Cytopoint® Versus Apoquel® For My Itchy Dog – Which Is Safer – Which Is More Effective – Can I Use Both? – Do I have Other Options?

Ron Hines DVM PhD

When I began this article on Cytopoint® (lokivetmab), Zoetis hadn’t gotten around to naming it yet – just called it CADI. The FDA approved and monitors its “cousin”, Apoquel® because it is considered a drug. The USDA approved Cytopoint®, and should be monitoring it because it is considered a biological. It was unclear why Zoetis planed to market two competitive drugs to treat the same condition. Over time, that became apparent. The Company realized that Apoquel®, because of its broader action, had more potential to produce unwanted side effects. They hoped that Cytopoint®, which is thought to target only a single signaling compound responsible for itch and inflammation, IL-31, would be more precise in its actions.

Zoetis also saw Cytopoint® as a great entry door into the precision drug market for animals. That follows the same trend occurring in human medicine today – the use of large, complex, bioengineered antibodies (read here) instead of smaller molecule drugs (like Apoquel®) to treat complex diseases. Subsequently, Zoetis purchased the only competing company in that business, a small Irish firm called Nexvet. Nexvet had figured out an ingenious way to quickly convert new human monoclonal antibody biologicals to work in dogs or cats. They either “caninized” the drug or “felinized” it so your pet’s immune system will accept them. Zoetis’ most recent entries in the field are aimed at controlling arthritic pain. They are Librela® for dogs and Solensia® for cats.

What Are The Differences Between Cytopoint® And Apoquel®?

Apoquel® tablets bring dramatic relief to most dogs who suffer from skin allergies. The medication short circuits your pet’s “misinformed” immune system that has mistaken harmless organic things in our environment such as pollen for things that might be dangerous if they invaded its body. It would be a superb drug – if it did only that. But it works at such a high level in the itch cascade (open the diagram at the top of this page) that it also interferes with a lot of important positive defenses that Nature designed your dog’s immune system to perform. When the inflammatory cascade is blocked at such a high level, your pet’s defenses against cancer, and infection are decreased as well. All legitimate medications come with their own risks. Their use in veterinary medicine and human medicine is a trade-off of benefit versus risk. Zoetis, the USDA, the EMA and various other world regulatory bodies, as well as many veterinarians and dog owners concluded that relief from the discomforts of canine atopy is worth taking those longer-term risks.

The chief advantage of Apoquel® is that it is a small molecule, so it can be absorbed through the intestine when you give it to your dog orally. Cytopoint® is a much larger molecule – too large to pass intact through your pet’s intestinal walls. That is why it must be injected. Pfizer, originally the parent company of Zoetis, uses injection fear to market Apoquel’s human “cousin”, a medication called Xeljanz®. They call it the “unjection”.

Apoquel® blocks a whole family of messenger chemicals produced by your dog’s immune system cells. These messenger compounds are called cytokines. But cytokines sometimes encourage needless inflammation such as allergies and anaphylaxis. Also, some of the same processes that cytokines play a role in are essential elements of immunity and other protective body activities such as cancer control. (read here)

Cytopoint® is a sophisticated monoclonal antibody (mAb) that targets and neutralizes a single itch-generating molecule produced by your dog’s immune system cells. It is called Interleukin 31 (IL-31). Although many cells in your pet’s body have the capacity to produce IL-31, most IL-31 appears to be produced by a type of lymphocyte that originated in your pet’s thymus gland and, after birth, dispersed to guard common entrances to your pet’s body. Those are the T helper cells (aka Th2 cells, CD4+ T cells). (read here & here) T stands for thymus.

As I previously mentioned, monoclonal antibodies like Cytopoint® are too large and complex to be absorbed intact if you give them by mouth to your dog. But smaller molecules like Apoquel® can be given to your pet orally and will still be effective. The European directions say not to give Cytopoint® to dogs weighing under 3 kg (6.6 lbs). The US insert I am reading at the moment says to give 0.09 ml/lb from a 10 mg vial to dogs under 5 lbs (2.3 kg). Instructions change, veterinarians read the insert that comes with the product they are about to use. Never rely on doses you see that are not on the manufacturer’s website, such as in this article or any other, because entry typos do occur.

Apoquel® is not approved for dogs that are less than one year old. Cytopoint® gives no age restrictions. Apoquel® is not approved for use in breeding dogs, or dogs that are pregnant or lactating. Apoquel® has not been tested in combination with corticosteroids, cyclosporin/Atopica®, or other immunosuppressive drugs. Cytopoint® does not give those restrictions. The directions just state that it has not been tested in pregnant, nursing or breeding animals.

Cytopoint® Safety

To date, we only have a couple of Zoetis-funded studies of a few healthy young beagles that were followed for relatively short periods of time: see here

Zoetis references “data on file” in a lot of their Cytopoint® brochures that discuss the safety and effectiveness of Cytopoint®. But they were not willing to let me peek at that data when I asked them. Once a drug gains governmental approval, there is no incentive for drug companies like Zoetis to continue formal research on their products. After approval, it’s strictly feedback from pet owners like you on sites like this one that modify opinions, and helps motivate the USDA to look out for your pet’s interests. USDA responses tend to be rather anemic, when compared to the FDA’s. From what we already know about Cytopoint®, it should be safer than Apoquel®. I am not alone in that belief. Veterinary school students have soft hearts and a penchant for adopting star-crossed, health-issue dogs. Reading their online chatter blogs, it’s apparent to me that most of the veterinary students with atopic (itchy) pets and the dermatology professors they interact with believe that Cytopoint® is a safer drug than Apoquel®.

Safety aside, Cytopoint® is approved for dogs less than one year of age. Apoquel® is not. Unlike Apoquel®, Cytopoint® has not been associated with liver enzyme changes. Cytopoint® is probably less likely to negatively affect pets with multiple health issues such as increased susceptibility to infections, concurrent tumors, blood abnormalities or the many medications used to treat them. However, the IL-31 that Cytopoint® blocks was put there for reasons, many of them yet to be discovered.

There are other factors to consider: Some dogs accept tablets more readily than injections and vice versa. In some dogs, skin allergies are seasonal, so Apoquel® potential side effects might be less of an issue. Canine atopy (= skin allergy= allergic dermatitis= AD) is a highly complex process with many alternative pathways that lead to the same urge to scratch. So one drug or the other could have quite different effects on one dog versus another. Your pet’s age is also a factor. Many elderly dogs have small tumors, kept in check by their immune system’s natural killer T and K lymphocytes. How either Apoquel® or Cytopoint® will affect them is unknown. The most common evidence of this effect are the warts that occasionally proliferate on dogs receiving Apoquel®.

How Does Cytopoint® Work?

That is not completely understood. In their original submissions to the EMA, Zoetis suggested that Cytopoint® decreases the skin inflammation that produces itching by blocking IL-31. (EMEA/V/C/003939/0000) Later they suggested that the drug primarily blocked nerve transmission of itch signals from your dog’s skin to its brain. In other pronouncements, they suggest that both occur. That is understandable because both Cytopoint® and Apoquel® came onto the market long before scientists understood much about the complex, intertwined signaling systems that they both affect. Sanofi’s mAb, human atopy drug Dupixent® which was developed in mice, blocks IL-4 & IL-13 to stop itching, not IL-31. (read here and here) I believe that Cytopoint’s acts primarily by blocking nerve sensations. In most dogs, when it is effective, it acts too fast for it to be working on the actual inflamed skin. That does not mean that your pet’s skin isn’t going to get any better when given Cytopoint®. It is just going to take time. Ninety percent of the damage you see in an itchy dog’s skin is caused by your dog scratching itself. With that eliminated or reduced, your dog’s skin is going to heal – just as well as if it were wearing an Elizabethan collar. There are others who disagree as to where IL-31 has its effects, and they have their evidence as well. (read here)

Is Cytopoint® As Effective As Apoquel®?

In some cases, Cytopoint® may not be, because it is more precise (focused) in what it does. Think of the difference between a shotgun (Apoquel®) and a rifle (Cytopoint®). But of the two, I believe that Cytopoint® is certainly worthy of being your first and safest of the two. Most dog owners are quite happy with the results it achieves. When Cytopoint® is counterproductive, administration is commonly accompanied by a a musty skin odor and/or the report of skin greasiness. I attribute that to a staphylococcal bacterial infection bloom. Staphylococcus is a normal part of your dog’s skin flora – and ours too. It is your dog’s immune system’s duty to confine those staphylococcus bacteria to the outer surface of your dog’s skin and not allow them to invade its deeper layers. (read here) In some dogs, it appears that Cytopoint® reduces that ability. Staphylococcus is also a major player in dog ear infections. As you probably already know, itchy skin, floppy ears and ear infections go hand in hand. However, the majority of dogs receiving Cytopoint® do not face those issues.

How Long Will It Take For The Cytopoint® Injection To Work?

About 80% of dogs show improvement in the first 24 hours. The rest that are going to show improvement, usually do so by the end of the second day. There are a few exceptional cases where it might take up to three days. It will take considerably longer for your dog’s skin damage to heal and its hair to grow back. If your dog is already on Apoquel®, a gradual decrease in Apoquel® as it transitions to Cytopoint® is probably going to give your pet a smoother transition. The EMA says that Cytopoint® starts working within 8 hours. I have known some cases where relief began even faster. But there doesn’t seem to be much relationship between how rapid relieve for your dog begins and how long that relief will last.

Some pet owners might have already had experience with periodic injections given by a veterinary dermatologist to desensitize their dog. That veterinarian might have indicated that with time, your dog might require fewer or no additional injections. That is not the case with Cytopoint® – if it actually “cured” a dog, we would have to rethink what we believe we know about the drug and the itch process. Monoclonal antibody therapies rarely get more effective with time. Usually, they are either effective by the third injection or they remain ineffective indefinitely. Of course, when allergies are seasonal, a drug like Cytopoint® might appear more effective or less effective depending on the time of the year.

How Long Will The Relief From A Cytopoint® Injection Last?

Zoetis advertises 4–8 weeks of relief from a single injection. But 3–5 weeks – with the average being about 3.5 to 4 weeks, before your dog begins to lick its paws again is more realistic. I do occasionally get emails about those 8-week miracles. Zoetis also conducted unpublished studies that showed that the half-life of a Cytopoint® injection (the time that half of the drug still remained in your dog) was approximately 9 days – not a month. (EMA/CVMP/113787/2017) The same report suggested that the amount of the drug remaining in your dog’s body might build up over time with repeated monthly injections and that that might increase the drug’s anti-itch effects. No evidence was given. One can still dream of 8-week protection. The Cytopoint® minimum monthly dose is 2 mg/kg. There is a human anti-IL-31 drug in development for itching called nemolizumab. In one study, it appeared to suppress itching in 5 out of 6 monkeys for almost 2 months when given at half the Cytopoint® dose. (read here) There are also cases where Cytopoint® started off quite effective after the first shot or two, but then slowly lost its effectiveness during later injections. That sort of effect has been seen with other similar biological medications. It is believed to be associated with the patient developing antibodies that attack and neutralize drugs like Cytopoint®. (ADAs=anti-idiotypic antibodies)The EMA report I mentioned earlier said that Zoetis detected none of those anti-drug antibodies in 18 beagle dogs that it gave Cytopoint® injections to over a 30-day period. The EMA then requested a field study. One hundred and forty-two client-owned dogs with AD were given Cytopoint® injections monthly for 3 months. Three developed ADAs. Post-injection hives are sometimes associated with the development of ADAs; although sensitivities to other constituents in the Cytopoint® bottle or pre-existing autoimmune issues have the potential to cause hives too.

How Frequently Can My Dog Receive A Cytopoint® Injection?

To satisfy the European EMA, Zoetis reported no health changes in beagles given 1, 3 or 9 mg/kg injections three times during a single month (2 mg/kg is the suggested minimum Cytopoint® dose). Later, Zoetis repeated the experiment and gave six more beagles 1 or 9 mg/kg once a month for 7 months and still reported no side effects. Although the current package insert says, “give every 4–8 weeks as needed”, there are veterinarians who give it more frequently in dogs that do not obtain sufficient relief for the full 4 weeks. I do not know of any dogs that were given Cytopoint® more frequently than every 3.5 – 4 weeks that developed problems that were thought to be associated with giving those shots closer together than suggested on the label. Cytopoint, being an mAb, should be inactive after it “locks onto” IL-31. (=target‐mediated clearance). Perhaps when that has been accomplished, further injections have no effect until enough new IL-31 is present. But check now and then with my website’s Cytopoint Comments page to see what feedback has arrived.

What Cytopoint® Side Effects Have Been Reported?

Most dogs have no immediate unwanted side effects to their Cytopoint® injections. Although rare, post-injection mopiness (lethargy), eye irritations and hives are the most common side effects that have been reported. Quite a few dogs aren’t themselves for a day or two after a visit to an animal hospital, even one that claims to be “fear free”, no matter what the reason was for their visit. It’s just not one of a dog or its owner’s favorite destinations. Your dog thought you were just taking it out for a drive to the park and then, bingo, strange scents, strange people and an ouch! Most of the reported side effects of Cytopoint® are minor. They include occasional post-injection vomiting and diarrhea – which could also be psychosomatic. Much rarer are severe reactions that affect breathing. When they occur, it is often in the bulldog breeds that have trouble obtaining enough air even on their best days. As I mentioned, it can be very difficult to decide if such an attack was due to the agitation of being brought to an animal hospital, the restraint necessary to inject the dog, or overheating that might have occurred in the process. I attribute hot spots that occasionally occur after a Cytopoint® injection to be more likely due to incomplete relief than to some side effect of the drug. Although the Cytopoint® instructions suggest that the complete dose be given in one location; some bigger dogs flinch less and show less signs of injection discomfort when the dose is divided and given at two locations. Allowing the refrigerated vial to warm up to room temp before injection also helps. Some folks report that their dogs gain weight on Cytopoint®. Perhaps they just feel better and are more inclined to a hearty appetite. Perhaps there is more to it than that. But most owners report that Cytopoint® did not cause their dog’s weight to increase the way corticosteroid shots do.

Do The Traditional Treatment Options For Your Itchy Dog Still Have Their Uses?

Yes

When your dog develops a staph skin infection while taking Cytopoint® or Apoquel® or when taking neither, I suggest that you first try medicated shampoos to see if they might get the problem under control? Hold off on the antibiotics if you can. Antibiotics are a scorch-earth option. They destroy the good bacteria on the inside and surface of your pet as well as the bad ones. Probiotics aren’t going to bring enough of the good ones back. (read here) My preference is for canine skin care products that contain benzoyl peroxide, salicylic acid, chlorhexidine or povidone iodine as their active ingredients. (read here, here & here) Colloidal oatmeal shampoos contain avenanthramides that are anti-inflammatory and aid in skin barrier repair. Many topicals contain essential plant oils. Many contain two or more of these ingredients. You won’t know which product(s) will give your dog the most relief until you try several different ones.

Medicated shampoos are most effective when your wet dog is gently finger massaged and the products are left on your dog for at least 10 minutes before you wash them off. Avoid getting any in your pet’s eyes or mouth. After these shampoos have been thoroughly rinsed off and your dog dried, some pets benefit from an emollient lotion designed to enhance filaggrin function. Filaggrin forms a part of your pet’s natural skin barrier against staphylococcus. It promotes normal skin acidity (pH), moisture retention and resistance to future staphylococcus penetration. Some of these products also contain high linoleic/oleic sunflower seed oil, others contain mineral oil, glycerin, propylene glycol or various carrier oils. I would avoid any that have lauryl sulfate or fragrances as ingredients. When your dog’s itching is minimal, or only present seasonally, topical lotions and medicated shampoos like these and a proven flea control products might be all your dog needs.

All dogs with an itch problem need to be on a monthly topical or oral flea prevention product – regardless of whether you have seen a flea on your pet or not. Regularly having your dog’s toenails professionally clipped short and then smoothed is very important too. (read here)

More potent topical products contain corticosteroids such as betamethasone, triamcinolone, or hydrocortisone. Overuse of any of those products can produce adverse effects, both thinning of your dog’s skin and systemic symptoms because a portion of all of them is absorbed. (read here & here) Atopica®, not much of an advance over corticosteroids when it comes to side effects. All were front-line medications that veterinarians of the past used to treat itchy dogs and cats before scientists gained a deeper understanding of the itch process. Corticosteroids still have justifiable short-term uses in treating itch (pruritus) in our pets, and many legitimate uses in treating autoimmune disease and possibly in septic shock. Few dog owners in the world have the income or even the access to medications like Cytopoint®. Corticosteroids like prednisone, Aristocort® or Temaril-P® exert their influence on almost every cell in your dog’s body to one extent or another. (read here) They are fine for extinguishing or lessening short-term itching flare-ups; but I do not suggest them for long-term or frequent use whenever it can be avoided. When administered too frequently, corticosteroids can all produce the same signs as Cushing’s disease, weaken joints, liver and blood glucose issues, increased obesity and fluid retention. Prednisone is so powerful in its itch-relieving abilities that Zoetis still consider it the gold standard in itch relief to which all other itch relief products are compared. (read here)

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