The past few years have been an exciting time for those who treat psoriasis and for many patients with severe disease because of excellent new therapies for this often intractable problem. Norman Levine, M.D., talks with Alan Menter, M.D., Baylor University Medical Center, Dallas, about recent developments in the treatment of psoriasis.
The past few years have been an exciting time for those who treat psoriasis and for many patients with severe disease because of excellent new therapies for this often intractable problem. Norman Levine, M.D., spoke with Alan Menter, M.D., Baylor University Medical Center, Dallas, about recent developments in the treatment of psoriasis.
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Norman Levine, M.D.: The biologic agents have turned out to be incredible advances for therapy for psoriasis and psoriatic arthritis; however, there are whispers of cardiovascular toxicity and other side effects. Is there anything new with regard to toxicity issues that have come up over the past few years?
Alan Menter, M.D.: I think the best review article was written by Gerd Burmester, M.D., of Leiden University Medical Centre, Leiden, Netherlands, and colleagues.[i]
They reviewed serious and non-serious adverse events in nearly 24,000 patients in 71 global clinical trials for the seven indications for which adalimumab (Humira, AbbVie) is approved. I think the two things that obviously everybody worries about are infections and malignancy. There is nothing that we did not know about beforehand related to infections. I think the issue that we all think about is nonmelanoma skin cancer, which was slightly increased in psoriasis, as well as RA (rheumatoid arthritis) or Crohn’s (disease). In addition, an interesting aspect is that lymphoma, which has a baseline increased risk in our psoriasis population of up to about 1.8 times baseline, irrespective of treatment, was slightly increased over the baseline risk only in RA patients, but not in psoriasis patients.
So I think after 12 years of adalimumab exposure, 15 years of infliximab, and the same for etanercept, I do not believe that there is any really new safety signal. The cardiovascular label warning issue, I think, has been put to bed because of the findings that methotrexate as well as for the TNFs (tumor necrosis factor) which actually have a positive effect on cardiovascular disease. Many of us take an aspirin every day to prevent cardiac events, in part, by reducing inflammation and likewise, TNF-alpha agents also reduce inflammation. All the current research going on in coronary artery disease is not based on statins but based on inflammatory molecules and biologics. There are many biologics in the marketplace in research for coronary artery disease for all the immune-mediated diseases, so there is no doubt reducing cutaneous inflammation will reduce coronary artery and other vascular inflammation over the long term. The biggest problem in our psoriasis population versus other autoimmune diseases is the obesity-metabolic syndrome issue, i.e., hypertension, diabetes and hyperlipidemia - all of which are more prevalent in our psoriasis population.
Thus, all the new drugs coming down the pipeline are looking very carefully at the coronary artery/cardiovascular issue in addition to other potential side effects.
Dr. Levine: There is a current review about the relationship between the use of immunizations and these TNF-alpha inhibitors and others.[ii] The idea was that there is a real problem associated with using these and live-virus vaccines such as the shingles shot. What is your sense of this now?
Dr. Menter: Now I would agree with that. The nasal mist is a live vaccine, so I think we have to be cautious even with that in flu season. The National Psoriasis Foundation has issued a nice paper on guidelines for vaccinations[iii] and we in our vaccination guidelines for psoriasis for the academy as well.[iv] The big question is: If you are on a drug like etanercept (Enbrel, Amgen) that’s used weekly, how long does one have to wait pre- and post- your live vaccine? I would tend to say that probably four weeks on either side is a reasonable expectation depending on the half-life of the drugs. If someone is on etanercept, I will say wait four weeks; if they are on infliximab, I say have the live vaccine midway between your eight weeks of infusions; and if you are on adalimumab, you are going to need to miss two adalimumab treatments given every other week so that you can actually have some degree of safety. For ustekinumab (Stelara, Janssen), which given every 12 weeks, I recommend taking the live vaccine halfway between the injections.
So I think if you stick to reasonable principles of missing approximately two weeks prior and two weeks post, there is no evidence of any risk clinically. We have in our clinic probably close to 1,000 patients on biologic drugs with or without methotrexate. This was never an issue in the methotrexate era and we have really talked about this a great deal; I think yes, there is a risk for live vaccines, but I think it can be totally ameliorated by just dosing appropriately as I have discussed, preferably prior to initiation of the biologic drug.
Dr. Levine: In that review article, they specifically cited methotrexate as one where it doesn’t appear to matter when the vaccines are given.
Dr. Menter: Right, I think that’s reasonable. We now have 40 years of data on methotrexate.
Dr. Levine: With all of the patients that you have now seen over many years on the biologics, do you see a clear winner here?
Dr. Menter: I frequently use infliximab for our obese psoriasis population, particularly as it is dosed on a weight-based dosage. On the other hand, I was involved in a review on all our patients on infliximab for over a year, and more than 50 percent of the patients needed a dose adjustment shortened interval between infusions, and/or methotrexate on board.[v] To answer your question specifically, I believe it is all based on pharmacogenomics. I believe in five years' time, hopefully if you and I are still around, we will be able to predict with a lot more certainty who is going to respond to which drug. You know when the new anti-IL-17 (interleukin-17), the vast majority of people are going to respond to these drugs coming down the pipeline. But on the other hand, from an obesity perspective, I often bring up the anecdotes of patients I have, who are morbidly obese in the 300-pound to 400-pound range, who failed infliximab on a weight basis then failed adalimumab, and finally responded completely well to etanercept - why?
Dr. Levine: Let’s move on to the new drugs in the pipeline. There are at least four that I am aware of that seem to have tremendous potential. Could you discuss the PDE (phosphodiesterase) inhibitor to start?
Dr. Menter: Just out of interest, I have just contributed to an expert opinion that was published a couple a months ago in which we did a full review on current and future biologics.[vi] Everybody wants a new oral agent, and we haven’t had a new oral since cyclosporine came down the pipeline almost 20 years ago. The issue is: is there really a group of patients who are needle-averse that we have to have an oral? I think the biggest problem with the two most important oral agents that we have coming down the pipeline - apremilast (Celgene) and tofacitinib (Pfizer), which is already approved in the United States for rheumatoid arthritis - is the efficacy. Are they any better than “methotrexate” that we currently have had available for the last 40 years? There is an interesting new formulation in early-stage development for methotrexate - remember the good old aminopterin days prior to methotrexate - a company has taken that molecule and tweaked it, and we are doing some studies now and we have already published a report showing that the new aminopterin molecule has minimal to no CSF concentration and appears to shows less toxicity than methotrexate. So we may finally have a new methotrexate on board.[vii]
But again, insofar as the two new oral molecules that I mentioned, the biggest issue is efficacy, vis a vis not only the future biologics but our current biologics. Neither of them appear to show in the dosing that has been used a PASI (Psoriasis Area and Severity Index) score much over the 50 percent to 60 percent range. The European Medical Agency (EMA) actually failed to approve tofacitinib for rheumatoid arthritis after it was approved for RA here in the United States. Tofacitinib is a nice drug with an interesting mechanism of action. The dosing is the biggest issue. In the higher 15 mg dosing, it was getting PASI scores above 60 percent, which was positive. The problem was side effect issues, particularly related to hypercholesterolemia, which we certainly don’t need in our psoriasis population. However, both these new oral agents appear to be relatively safe drugs in all studies to date.
It looks like both tofacitinib and apremilast are within a year to 18 months of coming to market. So I think in the current dosing schedule that has been used that pharmacogenomic research is presumed to target their drug to specific patients, and hopefully make it cheaper than the biologics, which we’ll probably come to when we discuss the biosimilars agents coming to market over the next few years. Tofacitinib has not done exceptionally well versus the biologics in the rheumatoid arthritis world. It has a niche, but is not a major player yet.
Dr. Levine: It’s notable that we are now becoming spoiled that a PASI score of 50 is not good enough anymore. We loved the PASI score of 50 in the old days actually.
Dr. Menter: Yeah, and I think with the new biologics coming down the pipeline, as I often say PASI 75 will be passé; it will be PASI 90 that we will be using.
Dr. Levine: Let’s talk about the IL-17 antagonist and IL-23 antagonist.
Dr. Menter: Well we have three IL-17 antagonists, one of which, brodalumab (AMG827, Amgen), is a human monoclonal IgG2a antibody targeting the IL-17 pathway. I think this is an interesting aspect to note, as there are multiple IL-17s all the way from A to F, and there are subtle differences between the three IL-17 molecules in clinical trials. Brodalumab is fully human, which is slightly different from the others. Again the PASI 75 score showed, pending the dosing that was used in the early studies, is up to 80 to 90 percent, and even the PASI 90 scores after 12 weeks were in the 70 to 75 percent range. Side effect-wise: the usual upper respiratory tract infections were noted with an occasional case of neutropenia, which we have also rarely seen with the TNF agents.
The second one is the ixekizumab (Eli Lilly), which is a humanized monoclonal IgG4 antibody binding to IL-17A. Likewise, in the phase 2 and phase 3 studies, the PASI 75 scores are above 80 percent, and the PASI 90 score in the 70 to 75 percent range.
The third one is secukinumab (AIN457, Novartis), which is a human monoclonal IgG1 antibody, binding IL-17A as well, and similar PASI 75 scores in the 80 percent range and PASI 90 scores a little bit lower at week 12, i.e., a 52 percent range.
Again, dosing is being adjusted for all these three IL-17s. I think there is a great deal of excitement. The question is long-term safety. I always bring up the article that Craig Leonardi and I wrote on efalizumab.[viii] We did a five-year safety review on 40,000 patients in which we said how safe efalizumab was. The following year there were three cases of PML (progressive multifocal leukoencephalopathy), and the drug was taken off market.
So long-term safety is nice. The TNFs are not going to go away. We haven’t talked about ustekinumab (Stelara, Janssen). We now have five years' safety data on ustekinumab. It has been used in 75,000 patients. But still, and I have often mentioned this: We only have slightly less than 1,000 patients on ustekinumab who have been dosed continually for up to five years. It appears that the safety data is stable with no evidence of increasing cardiovascular issues. So it’s nice to have spectacular clinical data, but it’s obviously nice to know what the effect is short-term and long-term, particularly on the cardiovascular system, which is such an issue in our psoriasis population.
There are a couple of new molecules targeting IL-23. When we did the original paper in the Journal of the American Medical Association on IL-12/23,[ix] working with immunology and cardiology colleagues, it appeared that possibly the IL-12 portion of the IL-12/23 molecule of ustekinumab was related to cardiovascular problems (MACE effects). That’s why companies are now going straight for IL-23.
MK-3222 (Merck), which is in phase 3, targets IL-23 specifically, and has had some significant responses in their initial study with the PASI 75 in the 60 to 75 percent range based on dosing again. Then Janssen, the manufacturer of ustekinumab, has a specific IL-23 drug by the name of guselkumab (CNTO 1959), which also has multiple dosages. We are actually studying it for palmoplantar psoriasis. This is a whole new area of concern because none of us do well with treating palmoplantar pustulosis. All of my gray hairs are because of that form of psoriasis. In the pustular form, we now actually have a genetic abnormality in the IL-36 gene. So we can hopefully now start targeting specific phenotypes of psoriasis, i.e., the pustular form with specific drugs.
Dr. Levine: I was wondering about the Janus kinase inhibitor. I have seen the data and it is not overwhelming. What do you think about that?
Dr. Menter: The data for the Janus kinase inhibitor is again in the 50 to 75 percent PASI 75 range; so, again, very similar to tofacitinib. There are a couple of others also under development just like there are two antibodies against IL-22, which look quite interesting - one of which is Pfizer and one of which is Boehringer Ingelheim. So a whole host of new molecules are under development. One of the interesting issues is that psoriasis is often used as a marker for immune-mediated inflammatory diseases because it’s so easy to study versus Crohn’s and RA. Thus, they use psoriasis as an initial tool to see if there is a response and then decide whether they’ll take their drug into these other diseases.
Dr. Levine: Let’s finish up talking about biosimilars in the pipeline. Is there any way that these drugs are ever going to come down in price?
Dr. Menter: It’s all based on patent. For instance, in the U.S., Amgen’s drug was due to come off patent toward the end of 2014. Amgen was able to get a patent extension because of some legal issue for another 15 to 16 years only in the U.S. So that means Enbrel is going to be with us for some time. On the other hand, Amgen has brodalumab coming down the pipeline, so where are they going to put their money? Will they put it into an old drug like etanercept or are they going to start pushing brodalumab? Thus, it will be an interesting perspective when brodalumab comes to market.
The EMA has become the first regulatory body to recommend the approval of two biosimilar drugs, i.e., infliximab, which they did back in July last year. They are a little bit ahead than the FDA guidelines. Our IPC group published a paper a couple of years ago on biosimilars.[x] All the companies that are producing our current biologics also have biosimilars in preparation. The reason is because the manufacturing process for biologics is so intense and so difficult that a start-up company can’t suddenly say, "I would like to make a biosimilar drug for X." The only companies that are going to be able to afford to make biosimilars or who have the technology and the plants available are our current giants in the field. It costs hundreds of millions of dollars to build a biologic plant. Companies in Japan, China and India are also looking at manufacturing biosimilars. They are going to be very stringently watched. Definitively the cost of the future biosimilars will be 30 to 40 percent less. Sandoz, which is a division of Novartis, has a biosimilar company. The manufacturing of the biosimilars for all the biologic drugs will take place in exactly the same plant that they are using for our current biologics say, for rituximab.
So it will be nice to have companies that are involved in the biologics that we trust, that do the appropriate research. The question is: Do you need a full-fledged phase 3 study of a biosimilar, or do you just need to show similarity in production? A lot of people don’t recognize that each of our current biologics that we have - the three TNFs - their molecules have been slightly changed on multiple occasions over the last 15 to 20 years. In other words, if you take any of those three TNFs, each one of them has been slightly changed from the manufacturing process and a molecular basis over the last 15 years. It is now not the same molecule as it was originally. By creating biologics that are 99.5 percent similar and have 99.5 percent similar efficacy, there is no doubt it’s going to have a dramatic effect. Working with some health economists, the prediction is that over the next decade, the biosimilars will reduce the Medicare program cost by up to $12 billion. So I think it’s going to be very important, but pharmacovigilance is going to be critical.
Dr. Levine: We have discussed this back and forth in print some years ago: the notion that the world can’t afford all of this expensive wonderful technology. I am coming to the reluctant conclusion that that’s true, but the patients want it and need it and we probably are going to have this into the future.
Dr. Menter: Well we have 7 million psoriatic patients in the United States versus 120 million worldwide, yet two-thirds of all the biologic agents used for psoriasis are used in North America, because we have access to it, and the rest of the world would love to have access to it if the cost would be reduced.
[i] Burmester G, Panaccione R, Gordon KB, Mcilraith MJ, Lacerda AP. Ann Rheum Dis. 2013; 72(4):517-524
[ii] Wine-Lee L, Keller S, Wilck M, Gluckman S, Van Voorhees A. J Am Acad Dermatol. 2013;69(6):1003-1013
[iii] Lebwohl M, Bagel J, Gelfand J, et al. J Am Acad Dermatol. 2008;58(1):94-105 [Epub 2007 Nov 5]
[v] Kamili Q, Miner A, Hapa A, Menter A. J Drugs Dermatol. 2011;10(5):539-544
[vi] Mansouri B, Patel M, Menter A. Expert Opin Biol Ther. 2013;13(12):1715-1730
[vii] Cole PD, Zebala JA, Alcaraz MJ, Smith AK, Tan J, Kamen BA. Cancer Chemother Pharmacol. 2006;57(6):826-834 [Epub 2005 Sep 17]. Erratum in: Cancer Chemother Pharmacol. 2006;58(3):418. Zebala, John A [added].
[viii] Leonardi C, Menter A, Hamilton T, et al. Br J Dermatol. 2008;158(5):1107-1116 [Epub 2008 Mar 27]
[ix]Ryan C, Leonardi C, Krueger J, et al. JAMA. 2011;306(8):864-871
[x] Strober B, Armour K, Romiti R, et al. J Am Acad Dermatol. 2012;66(2):317-322
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