Two new arthritis drugs are arriving for dogs and cats.

For dogs, there is Lenivia (izenivetmab).

For cats, there is Portela (relfovetmab).

Both are designed to control osteoarthritis pain for about three months after a single injection.

Both drugs block nerve growth factor, or NGF.

In other words, we are taking the same basic approach already used by Librela in dogs and Solensia in cats and making it last much longer.

Given what we have learned about anti-NGF drugs over the past few years, that gives me significant concerns.

First, What Are These New Drugs?

Librela (bedinvetmab) is an anti-NGF monoclonal antibody for dogs. Solensia (frunevetmab) is an anti-NGF monoclonal antibody for cats. Both are generally given monthly.

The new drugs use the same broad strategy.

Lenivia (izenivetmab) is a canine monoclonal antibody that blocks NGF and is designed to provide about three months of osteoarthritis pain relief from one injection.

Portela (relfovetmab) is a feline monoclonal antibody that also blocks NGF and provides up to three months of osteoarthritis pain relief from one injection.

They are not literally three-month versions of Librela and Solensia. They are different antibodies and bind NGF differently.

But from a practical standpoint, they represent the next generation of the same anti-NGF approach.

Monthly NGF blockade is becoming three-month NGF blockade.

Why Block NGF?

NGF plays an important role in pain.

Blocking it can reduce the pain an animal feels from osteoarthritis. There is no question that some dogs receiving Librela and some cats receiving Solensia have shown meaningful improvements in comfort and mobility.

But NGF does more than transmit arthritis pain.

It has biological functions in the nervous system and other tissues.

And blocking NGF does not treat the arthritis itself.

That distinction matters.

An animal may feel less pain and move more, but the underlying joint disease can still be present.

What Have We Learned From Librela and Solensia?

When Librela and Solensia were first approved, their controlled clinical trials provided the safety information available at that time.

Then the drugs were used in much larger numbers of animals.

That is when additional questions began to emerge.

With Librela, post-approval adverse-event reporting has raised concerns about neurologic, urinary, gastrointestinal, and musculoskeletal events. An adverse-event report does not prove that Librela caused an event, and these reports cannot tell us how often an event occurs.

But safety signals matter.

My colleagues and I have also published on concerns surrounding anti-NGF treatment, including the possibility of rapidly progressive osteoarthritis and severe joint changes in some dogs.

I have similar concerns about Solensia in cats.

My colleagues and I are currently investigating cats that developed severe and unusually progressive joint and bone changes after receiving frunevetmab.

That work is ongoing. We cannot say that Solensia caused every case.

But the cases are concerning enough that I believe we need to take the possibility seriously and investigate it.

Now We Want the Effect to Last Three Months

This is where Lenivia and Portela concern me.

The major selling point is obvious.

Instead of bringing your dog or cat to the veterinarian every month for an injection, one injection could provide pain control for approximately three months.

That is especially attractive for cats, where trips to the veterinary hospital can be difficult.

But convenience and safety are different questions.

If we still have unanswered questions about what happens when NGF is blocked, I am not convinced that making NGF blockade last longer should automatically be viewed as an improvement.

What Happens If Something Goes Wrong?

This is perhaps my biggest practical concern.

Once one of these medications has been injected, we cannot remove it.

There is no antidote.

With a monthly medication, if an animal develops a concerning problem, the veterinarian and owner can decide not to give the next monthly injection.

With Lenivia or Portela, the medication is specifically designed to continue working for about three months.

That does not mean a three-month drug is automatically less safe than a one-month drug.

But if an adverse effect is related to blocking NGF itself, the duration of that effect becomes very important.

We need to understand that risk.

The Timing Is Especially Interesting Because of the FDA

There is another reason I think veterinarians and pet owners should be paying attention.

The FDA recently released new draft safety guidance specifically for veterinary monoclonal antibody drugs.

I wrote about this in my recent blog post, “FDA Proposes New Safety Guidelines for Monoclonal Antibody Drugs in Pets.”

The FDA is not saying that monoclonal antibody drugs are unsafe.

Instead, the agency is proposing a more detailed framework for how the safety of these drugs should be evaluated.

Several parts of that guidance are especially relevant to anti-NGF drugs.

A Drug Can Hit the Correct Target and Still Cause Problems

One of the most important concepts is something called an “unintended on-target effect.”

That sounds complicated, but the idea is actually simple.

A drug does not have to accidentally attack the wrong target to cause a side effect.

It may bind exactly where it is supposed to bind.

The problem may come from what happens when that target is blocked somewhere else in the body.

For anti-NGF drugs, the target is NGF.

The goal is to block NGF and reduce arthritis pain.

But NGF has other biological functions.

So the important safety question is not simply:

“Does the antibody bind to NGF?”

We already know it does.

The bigger question is:

“What happens throughout the animal when we block NGF for a long period of time?”

And now we are talking about blocking it for approximately three months after a single injection.

The History of Similar Drugs Matters

The FDA’s new approach also emphasizes looking at what is already known about similar monoclonal antibodies.

I think that is extremely important here.

We should not evaluate Lenivia without considering what we have learned from Librela.

We should not evaluate Portela without considering what we have learned from Solensia.

And we should not evaluate veterinary anti-NGF drugs without remembering the history of anti-NGF drugs developed for people.

Human anti-NGF drug development encountered serious musculoskeletal safety concerns, including rapidly progressive osteoarthritis.

That does not prove that every anti-NGF drug will cause the same problem.

But it is biologically relevant information that should not be ignored.

Small Studies Cannot Find Every Rare Problem

There is another important lesson from the new FDA guidance.

Pre-approval studies can tell us a lot, but they cannot tell us everything.

A clinical trial involving hundreds of animals can identify common problems.

It may completely miss a serious problem that occurs in one out of several thousand animals.

That problem may only become visible after a drug is used in tens or hundreds of thousands of patients.

This is one reason post-approval safety monitoring is so important.

It is also one of the lessons we should have learned from Librela and Solensia.

The absence of a safety signal in a relatively small clinical trial does not prove that a rare safety problem does not exist.

What About the New Lenivia Safety Study?

A recent study combined safety data from three controlled clinical trials involving 289 dogs treated with izenivetmab and 285 dogs receiving placebo.

Overall, abnormal health events occurred at similar rates between the groups.

That is useful and somewhat reassuring information.

But the studies lasted only two to nine months.

The average dog was about 9 years old, and some clinical signs, including ataxia, decreased appetite, and lethargy, occurred in both groups. Increased drinking and urination were considered possibly related to treatment in a small number of dogs.

The study helps answer the question:

“What happened to 289 treated dogs during controlled clinical trials?”

It cannot completely answer the much larger question:

“What will happen when this drug is given repeatedly to a very large population of dogs over several years?”

Those are different questions.

We Have the Same Problem With Portela

Portela has also undergone clinical testing, including a nine-month European field study, which is not published in peer review yet.

Again, that provides useful information.

But osteoarthritis is not a nine-month disease.

Dogs and cats may live with arthritis for years.

A medication intended for chronic arthritis treatment therefore needs to be evaluated not only by what happens after one or two injections, but by what happens after repeated treatment over long periods of time.

And rare problems may not become apparent until a medication reaches widespread use.

This Does Not Mean These Drugs Will Be Unsafe

I want to be clear about that.

We do not currently know that Lenivia or Portela will reproduce every safety concern reported with Librela or Solensia.

They are different antibodies.

They bind NGF differently.

Their pharmacology is different.

And the available clinical trials contain useful safety data.

But I also don’t think we should assume that a different antibody eliminates concerns related to blocking the same biological target.

That is the question that matters most to me.

If some of the problems we are seeing are related to NGF blockade itself, rather than something unique about Librela or Solensia, then changing the antibody may not eliminate the problem.

And extending the duration of NGF blockade from about one month to about three months becomes particularly important.

Where I Stand Right Now

Anti-NGF drugs can provide meaningful pain relief for some dogs and cats.

That benefit should be acknowledged.

But I remain concerned about the possibility of uncommon, unpredictable, and potentially serious adverse events involving the joints, bones, and nervous system.

Those concerns already exist with the monthly anti-NGF drugs.

Now we are introducing medications designed to produce a much longer effect.

For dogs:

Librela → monthly anti-NGF therapy
Lenivia → approximately three-month anti-NGF therapy

For cats:

Solensia → monthly anti-NGF therapy
Portela → approximately three-month anti-NGF therapy

From a convenience standpoint, that is progress.

From a safety standpoint, I think it demands more caution.

My Take-Home Message

I don’t think the question we should be asking is simply whether one injection can control arthritis pain for three months.

We should be asking whether we understand the consequences of blocking NGF for three months at a time, especially when treatment may be repeated for years.

The FDA’s new proposed safety framework for veterinary monoclonal antibodies makes that question even more timely.

The agency is emphasizing the biology of the target, unintended effects that can occur even when a drug hits the correct target, the duration of treatment, what we already know from similar antibodies, and the limitations of relatively small safety studies.

Those are exactly the questions I believe we need to ask about the next generation of anti-NGF drugs.

Lenivia and Portela may eventually prove to be valuable options for some patients.

But longer-lasting does not automatically mean better.

Until we have much larger, longer-term, real-world safety datasets, I would personally be very cautious about routinely moving from monthly NGF blockade to three-month NGF blockade in dogs and cats.

Pain relief matters.

But so does what happens to the joints, bones, nervous system, mobility, and overall health of that animal six months, one year, or several years later.

That is the safety question I want answered before convenience becomes the reason we embrace longer-acting anti-NGF therapy.

That sounds like a major convenience. But I think there is another part of the story that deserves much more attention.