Apoquel Backorder Conspiracy Theories

By Jon Plant, DVM, DACVD

There is a huge demand for Apoquel®, the new Zoetis (NYSE: ZTS) drug for dogs with shutterstock_44704465atopic dermatitis or “allergic” dermatitis. I predict that Apoquel sales will exceed $1 billion per year for Zoetis after the supply issues are resolved. It has dramatically improved the quality of life of most of the dogs that I have been able to treat thus far. The dogs are happy, the pet parents are grateful, and I feel like a hero.

BUT, I am in the fortunate minority of veterinarians that has a reasonable supply, thanks to placing a large order early on, and the Zoetis policy of directing the available supply of Apoquel to the dogs which are already taking it. Many veterinarians are understandably upset that a) they can’t order Apoquel after having talked it up to their clients before the launch, and b) communication from Zoetis was a little herky-jerky for a few months regarding the supply issues that were emerging.

Some veterinarians are voicing conspiracy theories – Zoetis is trying to gin up the demand in order to raise the price, or there is some problem with the manufacturing process that they are hiding. I’ve even read speculation that the shortage is due to a conspiracy by veterinary dermatologists to buy it all up because it could be seen as a threat to referrals!
I don’t buy any of those theories. I suspect the real story goes like this:

  • Zoetis managers remembered the disappointing launches of some other companion animal drugs.
  • A very well-managed marketing strategy was executed, complete with flashy video animations, numerous research presentations, and webcasts for veterinarians at dinner meetings throughout the US.
  • The price was set reasonably, within the reach of many pet owners. This invalidated comparisons to the Atopica® launch, if they were using that to forecast.
  • Someone made a decision not to invest in the facilities that would have allowed for a higher level of Apoquel production, should the need arise.
  • A cumbersome manufacturing and packaging process was chosen which involves shuffling the active ingredient, tablets, and packaged product between countries. Is this really efficient and cost effective, or is it to avoid taxes? I don’t know.
  • Within a few weeks of the launch, it became clear that the amount of Apoquel available would not meet the demand.
  • The decision was made to allocate the available Apoquel supply such that dogs that had already started it would have priority.
  • No veterinarians are able to buy as much Apoquel as they want – some are just able to buy more than others in order to keep some of their current patients on it.

No conspiracy. Someone at Zoetis just didn’t quite believe their own data on the potential size of the market and Apoquel’s effectiveness. In a few years, this shortage will be behind us and many dogs will benefit. That is little consolation for pet owners who are seeking Apoquel now for their itchy dogs.

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Apoquel shortage? Try RESPIT!

By Jon Plant, DVM, DACVD

Bad news, good news about Apoquel® from Zoetis (NYSE: ZTS). We learned last week that the Apoquel backorder situation is likely to continue throughout 2014 and into the summer of 2015. That is very sad news for many itchy dogs and their owners.   On the positive side, those of us who started a lot of dogs on Apoquel when it was first released will seemingly have our current patients’ Apoquel requirements met, with regular allotments available for auto-shipping.

Despite the shortcomings in the supply, I am still a big fan of Apoquel based on my experience treating about 100 dogs. I have seen the pruritus (itch) score drop from a mean of 6.0/10 when beginning therapy to 2.5 after 4 weeks (the first point at which the score was recorded). In most cases, owners report that the pruritus improves within a few days, in accordance with the reports and publications from Zoetis. Meanwhile, I see very few adverse reactions. It is truly amazing and my clients are, on the whole, very grateful.

The Apoquel shortagshutterstock_105010115e leaves veterinarians with the traditional methods of controlling atopic dermatitis (“allergies”). The first step is to make the correct diagnosis by using a validated checklist and ruling out alternative diagnoses (see my short video on diagnosing atopic dermatitis). Once the diagnosis is made, the proven alternatives to Apoquel for effective therapy are:

  • Glucocorticoids – usually effective, but frequently cause undesirable short and long-term side effects.
  • Atopica® — often effective, but may cause vomiting and other gastrointestinal side effects.
  • Allergen testing/immunotherapy – both serum IgE testing and intradermal testing have reliability issues. See my recently published study that demonstrates that there is poor agreement between four serum IgE assays when you take into consideration random agreement.1 What is the value to the pet owner if we can’t be confident that the results are much more accurate than guessing?

All of which led me to develop RESPIT®, regionally-specific immunotherapy, a patent-pending approach that allows veterinarians to effectively desensitize patients with allergen mixtures optimized for their geographic region rather than based on an allergen test of questionable accuracy. Consider the following:

  • Every allergen testing company and most veterinary dermatologists report similar levels of efficacy for their immunotherapy based on these discrepant test results.
  • A committee composed of experts on canine atopic dermatitis found that there was no evidence to recommend one form of testing over another.2
  • Another study found that immunotherapy with a standardized allergen mixture is as effective as immunotherapy based on intradermal test results.3

Why are we still using these tests??? Would we submit blood for CBC’s if every lab gave us different results and we didn’t know which, if any, was accurate? More and more veterinarians are recommending RESPIT, recognizing it as a practical and cost-effective approach when you consider the facts about allergy testing.

Veterinarians can order RESPIT at www.skinvetproducts.com. Pet owners can learn more at http://vetrespit.com/pet-parents.html and request that more information is sent to their veterinarian.

References:

1. Plant JD, Neradelik MB, Polissar NL, et al. Agreement between allergen-specific IgE assays and ensuing immunotherapy recommendations from four commercial laboratories in the USA. Vet Dermatol 2014;25:15-e16. Best Clinical Research by an Established Investigator Award, ECVD-ESVD Congress, 2013.

2. Olivry T, DeBoer DJ, Favrot C, et al. Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Vet Dermatol 2010;21:233-248.

3. Garfield R. Injection immunotherapy in the treatment of canine atopic dermatitis: comparison of 3 hyposensitization protocols. 8th Annual Members’ Meeting of the American Academy of Veterinary Dermatology & the American College of Veterinary Dermatology 1992:7-8.

 

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Apoquel: now you see it, now you don’t

By Jon Plant, DVM, DACVD

In a somewhat embarrassing setback, yesterday Zoetis (NYSE: ZTS) was forced to inform veterinary customers that Apoquel, their new drug for canine atopic dermatitis, is now on back-order only 3 weeks after its national launch.  Veterinarians who have not ordered Apoquel up until now will not be able to receive any product.  Veterinarians who have ordered Apoquel and have begun treating patients will have a very, very limited supply available while on back-order.

I hope that this back-order situation is as temporary as Zoetis has suggested, but veterinarians are all too familiar with  back-order status dragging on and on with various pharmaceuticals.

While I am certainly not privy to the details of how this shortage in supply or distribution came about, it is perplexing considering that Zoetis has been heavily promoting the drug and the science behind it for a few years, had several months of ordering experience form the veterinary dermatologists in the Early Experience program, and projects that 7 million dogs in the United States are candidates for Apoquel.

I know that this is just a temporary hiccup, but a frustrating one for veterinarians and  the clients that may not be able to refill their pet’s medication.

Update (2/6/14): Dr. Candace Sousa, Associate Director of Veterinary Operations with Zoetis has provided me with some clarification on the short-term Apoquel shortage.  A large supply of tablets has already been manufactured and is stored in Europe, awaiting packaging for distribution in the various countries in which it is being launched. Veterinarians in the US ran through what was anticipated to be a 3-month supply within a few weeks of launch, thus we are waiting on the already manufactured tablets to be packaged appropriately, processed through customs, and shipped to the US distribution centers.

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Apoquel safety: how Apoquel is like fine wine – Part 2

By Jon Plant, DVM, DACVD

How much do we know about Apoquel’s safety? Quite a lot, I would argue.

Allergic dermatitis AEThe short-term safety profile, based on the data collected during multiple randomized-controlled trials at recommended doses looks good.  In a 28-day study of 436 dogs , the prevalence of diarrhea, vomiting, anorexia, and polydipsia were low (1.4-2.3%) and similar to the placebo-treated group (0-1.8%).  In most cases, the signs resolved with continued dosing of Apoquel. Similar results were found in other RCTs.

In a 28-day study of 123 dogs comparing Apoquel to prednisolone (0.5-1.0 mg/kg, once daily for 7 days, then every other day for 3 weeks), Apoquel compared favorably in terms of speed of onset, efficacy, and prevalence of adverse reactions.  In the Apoquel group, about 10% developed pyoderma, versus 6.5% in the prednisolone group.  This is probably not a statistically significant difference (6 dogs vs. 4 dogs) and a lower prevalence than I would expect in a population of dogs with allergic dermatitis. The prednisolone group had a higher prevalence of elevated liver enzymes (18%) than the Apoquel group (5%), as we might expect.  Three dogs (5%) in the Apoquel group were reported to develop Malassezia dermatitis. Other adverse events in this study were infrequent (0-2 dogs) in the Apoquel group.

Apoquel vs Atopica AEAn 84-day RCT comparing Apoquel to Atopica® (cyclosporine) in 226 dogs found that vomiting and diarrhea occurred with a greater frequency in the Atopica group (44 and 15%) than the Apoquel group (14 and 4%). I suspect that the higher rate of vomiting seen for Apoquel in this study compared to some other studies relates to its longer duration.  I have personally prescribed Apoquel for more than 50 dogs representing thousands of doses and have had very few clients contact our office regarding suspected adverse reactions.

So, if these clinical studies all sound good, why is there still concern amongst some about prescribing Apoquel? It stems from the target safety laboratory studies, often using 3 or 5 times the recommended dose, or giving it to young dogs, for which it is neither recommended nor approved. These are the studies that led to the recommended age restriction and dosing of a drug which admittedly represents a balancing act between the right amount and too much! Remember, Apoquel is like fine wine or anything else you are can overdo!

In the target safety studies, some of the concerning findings are dermatitis, interdigital furunculosis (apparently common in laboratory beagles), demodicosis (in 6-month old dogs), pneumonia (in young dogs treated with high doses), lymphadenopathy, decreased cellularity of other lymphoid tissue, and mild hematological effects.  Of the 4 dogs euthanized during the target animal safety studies, infection played a role in each.  Their Apoquel dosing for all of them was 6 to 12 times the recommended daily dosing and they all initiated treatment at less than 6 months of age.  Is this risk too great to use Apoquel?  I don’t think so. What if a pharmaceutical company was doing a similar target safety study as required by the FDA with prednisone, giving it at 6-12 times the recommended dose to young dogs for an extended period of time?  Wouldn’t you expect that we would see some immunosuppression related infections as well as other side effects?  Does that stop you from ever prescribing prednisone to alleviate a pet’s suffering? No, because you use the correct dose in practice!

Finally, what about the issue of neoplasia and cancer? It is thought that immunomodulating drugs can, in general, predispose patients (humans and dogs) to some forms of cancer, thus the FDA has certain labeling requirements concerning immunomodulating drugs. The Apoquel package insert carries a warning that Apoquel “may exacerbate neoplastic conditions.” There is no way to disprove this statement, so although no neoplasms were observed in the laboratory safety studies, and the causality of some of the tumors that developed in the field trials were ruled out based on a very short period of time between starting the drug and tumor diagnosis, the statement sticks. Here is the information available regarding the open-label, long-term continuation study (239 dogs) in the Freedom of Information Summary:

“Six dogs were euthanized because of suspected malignant neoplasms: including one dog each with thoracic metastatic, abdominal metastatic, splenic, frontal sinus, and intracranial neoplasms, and transitional cell carcinoma after 17, 120, 175, 49, 141, and 286 days of oclacitinib maleate administration, respectively. Two dogs each developed a Grade II mast cell tumor after 52 and 91 days of oclacitinib maleate administration, respectively. One dog developed low grade B-cell lymphoma after 392 days of oclacitinib maleate administration. Two dogs each developed an apocrine gland adenocarcinoma (one dermal, one anal sac) after approximately 210 and 320 days of oclacitinib maleate administration, respectively. One dog developed a low grade oral spindle cell sarcoma after 320 days of oclacitinib maleate administration.”

Ideally we would evaluate the prevalence of each diagnosis against a database of dogs with a comparator group with similar demographics.  But of course that isn’t readily available.  So we are left to consider whether the prevalence of neoplasia in these 239 dogs (5%) is unusually high. My local veterinary oncologist and I don’t find the prevalence unusual, although we don’t have all the demographic data that would help us evaluate it.

For the record, I do not have any financial conflicts of interest concerning Zoetis. I’m just a fan of Apoquel. For me, Apoquel is living up to expectations and I am very glad we can help out so many dogs. It needs to be used at recommended doses and under careful veterinary supervision. Let’s not forget how miserable it is to be itchy and how that negatively impacts quality of life and the human-animal bond!

In future posts I’ll discuss the patient monitoring that I recommend for Apoquel and how I incorporate it into my treatment with RESPIT to manage the underlying allergy. 

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Apoquel safety: how Apoquel is like fine wine – Part 1

By Jon Plant, DVM, DACVD

Apoqpinot-noir-glassesuel® (oclacitinib) is the new Zoetis drug for the treatment of atopic and allergic dermatitis in dogs at least 12 months of age. I’ve been prescribing Apoquel for almost 3 months now and I must say, wow, am I impressed with the efficacy! But, more on that another time.  My purpose today is to summarize some of the safety data on Apoquel.

Apoquel is a selective janus kinase (JAK) inhibitor.  JAKs are components of some cell receptors that receive instructions from other cells through molecules called cytokines.  There are many cytokines (interleukins and others) and different types of JAKs. By selectively targeting some of those involved in the itch and inflammation of allergic and atopic dermatitis, Apoquel reduces itch and inflammation, while having less of an impact on other aspects of the immune system.

How does Apoquel do this? It exerts its inhibitory effect on JAK-1 and JAK-3 at lower concentrations than it takes to inhibit JAK-2.  This is important because it allows the drug to target pruritogenic (creating itch) IL-31 and pro-inflammatory (IL-2, IL-4, IL-5, IL-6, IL-13) cytokines at concentrations lower than that at which it inhibits cytokines involved in hematopoiesis that are dependent on JAK-2 (IL-12, IL-23, EO, GM-CSF). It also means Selective JAK inhibitionthat we should follow the recommended dosing (0.4-0.6 mg/kg), even in those cases where it is not helping as much as we’d like.  Apoquel is like fine wine. Too little leaves you wanting more, but too much will make your head throb. The key is to aim for the sweet spot where we are inhibiting the “bad” cytokines but leaving the “good” cytokines to do their thing.

Apoquel appears to be safe when given with other medications. The risk of metabolic drug-drug interactions due to Apoquel inhibition of hepatic CYP450 enzymes is low, as it has minimal inhibitory effect on canine CYP450 enzymes.  The use of Apoquel concurrent with glucocorticoids, cyclosporine, and other immunosuppressive therapies is not recommended and hasn’t been investigated in any meaningful way so far.  There have been some (about 30 I believe is what I heard from a Zoetis dermatologist) patients in a long-term continuation study that did receive glucocorticoids for one reason or another, and no issues arose (this is how I remember it, at least).

The manuscript describing this long-term continuation study (the mean time on study = 402 days as of May 2013) was in preparation the last I heard.  A common concern expressed by veterinarians and pet owners alike is whether we know the long-term effects of this new drug. I suspect that we don’t know everything about it, but I do think that we know more than for most drugs that hit the market. When drugs are given to hundreds of thousands of patients after a drug is launched, uncommon adverse effects might turn up, such as toxicity due to a specific genetic mutation affecting its metabolism.  That is why the FDA requires drug companies to perform pharmacovigilence, monitoring for adverse reactions after going to market.  And why practicing veterinarians should take it upon themselves to report suspected adverse drug reactions.

More details in Part 2

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APOQUEL: will it live up to expectations?

Jon D. Plant, DVM, Dipl. ACVD

If you haven’t already, you will soon be hearing a lot about APOQUEL® for the management of allergic dermatitis and atopic dermatitis in dogs at least 12 months of age. APOQUEL® is a new drug from Zoetis that controls pruritus and inflammation by inhibiting janus kinase enzymes, and is therefore known as a JAK inhibitor.

APOQUEL significantly reduces itch within 24 hours, with continued improvement during the first 7-14 days of therapy. In clinical trials, APOQUEL-treated dogs with atopic dermatitis were evaluated after 28 days by the owners and veterinarians.  66% of dogs treated with APOQUEL and 4% of dogs treated with placebo were judged to have a significant reduction of itching.  Significant improvement was defined (in collaboration with the FDA) as a 2 cm reduction on a 10 cm pruritus visual analog scale (PVAS). Is this a case of what epidemiologist John Ioannidis calls “significance chasing?” Are the findings statistically significant, but clinically trivial?

The percent of dogs that achieved a “normal dog” level of itch (< 2.0 on the PVAS) has not been made available to us. This is, of course, the outcome measure than would mean the most to the owner of a pruritic dog, and the one that I am most interested in determining, even if the FDA was not.

I have had the opportunity prescribe APOQUEL to 20 dogs in the past 3 weeks, with follow-up examinations planned after 4 weeks of treatment. I’ve asked each owner to grade pruritus daily with the PVAS and am curious to see how many get into the “normal dog” range on the pruritus scale.  Will APOQUEL live up to the hype?  I hope so! But, I think we will all be more confident after we have some first-hand experience. APOQUEL is scheduled to be launched in January.

In my next post I’ll discuss the safety of APOQUEL and the patient monitoring that I am recommending to my clients.

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Veterinarian assessment of RESPIT for canine atopic dermatitis

Allergen-specific immunotherapy (ASIT) is frequently used to manage canine atopic dermatitis (AD). The selection of allergens for ASIT is based on intradermal testing (IDT), allergen-specific immunoglobulin E (IgE) assays, patient history, and aerobiological data. In theory, an optimal allergenic extract mixture would contain only antigens which elicit clinical signs upon natural exposure, but no others. There is no means of assessing how closely current practices approximate this optimal mixture. However, it is increasingly clear that the choice of allergy test technique, method or assay has the potential to influence the composition of ASIT.1

Despite poor agreement between testing techniques, the efficacy of ASIT does not correlate with a certain testing method or assay type.2 Our inability to discriminate between these allergen selection methods in terms of ASIT efficacy may reflect the paucity of prospective studies comparing ASIT based on different allergen selection techniques, or may indicate that they are indeed equivalent. If the techniques and methods that produce disparate test results are equivalent in terms of ASIT efficacy, this suggests that factors such as patient history, likely allergen exposure, and other parameters that may influence the antigens selected for ASIT (e.g. cross-reactivity) are as influential in determining the efficacy of an ASIT mixture as are allergy test findings. In this case, region-specific immunotherapy (RSIT) based on predicted allergen exposure may have efficacy similar to ASIT. This benefit could stem from the inclusion of some, if not all of the allergens to which a dog is sensitized, the influence of pan-allergens, or non-specific effects on the immune system.

There are two unpublished studies examining the efficacy of RSIT. In a double-blinded study, Garfield found a 76% “good” to “excellent” response rate to a stock mixture of 32 allergens in 29 dogs, not significantly different from those that received ASIT based on IDT results.3 In contrast, using a mixture consisting of four alum-precipitated allergens (house dust, dog dander, human dander, and grass mix), Willemse found that the response rate in 15 dogs was inferior to that obtained with ASIT.4 I would like to report the results of a survey of veterinarians who prescribed commercially-available RSIT mixtures that were selected based on a dog’s geographic location and predicted exposure rather than individual allergy test results.

All 160 veterinarians who had purchased the injectable form of RESPIT® (SkinVet Products, Lake Oswego, OR, USA) between March 2010 and September 2012 were contacted by mail in June 2013 and asked to review their patients’ records. Each aqueous allergen mixture contained 20 house dust mite and regional pollen antigens. Surveys were accepted up to a predetermined deadline of July 31. Veterinarians were asked to complete one survey per dog treated with RESPIT fulfilling defined inclusion criteria, estimating pruritus and lesion severity at Day 1 of RESPIT therapy and again at the time of the most recent follow-up examination.

Veterinarians graded the overall effectiveness of RESPIT for each dog on a categorical scale (poor = 0-24% reduction in itching, no reduction in additional medications; moderate = 25-49% reduction in itching, some reduction in additional medications; good = 50-74% reduction in itching, some reduction in additional medications; excellent = 75-100% reduction in itching, receives no additional medications).

Fifteen veterinarians completed surveys based on chart reviews of 50 dogs (24 males, 26 females, mean age of 6.7 years). Sixty-three percent of follow-up examinations took place during the months from April to September. No follow-up was available for 2 dogs. The majority of dogs had been treated for at least 12 months with RESPIT at the time of the follow-up examinations (median 382, range 27 – 920 days). The 15 veterinarians who completed the survey were located in seven states (California, Florida, Illinois, Nevada, Oregon, Tennessee, and Texas). The allergen mixtures were different for each of these states.

The median pruritus severity and lesion severity were lower at the time of follow-up than on Day 1 (Figure 1). PruritusLesions

Figure 1. (a) Pruritus severity and (b) lesion severity (median, range, interquartile range) in 48 dogs with atopic dermatitis pre-treatment and post-treatment with region-specific immunotherapy (RESPIT). The median interval between the two retrospective evaluations was 382 days.

Veterinarians assessed the overall efficacy as “good” or “excellent” in 69% of dogs evaluated beyond 90 days (29/42) and in 61% of all dogs treated (31/50). Adverse reactions (increased pruritus) were reported in 4/50 dogs resulting in the discontinuation of RESPIT in one dog.

The retrospective nature of this survey, the low participation rate and the likelihood of self-selection bias are significant limitations that affect the generalizability of these findings. It is, however, interesting that the response to RESPIT reported by 15 veterinarians for these 50 dogs is similar to the response rates often reported for ASIT in retrospective studies and for RSIT in the randomized-controlled trial by Garfield. Prospective studies are required to verify these findings.

1. Plant JD, Neradilek MB, Polissar NL, et al. Reproducibility of allergen-specific IgE assays and ensuing immunotherapy recommendations from four laboratories. In: Abstracts of the 26th Annual Congress of the ECVD-ESVD, 19-21 September 2013, Valencia, Spain. Veterinary Dermatology 2013;24:391.
2. Miller WH, Griffin CE, Campbell KL, et al. Muller & Kirk’s Small Animal Dermatology. 7th ed. St. Louis: Elsevier/Saunders, 2013;380.
3. Garfield R. Injection immunotherapy in the treatment of canine atopic dermatitis: comparison of 3 hyposensitization protocols. 8th Annual Members Meeting of the American Academy of Veterinary Dermatology & the American College of Veterinary Dermatology 1992;7-8.
4. Anderson R, Sousa C. Workshop report 7. In vivo vs. in vitro testing for canine aotpy. In: Ihrke P, Mason I,White SD, eds. Advances in veterinary dermatology. New York: Pergamon Press, 1992;425-427.

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