Nexvet, Nerve Growth Factor (NGF), And New Approaches To Arthritis & Pain Control In Dogs & Cats

 

Arthritis In Your Dog

The Special Needs Of Older Cats

Galliprant


 

Ron Hines DVM PhD

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Veterinarians in 2017 have the same tools that your physician has to treat arthritic and other pain:

1) They can give your pet NSAIDs like Rimadyl®, Previcox® or meloxicam to decrease the joint inflammation that grinding joint surfaces produce and that lessen pain sensations in the brain as well.

2) They can give your pet corticosteroid injections or pills like prednisone that are potent blockers of joint inflammation too.

3) A few dispense narcotics like tramadol or Duragesic® patches which are powerful blockers of all types of pain.

But all three have very significant drawbacks for your dog or cat. Cats in particular do not tolerate doses of NSAIDs for more than a day or two (perhaps longer at very low dose in cats [ref] ). In dogs, NSAIDs can cause erosions (ulcers) of the stomach and intestine. They can occasionally be rough on the kidneys and liver as well. (ref1 ref2)

Corticosteroids are very effective at decreasing the joint inflammation that arthritic dogs and cats suffer too. Their initial beneficial effects are very dramatic. But they have a host of very serious potential side effects when given frequently that include, diabetes, weight gain, fluid retention, and susceptibility to infection. (ref)

Narcotics are effective in blocking pain sensations in the brain. But with time, the dose that has to be given to obtain relief must be higher and higher. Because of diversion potential their long-term veterinary use is also frowned upon by the DEA. None of these medications actually block your pet's incoming pain signals from the inflamed area.

Some veterinarians suggest acupuncture and homeopathy. But there is no more evidence that these things work in our pets than there is that they do in humans. (ref1, ref2) Others suggest therapeutic laser therapy as an alternative to traditional physiotherapy and still others, drugs like amitriptyline and imipramine based on their use in human fibromyalgia. The jury is still deliberating on whether stem cell treatments lead to joint pain improvement. (ref) It probably won't do your pet harm to try any of them; but I personally do not believe they are helpful.

What Is Nerve Growth Factor (NGF) And How Does It Relate To My Pet’s Pain ?

Nerve growth factor is a small, protein-like molecule that individual nerve cells (neurons) use to communicate with each other. In 1956, it was identified as a critical messenger in how nervous system connections ("its wiring circuits") organize during development (ref1, ref2) NGF helps determine which neurons survive and prosper (ref) and has more recently been found to have a host of different functions within the mature body - ranging from insulin secretion from the pancreas (ref)  to allergic inflammation. (ref)

The nerve highway through which signals travel in you and your pet is a two way street - somewhat like a tree and its branches. Some impulses/signals travel from the brain to the far ends of its branches throughout the body to tell cells there what to do. Others travel in the other direction, from the fine ends of its branches throughout the body to the brain. Those that go in that second direction tells the brain what is going on in those distant locations. Those incoming messages can tell you if that distant location is hot or cold, its position in relation to the rest of the body, its taste, its feel, its smell.  Another message those nerves can send to the brain is pain in that distant area.

By 2006, it was known that blocking the effects of NGF blocked pain. (ref)   By 2010 pharmaceutical companies were making use of that new knowledge in attempts to formulate medications which would block pain. (ref) Pfizer and Lilly drug companies alone invested $550 million dollars in their research on Tanezumab ; anticipating that successful human NGF-blocking medications would be a $1.23 billion dollar market. (ref) All the drugs that were contemplated were monoclonal antibodies (mAb’s) - sort of "smart bombs" that seek out and disable key points in cell processes. They are very complicated products - expensive to produce, expensive to test. (ref) They are all large complex molecules (large molecule drugs=biologics), as opposed to the "small molecule" medicines of the past (Galliprant and other NSAIDs are "small molecule" medications). Today's mAbs are generally produced initially in rodent cells. Then the product antibody molecule must be “humanized” so that the human body’s immune system does not recognize it as a foreign protein and destroy it. Once done, they can not be used in dogs or cats because the immune system of either species will recognize that its “humanized” form does not belong in their bodies and it will destroy it. Needless to say, few veterinary pharmaceutical companies had the resources to develop such complex medications for dogs and cats. The only one on the market now is Zoetis' Cytopoint . That arrived in Dec. 2016.

What Can you Tell Me About The Company, Nexvet ?

Fast forward to 2010. An Australian startup company, Nexvet, incorporates in Melbourne. It raises $31.5 million dollars from American venture capitalists based on its patented method to rapidly “peticize” monoclonal antibody drugs originally developed for humans so that the drugs can be used in dogs and cats.  The pesky portion of the drug that was initially recognized as rodent is now recognized as dog or cat. The portion of the drug that actually neutralizes a target within the body remains unchanged.  This innovation allows monoclonal antibody drugs created for humans to be quickly and economically adapted for use in dogs and cats. In 2014, corporate headquarters move to Dublin, Ireland.  In
April of, 2017 Zoetis  purchases Nexvet for $85  million dollars. Zoetis is the owner of the, now patent-expired, Rimadyl® and the Trocoxil® dog arthritis patent and they saw it as "a good fit".

As with all modern start-ups, Nexvet operates at a loss since they have no products for sale. Their announcements and publications tend to be glowing to encourage the steady inflow of the capital they need to stay in business and pay salaries until – hopefully - their products come onto the market and prove their worth.  (ref1, ref2, ref3, ref4, ref5)      

In February of 2017, Pfizer, the developer of many of the original anti-NGF compounds (ref) , allowed their human NGF products to be the basis of Nexvet future products for $1 million + royalties. (ref)

Does The FDA Require Veterinary Drugs To Undergo The Same Rigorous Clinical Studies That Human Drugs Require Before They Are Allowed To Be Sold ?

No.

It used to be that approved veterinary drugs became available ~ 8-10 years after the FDA allowed their human use. Drug patents last 20 years, but traditionally it took up to 10 years to get FDA approval and the patent clock began ticking when the patent was issued. Most often, veterinarians began using them after the patent had expired and their cost in generic form had dropped. That is changing. Actually some of these mAbs might be coming out for vet use before they are available for human use. The FDA is often satisfied with 6-12 month studies in dogs and cats, vs a 38 month larger study costing much much more in humans. Or, the FDA can be induced to approve a veterinary drug’s short-term use although the drug companies know that vets and owners will be using it longer term if it proves effective. (ref) Shorter studies can be valid for dogs and cats because their lives are shorter and side effects often appear earlier. Also, FDA apparently does not feel that liability issues are as much a concern when it is a dog or a cat, and not a person, that does poorly. It is also a convenient way for drug companies get low cost feedback applicable to the human counterpart drugs they are developing. (ref) Those released high-tech veterinary products can be quite expensive – like Cytopoint. But  segments of the American and European pet-owning public now have the disposable income to purchase these high-cost, state-of-the-arts medications. Others are so attached to their pets that they will mortgage the farm or their soul to buy them.

The Dog, Cat and Rat Studies - What Do They Tell Us ?

To precisely study pain and pain control in animals, you have to inflict pain  in this case, to an unlucky rat. When a cartilage-destroying chemical was injected into its right knee, the pain of the induced arthritis was blocked by the injection of an anti-nerve growth factor antibody given a few days after. Given later, it was less effective. It did not appear to the authors that blocking NGF caused any improvement in the inflamed joint- it just blocked the pain  (ref)  A second team had a crack at it and their results were similar. (ref)

In 2014, a paid consultant for Nexvet, the Nexvet’s Chief Scientific Officer and a third veterinarian published an article on the dog formulation of NGF blocker that  Nexvet has in development. They concluded, based on questioning the 9 dog owners, that the dog’s pain level decreased after the injection (Better general activity, enjoyment of life, rising to stand, walking, running and climbing [ref]). They acknowledged that there was no control group of dogs that received no medication and no placebo group which got dummy injections nor was there a group that received a dog NSAID currently on the market to see if there product produced greater relief. (ref) (In a previous study, one of the same authors reported that the effect of the dog anti-NGF was similar to the relief obtained with daily oral meloxicam, an NSAID. [ref] )

In 2015, Nexvet funded another study in dogs in North Carolina. (ref) Twelve dogs were given the Nexvet dog product and 13 similar dogs were not. By the end of their 28-day study, there were “no changes detected within groups over time for either total pain score or index joint pain score” between the groups and “there were no statistical differences between the groups at any time point for absolute scores, or change in scores”. Their conclusions on effectiveness are based primarily on statistical P values. And for them to have much meaning, the dog numbers would have had to been considerably larger. (ref1, ref2) It would also have been nice if they had compared their mAb drug’s effect to a group given NSAIDs like Rimadyl® or meloxicam.  But that’s not to say that the drug was not effective - you just can’t really tell from the data submitted.

Nexvet publicized another in-house study in cats in 2016. They took 30 laboratory-bred cats, gave half the cats "felinized" anti-NGF (frunevetmab) and half only a saline injection. Four days later they injected an irritant into all the cat’s right hind paw. Over the next 7 days, the cats that had received the felinized anti-NGF injection appeared to recover from the footpad pain faster than the ones that did not. (ref)  Nexvet also made their cat anti-NGF available to 15 veterinary centers in the USA in 2015/2016 and presented their findings at a large veterinary conference. They reported that their drug seemed to help lame cats. But they noted that, like herding cats, judging if they were in pain was a very difficult thing to do and that the current client questionnaires left much to be desired. (ref) If frunevetmab is approved, they contemplate making it available to cat owners through their veterinarians as a monthly subcutaneous injection. Current trial result are planned to finish in the 4th quarter of 2017; with general distribution ~ 1 year later if all goes well.

Here and there in their promotional literature, Nexvet states that 92% of cats have arthritic joint changes and so, are good candidates for pain control treatment. They refer back to a 2010 study. (ref) That study reviewed the x-rays of 100 cats of all ages. I personally believe that it is highly unlikely that x-rays are a valid assessment tool for arthritic or chronic musculoskeletal pain in cats. It most certainly is not in humans.

Only 50% of people over the age of 65 that have x-ray evidence of arthritic knee joint changes experience any pain. And those that have joint pain do not necessarily have x-ray evidence of arthritis (ref) As for hip pain, only 9.1-15.6% of people experiencing it have any x-ray evidence of hip arthritis. Of those that did have evidence of hip arthritis, only 20% reported frequent hip pain. The same general finding apply to spinal arthritic pain. (ref) Cats and dogs can’t talk; but if they could I believe they would tell you  the same thing.

There are a few other NGF studies in dogs and cats. But none of them tell us much about long-term effectiveness of these anti-NGF products – that is chiefly because no one has devised an accurate, non-subjective way to directly measure pain in out pets (3-axis accelerometers aka activity monitors may be one solution [ref]). The studies do however indicate that short-term use of the two NGF inhibitors appears safe.

Those dog and cat studies all had flaws. They tell me very little regarding the true value of these medications. Pet owners and vets like myself are likely to be optimistic and hopeful - we tend to tilt toward the perception of improvement when we administer products - no matter what they are. The high placebo (sugar pill) effect seen in all of the Company-sponsored dog and cat studies attest to that. Most likely, it will only be when these Nexvet products are in general use that pet owners and veterinarians alike will come to know how effective they really are.  I do hope they are a better option for your pet than NSAIDs - but at this time, nobody can tell you that for sure. 

Reluctance To Move Is Not The Same Thing As Pain

There are a host of non-arthritic issues that these client check lists-based studies could confuse with pain. Overweight dogs and cats are likely to be sluggish. Pets with age or nutritionally-related sarcopenia (muscle wasting) won't get about as well as they once did. Vision problems create hesitancy. So does mental decline (CDS) and metabolic imbalances (HE). Heart, kidney, lung issues and anemia can be underlying causes of weakness and immobility as well. Shy dogs and cats are likely to be hesitant.

No part of your dog or cat’s body is immune to the effects of aging. The older you pet is, the more likely it is that it is facing a mixed group of health issues that is slowing it down - pain may or may not be one of them.

Are You Dodging The Question, Are These Drugs Likely To Help My Dog Or Cat Or Not ?

As I said, I hope they will, but I cannot tell you that with certainty - yet. 

The basic science behind them appears valid and it would be great if both of Nexvet's cat and dog NGF-blocking drugs were unqualified successes. Goodness knows our pets could use better pain control options than veterinarian like me have to offer you today.

But its impossible to evaluate these two products intelligently from the data that is out there because of the ways the studies were purposely set up. All the publications were underwritten by Nexvet. When a company has a product to sell and wants to interest you in buying it, exaggeration and a tilt to favorability can be assumed. Would Ford suggest you to buy a Chevy ? When one does a truck comparison test commercial, do your think their product will come in last ? It has also become harder and harder for me and others to judge the true worth of scientific publications across all fields of medicine. (ref1, ref2)

What keeps me most positive and hopeful is that Zoetis – an offshoot of Pfizer  - was willing to pay $85 million dollars for Nexvet as well as this class of drug's apparent effectiveness in rodents. But I do not know if Zoetis bought Nexvet to control its “petification” process - one that will have a multitude of other uses, because of the potential of these two medications, to eliminate a potential competitor or some combination of the above.

Pfizer itself is well on its way to marketing its own human NGF blocker, tanezumab. (ref1, ref2) There were some concerns that suppressing pain receptors with their NGF inhibitor might suppress or alter other portions of the nervous system (the sympathetic nervous system). But they seem to have been laid to rest. In June of 2017, Pfizer’s tanezumab’s clinical trials were placed on FDA Fast Track  approval/disapproval status for arthritis and lower back pain - partially due to their less addictive potential during our current opioid overdose crisis.

If Pfizer’s tanezumab is a success, these Nexvet products probably will be too.  FDA’s Pfizer human knee and hip clinical trials are set to complete by August 2, 2018; back pain by October 25, 2017.

So we have a little time to wait . If you have comments or anything to add, email me and I will post it. If you want to see if there are open trials that your pet might enroll in, inquire at the Nexvet office in San Francisco or perhaps at the Comparative Pain Research Lab at NC State.

Is Pain Always a Bad Thing ?

It is always unpleasant. But it is not necessarily bad.

Acute and chronic pain are quite different . . . . . When I was a boy, I thumbed a ride on a “refer” from Brownsville, TX to Chicago and went to work for Dr. Norman Cornelius, the best race track veterinarian In Illinois.  I was too young to enter the stands, but I could work the back stables with him dragging around his X-ray machine and holding the twitch. We dispensed a lot of “bute” in those days – the owners demanded it to get their horses back in the races as soon as possible. He was a wise man and he once told me as he was firing and bandaging a horses knee “you know, I could get this horse running again sooner with bute, but if I did, the trainer wouldn’t give the horse a chance to heal. He didn’t have faith in the firing and blistering processes, but he knew that, that, and the bandage, were the only ways to placate the trainers and give the horse time to heal on its own.  Johnson & Johnson had their own anti-NGF mAb in development  to compete with Pfizer’s. They began clinical trials of their mAb, fulranumab,  for knee pain in  2014. They abruptly ended those tests in late-stage human trials in 2016. The reason was not formally given, but many noted that considerably more patients taking the drug needed artificial knee replacements than those not receiving it. Similar issues lead the FDA in October 2016 to halt clinical trials of Regeneron's fasinumab - designed to test the drug for spinal arthritis. In the first case, it appeared that the patients wore out their failing knees faster because the drug had just worked too well in relieving their pain. (ref) - Not much different than those race track horses long ago. (ref) In the second, the FDA described their worry as accelerated joint deterioration (arthropathy).

So I would not suggest your dog or cat get these sort of medications if there is hope that time will mend its problem. It is also still unclear if they are even as effective as what we have now for acute (sudden) pain. (ref)

That can go for all forms of pain killers when it comes to ligamental tears and sprains. You want to give your pet's acute injuries a chance to heal - and rest and inactivity are part of that. Put the Frisbee away for a while.