Craig Leonardi, MD
IL-12/23 Safety Issues
Cardiovascular Safety in Psoriatics Using Biologic Drugs. Does a Signal Exist in the IL12/23 Pathway?
Case Report MACE in a Ustekinumab-Treated Psoriasis Patient
- 47 year old construction worker
- Caucasian male
- Weight: 290 lbs
- Negative Hx: DM, HTN, Tobacco
- 20 yr history
- 15% BSA; PGA: M-S; DLQI: 12
- No evidence of PsA
- Past Tx: MTX, Etanercept, Infliximab, Golimumab
- Current PsO Tx
- Ustekinumab 45mg x 4 doses à 90mg x 2 doses
- MTX 15mg SC QWk
- Folic Acid 1mg QD
- ASA 81mg QD (* This is something that Dr. Leonardi uses as add-on therapy)
- Anterior wall MI
- HgB A1C: 6.2
- LDL-Chol: 108
- Ejection Fraction: 45%
- Two stents were placed
The Cardiologist commented: “Young for this type of event given his health status”
The question lies…what is it about this patient and his health status and the drug that he is currently taking, does it give him any protection about MACE events that can occur?
The answer is: no one knows right now and this is a hot debate that we all try to answer as best as we can…
Psoriasis patients have a wide and rich subset of many of the components of the Metabolic Syndrome such as diabetes mellitus, hyperlipidemia, coronary heart disease, and arterial hypertension that has been shown in much of the data.
We know from Dr. Joel Gelfand and colleagues, that our patients with psoriasis are at increased risk for myocardial infarction.
Methotrexate Reduces Incidence of Vascular Diseases in Psoriatics
- Retrospective VAMC cohort study
- 7615 patients with psoriasis
- 6707 patients with rheumatoid arthritis
- Covariates included age, sex, DM, HTN, dyslipidemia, and certain medications
- MTX-treated pts had decreased vascular disease risk
- Better: Low dose vs high dose
- Best: Combination MTX and folic acid
From the Rheumatologists we have been following patients for many years….
So in treating RA patients with a TNF inhibitor, one could reduce cardiovascular events.
PsO: Risk of MI with anti-TNF therapy
This was a Kaiser Permanente psoriasis cohort of more than 24,000 patients. Patients had an ICD-9 of 696.1 (psoriasis) or 696.0 (PsA) for more than 3 prior visits and no MI prior to 2004 at the start of the study. The anti-TNF cohort was defined as receiving an anti-TNF for greater than 2 consecutive months. The oral/phototherapy cohort was anti-TNF-naïve, received oral/phototherapy for more than 2 consecutive months, and the “mild” cohort received no anti-TNF, oral therapy or phototherapy. The researchers conducted a multivariate analysis using cardiac risk factors too look at a comparison between anti-TNF and other systemic therapy.
IL12 and 23 Blockade: A New Approach to Treating Psoriasis and Psoriatic Arthritis
There are new therapies currently available to Dermatologists, ustekinumab has been available for about 2 ¼ years; however, it is still a relatively new product. Both ustekinumab (IL-12) and briakinumab (IL-23) both block the p40 subunit.
When you block IL-12, you down-regulate a set a cytokines from a Th1 pathway, including INFy, IL-2 and TNF-alpha. When you block IL-23, you down-regulate IL-17 alpha, IL-17f, IL-6, TNF-alpha, IL-21 and IL-22.
Function of Th17 Effector Cytokines
- Expressed by memory NK and T cells
- Increased in psoriatic skin
- Subcutaneous injection à neutrophilia
- Enhances inflammation
- Enhances angiogenesis
- Expressed in high levels by Th17 cells
- Increased in psoriasis (skin and plasma)
- Levels correspond to disease activity
- Induces keratinocyte hyperproliferation (in vivo, in vitro)
- Stimulates keratinocytes to secrete antimicrobial peptides
Both demonstrating positive effects…
Ustekinumab is a high-performing drug for psoriasis patients. One can see, by the data that at week 28, about 71-79% of patients are achieving a PASI 75; this is a huge achievement for these patients. Looking at briakinumab (ABT874), this product seemed to enable patients to achieve at PASI 75 within twelve weeks of treatment. Unfortunately, attached to this positive response was also a safety signal, specifically MACE events that is categorized as cardiac, stroke or death by cardiovascular reasons. There were five MACE events in treated arm and none in the placebo arm. There were also some other troubling issues such as six malignancies, all of which were squamous cell (2 were internal and 4 cutaneous), and again, none in the placebo group and there were five serious infections to one in the placebo arm. There was an imbalance to MACE events, malignancies and infections as compared to placebo. This is problematic as with malignancies as to the fact that no one knows as to why the cancer issues showed up some early in this trial. MACE events are very significant as it defies the conventional thought regarding systemic inflammation and cardiovascular disease—we expect that when inflammation is decreased, the cardiovascular status should improve; however, with that in mind, when looking back at the ustekinumab SAEs that occurred within the first twelve weeks, one can see an imbalance in the placebo versus the treated arms. One can see angina, stoke, congestive cardiomyopathy (and death), and CABG. Dr Leonardi points out that angina and coronary artery bypass are not necessarily MACE events, they would not actually qualify. All in all, between the phase II and phase III trials for ustekinumab there were five MACE events, an equal number to that of the briakinumab events.
What about infection rates?
When you’re looking at a subset of the drugs or patients who are doing well, you see positive results; however, that’s the not the case for the patients who are not doing well on drug.
Summary of MACE Events in Randomized Controlled PSO Trials (meta-analysis)
Dr Leonardi, along with a group of other concerned dermatologists, statisticians, cytokine biologists and cardiologists convened for a meeting. The goal of this meeting was to analyze the data from the published studies regarding the MACE events that occurred among these patients. The group was able to tabulate the data that exist among the IL-12/23 drugs and the TNF antagonists.
When looking at the data, one can see that there was one case of MACE reported in an adalimumab trial and there was another MACE event reported in an etanercept trial (one on treatment; one on placebo in the TNF antagonist trials). When looking at the IL-12/23 drugs, there are ten versus zero; that is a pretty compelling number. Many argue that this is due to an unhealthy status of the patients; however, this is not seen with the placebo arm, so that question still remains.
What are the statistics?
*There was no statistical significance among the TNF trials
In both drugs, we see a flurry of activity and then it flattens out over time; therefore, the kinetics of both drugs seems to be similar.
We expect MACE events to DECREASE when systemic inflammatory diseases are treated. Why are we seeing a paradoxical increase in MACE events?
Dr Leonardi’s hypothesis tells us that when we look at serum p40 subunit levels following a single dose of ustekinumab, they peek at about 3-3 ½ weeks, and then they settle down over a 32-week period. Therefore, one can see an increase in drug concentration and in binding of the ligand, p40, during the initial period. The target for this drug is in the tissue (inflamed) skin; i.e., it is expected to pull p40, presumably in the form of IL-12 or IL-23, into the serum and perhaps it interacts with an atherosclerotic plaque. It could also be an increase in IL-12 or IL-23 delivery, indirectly, to atherosclerotic plaques. Literature also suggests that p40 subunits can also have a form of bioactivity if they dimerize. It is also possible that it is an expected biologic activity of the drug. It is unlikely; however, that it is due to patient selection bias, as it is not apparent in patients taking placebo.
IL 12/23 Antagonists: Possible Next Steps
- Obtain complete datasets from Abbott, Centocor
- Time-to-event details
- Patient details (risk factors, basic demographics)
- Pharmacokinetic profiles
- All ischemic non-MACE events
- Analysis of p40, IL12, IL23 serum levels during long term therapy
- Routine and frequent safety updates (especially in relevant psoriasis populations)
- Determine whether a pattern of comorbidities exists
- FDA, EMA input based on review of both datasets
Ustekinumab: Recommendations for Use (Dr Leonardi’s Approach)
- Consider all options when selecting a biologic tx
- Know that psoriatics typically have multiple cardiac risk factors
- Consider starting with low (45mg) dose regardless of pt weight
- Consider adding ASA 81mg QD
- Await further analysis (FDA, EMA, Abbott, Centocor)
- Remember that all new drugs are ‘new’
IL 12/23 Blockers and CV Risk? (Dr Leonardi’s Opinion)
- Probable class effect demonstrated in 2 drugs
- Equal number of MACE events in 1st 12 weeks (DBPC)
- Increased rate of MACE in the early part of trials
- Rate of MACE appears to decrease over time
- Peak serum concentrations of drug correspond to MACE activity (ustekinumab)
- Unanticipated finding
- P= 0.11
- Not significant at traditional levels (0.05)
- Underpowered study for CV events
- 11% probability that results (10 vs 0) is “by chance”