Small molecules were the mainstay for systemic psoriasis therapy for about forty years. Many patients would say that they prefer small molecules, i.e., a pill to a shot and, in fact, sometimes physicians feel more comfortable with a pill as well. In the last decade; however, all attention with regards to the treatment of psoriasis has been given to the biologics.
How will these small molecules impact the dermatology practice?
Methotrexate (MTX) is the small molecule standard and, for the most part, well-tolerated. Most countries require the use of MTX before trying a more expensive medication. Unfortunately, some of the first studies for MTX were conducted poorly. Overall, you can expect to achieve a PASI 75 of about 40 percent with relatively aggressive MTX dosing when compared to biologics.
Apremilast
Apremilast, an inhibitor of PDE4, is currently under development for the treatment of psoriasis.
In Phase III studies, apremilast (30 mg BID) has achieved a PASI 75 achievement rate of 33%. The majority of adverse events (AEs) were not serious. The phase III results (ESTEEM I and II) demonstrate greater improvements from baseline Dermatology Quality of Life Index versus placebo and a greater proportion of patients reported improvements in the MCID versus placebo. Apremilast seems to be well tolerated in patients with moderate to severe psoriasis, with mild and infrequent gastrointestinal side effects (nausea and diarrhea).
The JAK/STAT Pathway
Tofacitinib, a novel, oral JAK inhibitor recently approved for the treatment of rheumatoid arthritis, is currently being investigated as a treatment for psoriasis among other indications. Although tofacitinib is a small molecule that binds to a specific area, it may have a wide range of effects; therefore, targeting various phases of the inflammatory process.
The phase II data on tofacitinib (15mg BID and 5 mg BID) demonstrate a PASI 75 achievement rate of 67 percent and 40 percent at week twelve, respectively; therefore, showing that this could be quite effective for the management of psoriasis. The issue that we have with this therapy is the overall safety of this medication.
When looking at some of the data that we have in rheumatoid arthritis, we see changes in baseline in hemoglobin and also lymphocyte changes. An FDA briefing document states that as the dose of tofacitinib increases, as does the risk of malignancies, this also seems to be true for lymphoma and infection. While this medication has a broader immunosuppressive effect, there may be more issues with side effects and that is something, as dermatologists, that needs to be considered.
In conclusion, you can see that small molecules are again being developed for systemic psoriasis therapy. While they have exciting mechanisms of action, it remains to be seen if they will be superior to methotrexate in both efficacy and safety, especially with regards to the immune system. Pricing and prior authorization requirements will be critical when it comes to treating patients.
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It is crucial that dermatologists recognize the major advances in the management of psoriasis. Psoriasis affects approximately one to two percent of the general population in the United States, plaque psoriasis being the most common form accounting for approximately 90 percent of all cases.
It is important to look at where dermatologists have been with the use of biologics over the last decade. The first set of drugs were the T-cell inhibitors. T-cell inhibitors work by blocking T-cell activation; it is a multi-step process. The primary signal was the presentation of antigen; the secondary signal was that of the binding of accessory ligand pairs; therefore, forming immunologic “synapse.” According to Dr Leonardi, this was a wonderful rationale, but since then these drugs have fallen by the wayside for a number of reasons. For example, alefacept (withdrawn from market in 2012) was probably one of the least efficacious drugs approved. Efalizumab had serious infections (i.e., progressive multifocal leucoencephalopathy (PML)) and was taken off the market in 2009. From that point, attention then drifted over to cytokines and cytokine inhibitors for the treatment of chronic inflammation.
The 2nd generation biologics are what Dr Leonardi characterizes as the TNF-alpha inhibitors. Etanercept, in its usually approved dose of 50 mg once weekly, achieves a 45-50% PASI 75 response and you can see even more improvement with the double dose of 50 mg twice weekly.
Infliximab, three infusions in the first six weeks, will carry patients up to about an 80% PASI 75 achievement rate, and then you will see a slow loss of response over time; however, there will still be about 60% PASI 75 achievement rate over the long term.
Adalimumab achieves a 71% PASI 75 at week 16.
Third generation biologics include ustekinumab and briakinumab (which never completed the FDA-approval process for psoriasis). Phase III data on ustekinumab was positive in both the PHOENIX 1 and PHOENIX 2 studies, and demonstrates that it is a high performance drug blocking IL-12 and IL-23 showing a sustained PASI 75 response of approximately 67-75% (depending on dose) as compared to placebo. Ustekinumab also has a nice, durable effect.
What about breakthrough early on with ustekinumab? In between doses of ustekinumab it’s very common to see patients who have some return of disease prior to their next dose, but Dr Leonardi urges clinicians to encourage patients to continue and hold on to see the positive effects.
Ustekinumab Safety Data
Over time, adverse events on ustekinumab are coming down, infections are low and stable over time, and SAEs that lead to discontinuation seem to be low and stable as well. One caveat to keep in mind is that in any long term analysis like this, patients are coming out of the trial because they either are not responding or are not tolerating the drug well. From this perspective, long-term safety data from open label extension studies usually looks favorable.
New Development Efforts
There are several new drugs currently in development of the treatment of psoriasis. These therapies target IL-23 (without targeting IL-12) and IL-17. Ixekizumab, an IL-17 inhibitor, appears to be a very promising drug in the pipeline with almost 50 percent of patients in the studies achieving a PASI 100. As far as adverse events (AEs) are concerned, there were no serious AEs and this is extremely comforting.
The IL-17 receptor blocker, brodalumab, was studied in a variety of different dosing strategies. Brodalumab showed about an 80 percent PASI 75 achievement rate, demonstrating a very high performance. There were a couple of serious adverse events (four), but they seemed to be unrelated to medication and no serious infections or cancers were reported.
The data on secukinumab, another inhibitor of IL-17, is difficult to explain as the studies are rather disjointed, in that, as a dermatologist, one has to look past the published data. The higher dose of secukinumab (150mg) was selected for the phase III trials because of its PASI 75 response rate of approximately 81%. There were no serious adverse events with secukinumab.
Conclusions
Dermatologists have seen an explosion of biologic drugs that are mostly targeting the IL-17 and IL-23 pathway
There are a variety of novel small molecules that are under investigation
JAK inhibitor may be a new topical approach
Short and long-term safety issues will depend on the results of the ongoing phase III studies and subsequent post-marketing data capture.
Assess benefit/risk ratios when deciding on appropriate treatment strategies
There are many potential therapies currently under development for the treatment of psoriatic arthritis (PsA) and appear to fall under two categories: biologic agents and oral agents (kinase/enzyme inhibitors).
Th Cell Development
Th17 cells are elevated in PsA patients. One of the exciting areas of research now is that of additional subsets of Th cells. This is leading to the development of new products in the pipeline for inflammatory diseases such as PsA.
Ustekinumab in PsA
This data was just presented a few months ago at the American College of Rheumatology looking at ACR scores and PASI scores both of which demonstrated improved response versus placebo. It is important to keep in mind the effect of weight on therapeutic response as heavier patients experience a lower response in therapy. Obesity seems to be very proinflammatory and it effects how people are responding to their current therapies.
What do we do with patients who have been on TNF inhibitors already and are not responding?
This group of patients is tough and demonstrates the need for more research.
Emerging Molecules Under Development for Psoriatic Arthritis
Secukinumab (IL-17a receptor)
Abatacept- (T cell inhibitor)
In PsA, you don’t see a great response, particularly in those who have been previously exposed to a TNF inhibitor
Tofacitinib
Quite effective and lots of data for the RA patients; Safety issues are of concern
Apremilast
Physicians want patients to do the best that they can on the drug
There are rather respectable results with apremilast
The skin response was significantly better than placebo, but not robust (about 20% at PASI 75)
Few discontinuations due to mild AEs
Laboratory parameters appeared rather normally. Lab tests probably won’t have to be done as a part of reevaluation.
CZP in PsA
Data on certolizumab (CZP) (RAPID-PsA) was presented at ACR and rapid improvements in the signs and symptoms of PsA, as well as skin manifestations and nail disease of psoriasis, were observed among both CZP doses (200mg q2W/400 mg q2W). Similar ACR response rates with CZP were also seen in patients with and without prior anti-TNF exposure.
Final Thoughts
Obesity is a major issue in PsA patients and encouraging patients to lose weight is important to therapeutic response
The biosimilar (CT-P13) will be coming soon and it seems to demonstrate similar efficacy, safety, and a PK similar to that of infliximab
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Comorbidities and Cardiovascular Status of Psoriasis Patients
Craig Leonardi, MD
In this final session of the psoriasis discussion, Dr Leonardi discussed co-morbidities and the cardiovascular status of patients with psoriasis.
Metabolic Syndrome and Psoriasis
Psoriasis patients are at an increased risk for the metabolic syndrome. There are meta-analyses that have been performed that have shown that these patients have an increased risk for type 2 diabetes, hyperlipidemia, hypertension, and obesity.
Myocardial Infarction (MI) in Patients with Psoriasis
Joel Gelfand and colleagues conducted a cohort study of 130,976 to determine the risk of MI in psoriasis patients. The results showed that patients with severe psoriasis had a marked increase of MI as compared to those patients with mild disease.
Why do psoriasis patients have increased cardiovascular risks?
The use of dyslipidemic therapies, such as corticosteroids, acitretin, and cyclosporine
The increased prevalence of associated and/or independent risk factors: smoking, obesity, hypertension, and alcohol misuse
Uncontrolled inflammation leading to endothelial dysfunction and dyslipidemia
Does the treatment of a chronic inflammatory disease reduce cardiovascular risk?
A retrospective cohort study demonstrated that the use of methotrexate reduces the incidence of cardiovascular disease in patients with psoriasis. It is also shown that treatment with TNF blockers decreases the mortality risk in patients with rheumatoid arthritis. In psoriasis, TNF-inhibitor treated patients had a 48 percent reduction of MI risk.
What about CV risk in the setting of IL 12/23 inhibition?
Briakinumab’s Phase III demonstrated an increased number of CV events ( 5 compared to 0 in placebo) and MACE signals were also seen in the ustekinumab phase III trial as well.
Association between biologic therapies for chronic plaque psoriasis and cardiovascular events- a meta-analysis
This study looked at 19 high quality studies. In the TNF studies, only two MACE events were reported (one in treated/one in untreated). In the 12/23 inhibitors, there were 10 events compared to 1 in placebo. Statistics show that the TNF antagonists are not associated with MACE.
In the JAMA article that was published, the conclusions (above) had to be tempered. Tzellos et al re-looked at the data and published a re-analysis of the data using different statistical modeling (they used the PETO method), they found no increased risk of MACE events.
Risk of MACE in IL 12/23 Psoriasis Trials
Background rate of MACE 0.0012/pt-yr, which was based on the aggregated rate in the placebo group for all 22 studies.
Rate in the IL-12/23 studies was 0.012 (10 times the background rate)
What are some of the next steps that need to be taken?
Pay attention to the issue
Emerging therapies-need to wait for phase III data (blocking 12/23 downstream)
Pay attention to Amgen’s development efforts on brodalumab in which brodalumab and ustekinumab are involved in a comparator trial
PSOLAR (Janssen registry) may provide data
Final Comments
American Academy of Dermatology Guidelines Recommends Monitoring; Basic CV screening includes:
Laboratory evaluation
Fasting comprehensive metabolic panel
Fasting lipids
Blood pressure
Assessment of overweight/obese status
Inquiry
Alcohol
Smoking
Depression
Arthritis
Ustekinumab: recommendations for use
Consider all options when selecting a biologic
Know that psoriasis pts typically have multiple cardiac risk factors
Consider starting with low (45mg) dose regardless of patient weight
Consider adding ASA 81mg QD
Await further analysis (FDA, EMA, Abbott, Janssen, Amgen)
Remember that all new drugs are ‘new’
Consider additional specialty care for psoriasis patients
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Pipeline Psoriatic Arthritis Therapies that Have Efficacy in Psoriasis
Arthur Kavanaugh, MD
There are many potential therapies currently under development for the treatment of psoriatic arthritis (PsA) and appear to fall under two categories: biologic agents and oral agents (kinase/enzyme inhibitors).
Th Cell Development
Th17 cells are elevated in PsA patients. One of the exciting areas of research now is that of additional subsets of Th cells. This is leading to the development of new products in the pipeline for inflammatory diseases such as PsA.
Ustekinumab in PsA
This data was just presented a few months ago at the American College of Rheumatology looking at ACR scores and PASI scores both of which demonstrated improved response versus placebo. It is important to keep in mind the effect of weight therapeutic response as heavier patients experience a lower response in therapy. Obesity seems to be very pro-inflammatory and it effects how people are responding to their current therapies.
What do we do with patients who have been on TNF inhibitors already and are not responding?
This group of patients is tough and demonstrates the need for more research.
Emerging Molecules Under Development for Psoriatic Arthritis
Secukinumab (IL-17a receptor)
Abatacept- (T cell inhibitor)-in PsA, you don’t see a great response, particularly in those who have been previously exposed to a TNF inhibitor
Tofacitinib-quite effective and lots of data for the RA patients; Safety issues are of concern
Apremilast-physicians want patients to do the best that they can on the drug; there are rather respectable results with apremilast; skin response was significantly better (about 20% at PASI 75); few discontinuations due to mild AEs (laboratory parameters appeared rather normally. Lab tests probably won’t have to be done as a part of reevaluation)
CZP in PsA
Data on certolizumab was presented at ACR and it appears to work well in PsA patients who have previously been on a TNF inhibitor.
Final Thoughts
Obesity is a major issue in PsA patients and encouraging patients to lose weight is important to therapeutic response
Biosimilars (CT-P13) will be coming soon and seem to demonstrate similar efficacy, safety, and PK similar to infliximab
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Dr Leonardi began this session with an update on what’s new in the first quarter of 2013 with regards to biologic therapy. So, where have we been? Our first set of drugs was T-cell inhibitors. This was a wonderful rationale, but since then these drugs have fallen by the wayside for a number of reasons. For example, alefacept (withdrawn from market in 2012) was probably one of the least efficacious drugs approved. Efalizumab had serious infections (PML) and was taken off the market in 2009. Our attention then drifted over to cytokines and cytokine inhibitors for the treatment of chronic inflammation. Our 2nd generation biologics are what Dr Leonardi characterizes as the TNF-alpha inhibitors.
Etanercept, in its usually approved dose, achieves a 45-50% PASI 75 response and you can get even more improvement with the double dose. Infliximab, three infusions in the first six weeks, will carry patients up to about 82% PASI 75, and then you will see a slow loss of response over time; however, still about 65% PASI 75 responders over the long term. Adalimumab achieves a 71% PASI 75 at week 16.
Third generation drugs include ustekinumab and briakinumab (withdrawn). Phase III data on Ustekinumab was positive in both the PHOENIX 1 and PHOENIX 2 studies, and demonstrates that it is a high performance drug blocking IL-12 and IL-23 showing a sustained PASI 75 response of over 80% as compared to placebo. Ustekinumab also has a nice, durable effect.
What about breakthrough early on with ustekinumab? It’s very common to see patients who have some return of disease, but just encourage patients to continue and hold on to see the positive effects.
Ustekinumab Safety Data
The 5 year safety data show that over time, adverse events on ustekinumab such infections are low and stable over time, and SAEs that lead to discontinuation seem to be low and stable as well. One caveat to keep in mind is that in any long-term safety signal monitoring study like this, patients are coming out of the trial because they either are not responding or are not tolerating the drug well.
New Development Efforts
There are several new drugs currently in development of the treatment of psoriasis. These therapies target IL-12, IL-23, and IL-17.
Ixekizumab, an IL-17 inhibitor, appears to be a very promising drug in the pipeline with almost 50 percent of patients in the studies achieving a PASI 100. As far as adverse events (AEs) are concerned, there were no serious AEs and this is extremely comforting.
The IL-17 receptor blocker, brodalumab, was studied in a variety of different dosing strategies. Brodalumab showed about an 80 percent PASI score, demonstrating a very high performance. There were a couple of serious adverse events (four), but they seemed to be unrelated to medication and no serious infections or cancers were reported.
The data on secukinumab is difficult to explain as the studies are rather disjointed, in that, as a dermatologist, you have to look past the published data. The higher dose of secukinumab (150mg) was selected for the phase III trials because of its PASI response of approximately 81%. There were no serious adverse events with secukinumab.
Conclusions
We have seen an explosion of biologic drugs that are mostly targeting the IL-23 pathway
There are a variety of novel small molecules that are under investigation
JAK inhibitor may be a new topical approach
Short and long-term safety issues exist for therapy
Assess benefit/risk ratios when deciding on appropriate treatment strategies
Small Molecules For Psoriasis
Kenneth Gordon, MD
Small molecules were the mainstay for systemic psoriasis therapy for about forty years. Many patients would say that they prefer small molecules to a shot and, in fact, sometimes physicians feel more comfortable with a pill as well. In the last decade; however, all attention with regards to the treatment of psoriasis has been given to the biologics.
How will these small molecules impact our practice?
Methotrexate (MTX) is the small molecule standard and, for the most part, well tolerated. Unfortunately, some of the first studies for MTX were conducted poorly. Overall, we can expect to achieve a PASI 75 of about 40 percent with relatively aggressive MTX dosing when compared to biologics.
Apremilast
Apremilast, an inhibitor of PDE4, is currently under development for the treatment of psoriasis. In Phase II studies, apremilast (30 mg PO BID) has achieved a PASI 75 score of about 41 percent. More than 96 percent of adverse events (AEs) were not serious. The early phase III results have not yet been released, yet a recent press release said that the studies met their clinical endpoints. Overall, apremilast seems to be well tolerated, but we don’t have the results to date.
The JAK/STAT Pathway
Tofacitinib is a novel, oral JAK inhibitor currently being investigated as a treatment for psoriasis among other indications. Although tofacitinib is a small molecule that binds to a specific area, it may have a wide range of effects; therefore, targeting various phases of the inflammatory process.
The phase II data on tofacitinib (15mg BID and 5 mg BID) demonstrate a PASI 75 response of 67 percent and 40 percent at week twelve, respectively; therefore, showing that this could be quite effective for the management of psoriasis. The issue that we have with this therapy is the overall tolerance of this medication.
When looking at some of the data that we have in rheumatoid arthritis, we see changes in baseline in hemoglobin and also lymphocyte changes. An FDA briefing document states that as the dose of tofacitinib increases, as does the risk of malignancies, this also seems to be true for lymphoma and infection. While this medication has a broader immunosuppressive effect, there may be more issues with side effects and that is something, as dermatologists, that needs to be considered.
Conclusions
Small molecules are again being developed for systemic psoriasis therapy
While they have exciting mechanisms of action, it remains to be seen if efficacy will be superior to methotrexate
Small molecules, since they work on multiple areas of the immune system, can have a very significant effect on the immune system
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Infliximab (initial response, with subsequent failure)
History of:
Hypertension
Hypercholesterolemia
Hypertriglyceridemia
Obese, 120 kg, BMI = 33
[poll id=”2″]
There is concern for this patient because he is at a relatively high risk for cardiovascular disease. However, he has not responded to various treatments and needs therapy in order to function.
How do you discuss ustekinumab with this patient prior to initiation of therapy?
Discuss his risks of cardiovascular disease and conduct a benefit/risk assessment of ustekinumab prior to starting therapy
[poll id=”3″]
[poll id=”4″]
[poll id=”5″]
Case Study 2- Topical Therapy
42 year-old man
Psoriasis affecting 4% of BSA
Inverse pattern
Inguinal
Intergluteal and perianal
Refractory to alclometasone dipropionate cream
No psoriatic arthritis
[poll id=”6″]
Case Study 3- Scalp Psoriasis
22 year-old woman
Severe scalp psoriasis, affects 50% of scalp surface area, failed:
OTC preparations (T-gel)
Fluocinolone acetonide topical scalp oil 0.01%
Clobetasol shampoo, solution and foam
[poll id=”7″]
Case Study 4- Refractory Local Psoriasis in a Patient on Biologic Therapy
46 year-old man with > 20 years of severe psoriasis and psoriatic arthritis
Baseline: 20% BSA, PGA = 4
Currently managed effectively with:
TNF-inhibitor in combination with MTX 10 mg per week
BSA currently 4%, with residual disease on the elbows and lower extremities
Refractory to topical class 1 corticosteroids
[poll id=”8″]
Case Study 5- Latent TB
52 year-old man with 40% BSA
Active psoriatic arthritis
Only treated with UV Phototherapy and topicals, neither of which is effective
PPD is positive to 12 mm induration
Chest X-ray shows no infiltrate and chest CT is normal
What if this patient had previous BCG vaccination?
Verify latent TB status with Quantiferon Gold test
What are your steps to starting therapy for this patient?
Quantiferon Gold test
If positive, treat with a full course of latent TB infection prophylaxis prior to initiation of immunosuppressive/immunomodulatory therapy. Therapy for psoriasis may be begun 1 month into treatment for latent TB.
Discuss various treatment options review the benefits/risks
How do you follow/monitor a patient with treated latent TB while on a TNF-inhibitor?
Be vigilant of signs and symptoms of TB
[poll id=”9″]
[poll id=”10″]
Case Study 6- New Onset Psoriasis
53 year-old woman
Crohn’s disease on TNF-inhibiting antibody with gastrointestinal disease is well-controlled
Develops palmoplantar pustular dermatitis
Could the psoriasis have been induced by the TNF-inhibitor?
Obesity appears to be a common comorbidity in pediatric patients with psoriasis. It is uncertain if the cardiovascular risks seen in adults with psoriasis is fundamentally related to obesity, skin inflammation, or other factors. It is reasonable to discuss these issues with families of children with psoriasis, though much research is needed about long-term risks and modifying them.
Regarding psoriatic arthritis (PsA) in children, consider asking children with psoriasis about morning stiffness, as this can be a sign of PsA. Pediatric psoriasis is typically treated with topical corticosteroids and Vitamin-D analogues; however, clinicians should not forget the appropriate placement of light therapy (NB-UVB is the most studied), which can be very effective. The National Psoriasis Foundation has a pediatric site that is kid-friendly and provides much needed information and resources.
Systemic treatment is appropriate for severe psoriasis in children and adolescents, though it can be much work to have third party payers cover the costs of systemic therapies including biologic agents as there are no specifically approved systemic treatments for children and adolescents with psoriasis.
In summary, there is a fair amount of new information for both Atopic Dermatitis and psoriasis and, in the future, hopefully more treatments will become available for pediatric patients.
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POINT: COUNTERPOINT – MACE and Its Relationship to IL 12/23 Inhibition
Ken Gordon, MD
Dr. Gordon presented a counterpoint to Dr. Leonardi’s perspective regarding the association of IL 12/23 inhibition with MACE events. Dr. Gordon feels that while there is not a definitive answer at this time regarding the association it is important to discuss both sides to the story.
When a dermatologist thinks about the data that has been presented, specifically on ustekinumab, one needs to consider whether IL 12/23 has a true effect on MACE events. There are two approaches to this: 1. Observe the world, here is the observation and it needs to be explained; 2. Utilize the Scientific Method.
In the context of IL 12/23 and looking at MACE events, there has been an inductive moment, and that is the paper that Dr. Leonardi referred to, i.e., the Meta-analysis regarding IL 12/23.
In reviewing the overall conclusions that were presented in the meta-analysis of the association of IL 12/23 inhibition and MACE events, Dr. Gordon concluded that at least in the case of ustekinumab, there may not really be an answer. It is important to remember that meta-analyses have two required aspects in order for them to be effective: 1. The trials have to be similar in structure; 2. The intervention that is used has to be similar. In combining the trials using ustekinumab with those using briakinumab one can see that despite their effect on IL 12/23 these drugs are actually quite different in the dosages used. For example, Dr. Leonardi pointed out that briakinumab had issues with infections and malignancies. Briakinumab has opportunistic infections; whereas, ustekinumab does not. Additionally, there are a large number of squamous cells carcinomas developed in patients treated with briakinumab. There is a change in squamous cell carcinoma to basal cell carcinoma ratio in briakinumab versus placebo. This was not seen with ustekinumab. Therefore, putting the trials using briakinumab and ustekinumab together in a meta-analysis is difficult.
Regarding other differences, looking at the long-term data and only patients who are tolerant of medication in the ustekinumab trials is unfair. Dr. Gordon would argue that if you look at data over time, the retention rate was over 80% over five years in the ustekinumab trials. He pointed out that the high percentage rate of retention is rare in clinical trials and he doesn’t feel that eliminating a large number of patients is an issue here.
When you look at 0.11 what does that mean?
Dr. Gordon feels that the P value being 0.11, as presented by Dr. Leonardi, is very significant. If the experiment were redone 100 times, one would expect to find a difference between the intervention and the placebo 89 times out of 100. That is quite significant.
However, we have a P value and a standard for statistical significance for a reason and that is because we need to be stringent about our conclusions and when they get too close together, it can be difficult to draw any final conclusions. It doesn’t say the magnitude of the problem, only that the two populations will be different.
With meta-analyses, there is another problem, and that is when trials are combined, you can have a trial that is the “driver”, i.e., one or two of the trials out of a larger group of trials will drive the results in one direction and everything else will be inconsistent with that; therefore, the validity of the meta-analysis can be called into question. In particular, when you combine drugs that are distinct and have a driver that is utilizing one of the medications, the validity can be questionable.
(Of note, Dr. Gordon is an author on the meta-analysis with Dr. Leonardi and feels that it is the best analysis that we can have)
A recent article in JAMA (August 2011) reported that there are two studies that are the drivers of all of the IL 12/23 data. The first of which is the briakinumab trial, the second of which is the ustekinumab Phase II trials in which the drug was given in a different fashion than it was given in Phase III. In fact, the numbers in the Phase III trials do not appear to have any statistical significance in the occurrence of MACE events. This makes it very difficult to draw conclusions on ustekinumab and MACE events. In fact, ustekinumab, at the doses given during the phase III, does not seem to statistically show effects at all—observationally, less so than anything else that has been seen.
Dr. Leonardi pointed out the initial increase in risk of MACE events with the initiation of treatment and then it levels off. However, other data presented shows that there are events (randomly) throughout the course of treatment. Regarding the p40 subunit serum levels, there may not be enough information to draw conclusions based on this time course and the multiple events that are seen.
What does Dr. Gordon do for patients on ustekinumab?
Do you warn patients for potential cardiovascular risk? Yes, patients should be aware of the potential risks.
Do you put patients on aspirin? In general, Dr. Gordon does not put people on aspirin; however, if the patient is at risk and should be on aspirin, then he recommends it. If a patient does not have risk factors, is under 40 and is hypertensive, he does not use aspirin.
Conclusions
This is a very difficult topic and many people have many differing opinions and feelings on it. The answer regarding ustekinumab is not fully understood. Regarding briakinumab, Dr. Gordon feels that there is a definite. Only with experience and time will clinicians have the answers regarding IL 12/23 and MACE events.
