disease, occurred in 12 of 182 patients in the field study. The prescribing information for Librela notes one of the adverse reactions resulting in a patient’s death occurred in an older dog with elevated kidney values.

The likelihood of renal disease in a 16yo cat, the frequency of adverse effects, the physiology and mechanism of action of a drug, and the diagnosis are all things a veterinarian should know before administering any medication. Was Max’s death the result of a dangerous medication? Or was it the result of an improperly applied medication?

Again, I don’t know. There is not enough information provided to draw a conclusion. There is enough, however, for me to reject the conclusion drawn by the cat’s grieving owner as the only possibility.

Soren

Soren is a patient owned by a veterinary technician, so there is likely more credibility to the side effects when presented by someone with education and experience in veterinary medicine.

However, since I’ve made a habit of considering comorbidities I’ll bring up some possibilities for Soren as well.

It’s possible that an injection intended for subcutaneous administration was inappropriately administered into a joint space. This could result in a polyarthritis. I consider this at least somewhat unlikely because, well, you’d have to really fuck it up miss rather badly to hit the joint space rather than the subcutaneous space with such an injection. Further, the joint tap indicated an immune-mediated polyarthritis, which would likely not be the result of a joint stick.

The other possibility is that Soren contracted any of a number of tick-borne diseases present in San Marcos, Texas, where his owner resides. Ehrlichiosis, anaplasmosis, Lyme Disease, and more can all cause polyarthritis in dogs. Although it’s fairly likely that a veterinary professional’s dog would be protected against parasites, it’s not a given, and every preventative has breakthrough events.

In my opinion, this case merits the most scrutiny from the perspective of adverse drug events.

Unfortunately, I still find myself short of adequate information to draw a conclusion about the fault or absolution of the pharmaceutical. While such medical details are likely beyond the reach of a mainstream media article, without such details I find myself unable to reach meaningful conclusions.

Conclusions

I’m not a journalist, epidemiologist, or pharmacologist. Although there are elements of some specialties in my role as a veterinarian, I’m a generalist at heart. I’m a clinician who writes these articles on Substack in between splenectomies, vaccinations, and ultrasounds —and finding to do things like the management and operation of a veterinary hospital. I’m a ten-year veteran of the five-or-six-day-a-week habit of practicing veterinary medicine.

To do this job well takes not just years of study and practice, but the continuous commitment to improvement of knowledge and competence. I do my best to do that and to honor that commitment in my hospital as well.

My job also requires a dedication to the fundamentals of statistics and, in this case, an acute understanding of the “correlation does not imply causation” or question-cause fallacy.¹ The Journal article sparks interest because of the apparent correlation between the use of the drugs and adverse effects, but given the information at hand the causation is speculative. But the Journal’s report lacks crucial details. Heck, the piece I’ve written here is almost twice as long as the Journal’s.

Pets at the age of arthritis often have comorbidities, and certain comorbidities are known to result in adverse events. At what point do we blame the doctor for misusing the drug rather than solely the drug in question? There are considerable resources available to give guidance on the use of monoclonal antibodies like these. If a veterinarian does not avail themselves of said resources and administers an inappropriate medication to a patient, should we really blame the medication? What if an owner’s attitude or financial circumstances impede the veterinarian’s ability to confirm the diagnosis or determine the safety of the pet? Would we blame the doctor? Or the drug? Or neither?

Honestly, I’m hoping that articles and scrutiny like this will make veterinarians more conscious of the side effects and mechanisms of not just Librela and Solensia, but all the drugs we use with the casualness of expert habit.

Meaningful Conclusions

I have used Librela in one of my own pets, a nearly 14-year-old mixed-breed canine creature who has been lucky to live a life of sufficient duration to acquire some comorbidities beyond just arthritis in a few of her joints.

After two months of use with Librela, I noticed her kidney values climbed slightly and her red blood cell values had declined slightly. I have an extensive history of bloodwork for her (one of the perks² of owning a veterinary hospital). While the values are still within the normal range, I’m cognizant of the change. And given the modest positive impact of Librela on her mobility, I’m choosing to stop treatment for my dog.

I think I may have a different opinion if the drug had a profoundly positive effect. I may have a different opinion if the kidney values return to normal next month. I may have a different opinion for a thousand different reasons, but in this specific situation, I will stop using it. And not because the Wall Street Journal made me fearful.

The article made me dig into the research, the data, the studies, the publications and look even harder at the medication’s mechanism and effects. It made me rethink the frequency and intensity of monitoring profiles for patients on these drugs. If you’re a veterinarian, you can let these things spark a bit of fury. Or you can let it make you do better.

I tend to do both. Sometimes one and then the other. Sometimes simultaneously.

I think that’s because I spend most of my day with my hands on patients rather than a keyboard. More than anything else, I want to do right by them.

—

Don’t let some veterinarian tell you what to think —I’m no expert!³

Below are a number of the resources I used to write this article. Read them and decide for yourself.

Resources:

WSJ: What Killed Their Pets? Owners Blame Meds, but Vets Aren’t Sure

WSJ: Zoetis Stock Price Falls After Journal Reports Scrutiny of Its Arthritis Drugs for Pets
FOI Summary NADA Librela (bedinvetmab injection)

Full Librela Prescribing Information

FOI Summary NADA Solensia (frunevetmab injection)

Full Solensia Prescribing Information

Peer-Reviewed Publications:

Librela

In dogs diagnosed with osteoarthritis, how safe and effective is long-term treatment with bedinvetmab in providing analgesia?

Laboratory safety evaluation of bedinvetmab, a canine anti-nerve growth factor monoclonal antibody, in dogs

A prospective, randomized, blinded, placebo-controlled multisite clinical study of bedinvetmab, a canine monoclonal antibody targeting nerve growth factor, in dogs with osteoarthritis

Solensia

Frunevetmab, a felinized anti-nerve growth factor monoclonal antibody, for the treatment of pain from osteoarthritis in cats

Efficacy and Safety of an Anti-nerve Growth Factor Antibody (Frunevetmab) for the Treatment of Degenerative Joint Disease-Associated Chronic Pain in Cats: A Multisite Pilot Field Study

The effect of anti-nerve growth factor monoclonal antibodies on the clinical signs of degenerative joint disease in cats

1. You can have some fun with this one.

2. A perk for me, anyway. She may disagree.

3. Wait a minute, no… yeah, I am an expert.