New Drugs and Therapies for 2016: Foams

Drs. Neal Bhatia and Ted Rosen

Part 1 of an 8-part series on the large number of new topical and systemic medications that have become available or moved closer to approval in the last 12 months.

Patients love foams and several new ones entered the market during the past year.

Azelaic acid (AzA) for treatment of mild to moderate rosacea

Reduction in inflammatory lesions with AzA foam.

Reduction in inflammatory lesions with AzA foam.
AF, azelaic acid foam; V, vehicle
Draelos ZD, et al. Cutis. 2015;96:54-61.

AzA is used for the management of rosacea and a new 15% foam formulation (Finacea®) has been shown to be safe and effective for papulopustular rosacea (PPR). This new formulation was shown to be significantly superior to vehicle for the co-primary efficacy end points of treatment success according to investigator global assessment (IGA) and the nominal change in inflammatory lesion count from baseline to the end of treatment in patients with PPR (Figure 1). This new AzA formulation is also well tolerated and provides another option for patients with PPR that will help dermatologists match needs and preferences of individual patients and skin types with appropriate delivery modalities.

Calcipotriene 0.0005% and betamethasone dipropionate 0.064% foam

Percentages of patients achieving PASI 75.

Percentages of patients achieving PASI 75.
Cal, calcipotriene 0.0005%; betamethasone dipropionate 0.064%
Leonardi C, et al. J Drugs Dermatol. 2015;14:1468-1477.

A new foam formulation of calcipotriene 0.0005% and betamethasone dipropionate 0.064% (Enstilar®) was approved by the U.S. Food and Drug Administration (FDA) for the topical treatment of plaque psoriasis in December of 2015. It provides plaque psoriasis patients a new treatment option in an “elegant” vehicle that provides rapid relief from symptoms of this disease. In the pivotal phase III trial for Enstilar, over half of patients treated with the new foam were clear or almost clear according to IGA by week 4 (Figure 2). In addition, >50% of patients achieved PASI 75 with Enstilar. This foam was more effective than the ointment fixed combination of calcipotriene and betamethasone dipropionate as well as the individual components used alone in an additional phase IIa study.

Econazole 1% foam for Tinea versicolor in patients with skin type VI

Tinea versicolor is a common superficial fungal infection of the stratum corneum caused by lipophilic yeast of the genus Malassezia. The fungus interferes with the normal pigmentation of the skin, resulting in small, discolored patches that may be lighter or darker in color than the surrounding skin. Econazole nitrate is a broad-spectrum topical antifungal with activity against a variety of dermatophytes and yeasts. A new topical dosage form, econazole nitrate topical foam has been developed for treatment of interdigital tinea pedis and tinea versicolor and it has been shown to be effective for both indications.

New Drugs and New Concepts: Clinical Pearls

Neal Bhatia, MD & Ted Rosen, MD

  1. New drug for papulo-pustular rosacea: QD 1% ivermectin cream (Soolantra®, 30g tube)
  • Better than placebo and superior to metronidazole 0.75% BID
  • “Clear” or “Almost clear” by IGA : 38-40%
  1. New HPV vaccine (Gardasil 9®)
  • Contains VLP to prior quadrivalent vaccine (HPV 6,11,16,18)
  • PLUS: contains VLP to immunize against HPV 31,33,45,52,58
  • Now 97% protective against genital SCCA due to 90% etiologic HPV
  • Also recommended for MSM, where ~75% protective against anal SCCA
  1. Miltefosine (Impavido®) for leishmaniasis
  • Both old world and new world organisms (more evidence for new world)
  • 100-150mg daily (higher dose if over 45kg weight)
  • AEs: anorexia, nausea, vomiting, diarrhea, H/A, mild ↑ LFTs, mild ↑Cr, and mild thrombocytopenia; but is Pregnancy category X (contraindicated): Do not take if pregnant, use adequate contraception during Rx and for five months after therapy has been discontinued
  1. Biologics are coming for atopic dermatitis
  • Duplilumab (anti IL4, IL13)
  • Lebrikizimab (anti IL13)
  • Mepolizumab (anti IL5)
  • Various anti IL31 monoclonal antibodies
  1. Watch for Vitamin D deficiency in various derm diseases: psoriasis, SLE, hidradenitis, alopecia areata; Not known if repletion of Vitamin D will be therapeutic
  2. Tofacitinib, a JAK3 janus kinase inhibitor, currently approved for RA, may be effective in psoriasis and psoriatic arthritis. A case report appeared showing benefit in alopecia totalis!
  3. Adalimumab appears beneficial for hidradenitis in a Phase III RCT.
    • Dosage 40mg weekly
    • Still not a miracle drug
  4. Tonsillectomy improved refractory psoriasis!
  5. Red henna tattoo does NOT affect pulse oximetry
  6. RUSHING to put on condoms leads to errors and failures, including increased STDs

New Drugs: 2014

Neal Bhatia, MD

Ted Rosen, MD

In this presentation, Drs Bhatia and Rosen bring us the latest information on drugs that are, or will be available to the practicing dermatologist.

Apremilast is an inhibitor of PDE4 and is currently in phase III trials for ankylosing spondylitis, psoriasis, and psoriatic arthritis along with orphan status for Bechet’s disease. A published case report for apremilast for lichen planus (Paul et al. JAAD, 2013) demonstrated that 30 percent of the patients experienced a 2-grade improvement. This study was, however, small in numbers, treatment time and dosages.

As Dr Tsao mentioned in his presentation, omalimuzab has demonstrated promising results for the treatment of chronic idiopathic urticaria.

Dr Bhatia commented on the new treatments for onychomycosis, and feels that we have a “flood year of antifungals this year.” What we need to know:

  • Naftifine 2% gel—tape strips show stratum corneum residual after 4 weeks
  • Luliconazole is approved
  • Efinaconazole and Tavaborole are not
  • Itraconazole 200 mg tablets with new dosing protocol
  • Ketoconazole gel (Xolegel) and Itraconazole tablets (Onmel) are back
  • Econazole Foam is coming

In a Phase II study of luliconazole cream 1 percent for the treatment of interdigital tinea pedis, the researchers found that complete clearance was 26.8 percent and 45.7 percent in subjects in the two-week and four-week treatment group, two weeks post-treatment. Four weeks post-treatment complete clearance rates were 53.7 percent and 62.9 percent, respectively. A phase II study of efinaconazole for toenail onychomycosis also demonstrated favorable efficacy. Tavaborole, representing a new class of anti-fungals, met all primary and secondary endpoints in the treatment of nail fungus when compared to ciclopirox lacquer.

Ketoconazole gel 2 percent has the same side effect precautions as oral products, on label, but these are doubtful. It’s important to remember that the brand name in some markets may be cheaper than the generic. Also of importance, rates of mycological cure and effective treatment (secondary efficacy endpoints) were observed in the Econazole Nitrate Foam 1% group relative to the Foam Vehicle in both phase 3 studies (P<0.001). Itraconazole (200 mg) (OMNEL)  is available with a new dosing protocol. In a study, 200 mg tablets were found to be noninferior to itraconazole 100-mg capsules at 52 weeks. The safety profile of Omnel is not statiscially different from that of itraconazole.

Dr Rosen began his section of this presentation discussing Pliagils (Lidocaine 7% + Tetracaine 7% Cream). Pliaglis is a topical, local analgesia for superficial dermatological procedures. It is applied 20-30 minutes for most minor procedures and 60 minutes for more major procedures and is available in 30,60 and100gm tubes.

Sitavig (acyclovir 50mg Buccal) is indicated for recurrent oro-labial HSV. The technology is a natural polymer derived from milk which adheres to the mucosa; therefore leading to high local drug concentration, but minimal blood levels. It is one tabe, applied within one hour of prodrome onset and reduces the duration of an attack by 0.5 days based upon a randomized controlled trial of 775 patients. Another advancement includes the approval of carbinoxamine maleate susp (Karbinal ER), which is a mildly sedating H1 antihistamine in an extended release formulation. It is used for the treatment of allergic rhinitis and conjunctivitis, uncomplicated urticaria, angioedema, and dermatographism. Aurstat Anti-itch hydrogel was also approved in early 2013 to treat the symptoms of atopic dermatitis and various dermatoses.

Old Drugs, New News:

  • Adapalene/BPO 1.2%/2.5% (Epiduo®)
    • Now FDA approved down to age 9
  • Desoximetasone 0.25% (Topicort®)
    • Now available as a spray
  • Ketoconazole 200mg tab (Nizoral®)
    • Severe limitations on use due to liver and adrenal toxicity, as well as drug interactions
  • Certolizumab pegol (Cimzia®)
    • Now approved for psoriatic arthritis

In conclusion, clinicians should pay special attention to the Nizoral FDA warnings published in July of 2013. (www.fda.gov) If you use it and there is any hepatotoxic event, that could cause a great problem as a practitioner.

In summary, the dermatology landscape is continuing to grow with promising new drugs and it is imperative to stay on top of the latest data.

 

New Drugs in 2013

Ted Rosen, MD & Neal Bhatia, MD

Drs Ted Rosen and Neal Bhatia discussed new drugs and devices in 2013.

Ted Rosen, MD

Modified release prednisone (Rayos) is now on the market. Why would this be a reasonable therapeutic choice? For many inflammatory diseases, the cytokines peak overnight; yet, steroid administration is often done in the morning. This treatment delays the bioavailability for about four hours. The idea is to take this at bedtime so that it releases overnight and; therefore, reduces morning symptoms associated with inflammatory diseases. Rayos is approved for steroid-responsive inflammatory disorders.  It is available in 1, 2 and 5mg doses.  Larger size tablets will be come available soon.

Cellulite is seen in 90 percent of women over the age of 40. Cellulaze Laser was approved in January 2012. It is a side-firing 1440nm wavelength laser that destroys fibrous bands and excessive fat. Dr Rosen feels that it may actually work and there may be a reasonable rationale for its use. However, there is not a lot of published data (n= 10) and it is rather costly ($5,000-$10,000 per treatment). There have also been instances of bruising, swelling, pain, and numbness associated with its use.

Vismodegib, a hedgehog pathway inhibitor, is a novel therapy for basal cell carcinoma (BCC). This treatment has dermatologists thinking a little more like oncologists, i.e. is the tumor stable? is it shrinking?  In other words, some response is a good thing even if it isn’t a complete response. It is important to remember that even with ongoing therapy, there may be a recurrence of BCC. This is a unique and outstanding therapy and has a place in the dermatological armamentarium. It really offers the small subset of BCC patients a new option.

Recent FDA Warnings that dermatologists should keep in mind

  • Minoxidil 15%- may cause hypotension
  • Vicrelis and Incivek (PIs for Hep C) Incivek- serious skin reactions (All patients who develop a skin reaction should receive urgent medical care)
  • Nature Relief-Recall because calcium oxide that burns the warts and moles can burn the skin
  • Bleaching creams- may contain mercury
Neal Bhatia, MD

Dermatology has become reliant on botany with regards to some of the newer therapies. These include:

  • Ingenol mebutate for AKs
  • Polypodium leucotomos (Heliocare) is an anti-inflammatory agent with antioxidant effects and an impact on photodamage
  • Sinecatechins (Veregin) for HPV-related dermatoses also has antioxidative effects, antiviral effects, and is immune-stimulatory.  This is probably not an option for AKs; could be used for Molluscum, maybe more so than genital warts.

Photodynamic therapy

What is the appropriate incubation time?  Two hours and maybe even one hour. This is not just treating spots, but also surface areas.

It is important to choose patients wisely and avoid overexposure.

 Atrapro versus Aurstat: Battle of the Hydrogels

  • Microcyn is the active ingredient in Atrapro. This causes stabilization of mast cells and leads to a direct anti-itch effect
  • Hypochlorous acid and sodium hydrochloride are the active ingredients Aurstat Hydrogel; therefore leading to the reduction of itching in mild to moderate atopic dermatitis
  • Both of these products may reduce the need for steroids and antibiotics and that may be where we see their potential utility

Nuvail was recently approved as a product for restoring the health of nails. Polyureaurethane is the active ingredient. Clinical data demonstrated 62% improvement after six months of treatment.

Pediatric Pearls Perfectly Repolished: Part 2 Rapamycin Sheila Fallon Friedlander, MD

In this presentation, Dr Friedlander  discusses the many clinical applications of rapamycin, a target of the P13K pathway which was previously discussed by Dr Frieden.

Is Rapamycin the new wonder drug for kids?

Rapamycin (sirolimus) is an immunosuppressant used to prevent rejection. It is a macrolide and derives from a  Streptomyces species. Rapamycin was first discovered on Easter Island (Rapa Nui) and was originally used an antifungal.. It  blocks the mammalian target of rapamycin (mTOR) pathway by affecting  cyclin-dependent pathways .  These pathways are essentially messengers which can mediate cell  proliferation, metabolism and angiogenesis.

If you think of mTOR as a conductor that is mediating the effect of various growth factors, then  if we have a substance  which can inhibit mTOR, we can impair cell proliferation, cell metabolism and angiogenesis.

Why do dermatologists care about Rapamycin?

There are several diseases with cutaneous manifestions in which  proliferation is a major component of the pathology, for which we have no safe effective treatment. There is evidence that Rapamycin may be effective in treating at least a few of these disorders; in particular  tuberous sclerosis, port wine stains have been investigated,  Rapamycin has also been utilized in an animal model of infantile hemangiomas.

It has been  established that Rapamycin significantly improves facial angiofibroma lesions in patients with TS.  What about port wine stains (PWS)? We know that PWS can recur after PDL treatment. It is hypothesized that the cell trauma of treatment stimulates new blood vessel growth.  Dr Stuart Nelson and others have conducted studies in animal models which show that rapamycin can inhibit regrowth of vessels following laser therapy.

 

Rapamycin is currently under investigation by Nelson and his colleagues to determine if PWS treatment outcomes can be improved with the use of rapamycin in addition to pulsed dye laser.

One of the challenges with Rapamycin, as found by De Klotz et al, is that of compounding the agent into the right formulation. Scientists are working on optimizing the formulation. Rapamycin is also rather expensive.

Side Effects

Because Rapamycin is an immunosuppressant we have to worry about oral ulcers, diarrhea, and infections, to name just a few concerns. Topical Rapamycin appears to have less side effects.

Rapamycin and Infantile Hemangiomas

In an animal infantile hemangioma model, rapamycin was able to suppress the growth of the tumor via the inhibition of stem cell renewal capability, vasculogenesis, and differentiation.  What’s the difference between angiogenesis and vasculogenesis?  Many healthcare providers are confused regarding angiogenesis and vasculogenesis.  Angiogenesis occurs when new  vessels sprout  and develop  from an existing vessel. Vasculogenesis is de novo new formation of a  vessel presumably from stem cells. The effect of Rapamycin is distinct from that of corticosteroids, i.e., the pathways are  very different.

The Promise of Rapamycin

Rapamycin is a topical  as well as systemic formulation that can inhibit angiogenesis, proliferation and perhaps vasculogenesis. Rapamycin also inhibits stem cell renewal. Given these characteristics, , it could well be an excellent therapy in topical formulation for both angiofibromas and PWS., and perhaps infantile hemangiomas.  However, we  do need to better investigate its possible  side effects before  utilizing on a wide scale basis.

 

 

New Drugs 2012 Part 2

Ted Rosen, MD & Neal Bhatia, MD

Imiquimod for Actinic Keratosis

There are three doses of imiquimod: 5%. 3.75% and the new 2.5% (which is approved, but not commercially available at this point).  What are their uses? Where does the 2.5% fit in? According to Dr Bhatia:

  • 5% for solid tumors or more aggressive fields?
  • 3.75% cycle therapies for routine or initial courses? It can also probably still be used for solid tumors
  • 2.5% for low-grade maintenance, weaning down from 6 week cycle, or routine for high-responders
  • Alternate among them?
  • Don’t expect any new trials or indications for awhile, so use your own experience

 

Icatibant

Icatibant is a SQ injected bradykinin B2 receptor antagonist, i.e., has a receptor affinity similar to bradykinin. Icatibant inhibits bradykinin, binding the B2 receptor; therefore, resulting in symptomatic relief and modulation of episodic flares of hereditary angioedema (HAE).

The injection is 10 mg per mL and comes as a 3 ml syringe, 25-gauge needle. Icatibant is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older. Pediatric studies are currently underway. Icatibant is dosed at 30 mg injected subcutaneously in the abdomen. If the response is inadequate or symptoms recur, additional injections of 30 mg may be administered at intervals of at least 6 hours. It is important that healthcare providers and patients know not to administer more than 3 injections in 24 hours. Patients may self-administer upon recognition of an HAE attack.

The pivotal FAST-1 and FAST-2 trials studied icatibant and showed that it had a median time to 50% reduction from baseline symptoms ranging from 2.0 to 2.3 hours. Icatibant was approved in 2011 in the US.

Belimumab

The FDA approved Belimumab (BenlystaTM) for the treatment of autoantibody positive systemic lupus erythematosus (SLE) in March 2011. Belimumab is a human monoclonal antibody that is delivered via IV infusion and targets the soluble B lymphocyte stimulator (BLyS) protein.

BLyS was discovered by the Human Genome Sciences program in 1996 and plays a pivotal role in B-cell survival and B-cell proliferation by preventing normally occurring apoptosis.  During a normal immune response to infection, BLyS facilitates more B-cells to survive, proliferate and produce antibodies to fight infection. In many patients with SLE, higher concentrations of BLyS promote increased B-cell survival including the survival of autoreactive B-cells that in turn can mature into autoantibody-producing B-cells. Belimumab does not bind directly to B cells and does not directly deplete B-cell populations but instead binds BLyS.  In doing so belimumab inhibits the survival of autoreactive B-cells and reduces their differentiation into immunoglobulin-producing plasma cells. Belimumab has demonstrated proven efficacy in reducing SLE disease activity.

Azficel-T

Azficel-T is indicated for the improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults. It is an autologous cellular product; in that, it is made especially for patients from their own skin cells which are harvested via punch biopsy which is then shipped to a specialized lab for harvesting and growth of the patient’s fibroblasts. It is best used for acne scarring and nasolabial folds. It is important that dermatologists screen for any hypersensitivity and allergies. It is also important to recognize that this product is not meant for the “impatient” patient, as one cannot see instant results.

In reality, dermatologists should keep in mind that azficel-T is not inexpensive, i.e., $1000-$2000 to create a personalized bank of fibroblasts and each injection session costs between $700 and $1,000; therefore, the total cost may range from $3,100 to $5,000. There have been isolated cases of vasculitis, collagen vascular diseases, and keloids. There is lots of potential for good outcomes as well as mistakes with the use of azficel-T.

 

New Drugs 2012 Part 1

Ted Rosen, MD & Neal Bhatia, MD

New Treatment for Orolabial Herpes

 Acyclovir 5% + Hydrocortisone 1%

This is a cream formulation that was approved in late 2009. It is designed to supplement the anti-viral effect of acyclovir with an anti-inflammatory effect of hydrocortisone. Inflammation may be responsible for some of the signs/symptoms of HSV-1. There is a concern as to whether or not corticosteroids lead to blunted immune response, worsening of lesions, and resistance; however, the answer is no.

This medication is applied five times daily for five days, starting at prodrome if possible. Success parameters demonstrate:

  • Reduced percent ulcerated:  58% v 74%
  • Reduced time to healing: 1.4 days
  • Reduced lesion size: 78 v 155 mm2
  • Reduced duration pain: 1 day
  • Well tolerated; No major AEs
  • No TK mutations or acyclovir resistance

There is still a good reason to use topical therapy. There are few real or potential side effects. There are also no drug-drug interactions to consider. With topical therapy, there are no long-term health concerns. Other reasons to consider topical therapy include:

  • Easily portable, easily started quickly
  • Directed therapy: onto the pathology
  • Patient empowerment
  • Makes sense: wound healing
  • Cost effective
  • It works….sometimes

New Treatment for Post-herpetic Neuralgia (PHN)

PHN is burning and throbbing that persists after zoster that typically occurs after 90. It is most prevalent in patients over 50 and who have pain greater than 4 at onset. PHN occurs in 9-73% of all zoster cases. It is important that healthcare providers understand that PHN can be difficult to treat.

Treating PHN

Dr Rosen prefers to treat his patients with gapapentin 900 to 1800mg/day (divided dose, TID), pregabalin 150-300 mg/day (divided dose, BID), or the new extended release gabapentin once daily, which was approved in October of 2011. With this new product, patients begin with a 30-day “Starter Pack” to titrate, and then switch to 600mg (three as single dose, QD). It is given QD with evening meal (dinner). Data demonstrated over an 11-week study (2 weeks titration, 8 weeks active therapy and 1 week taper off), the drug far surpassed placebo in its ability to reduce pain. 50% of patients achieved > 30% improvement in pain scores and mean decrease of 2.1 on a visual analog pain scale (0-10). The most common side effects included dizziness (11%) followed by somnolence (4.5%), headache (4.2%) and peripheral edema (3.9%) (> edema, > age).

The Capsaicin 8% Patch is another new treatment for PHN. It works through transient stimulation and then the depletion of nociceptive (TRPV1) nerves. Each patch contains 179mg capsaicin. The healthcare provider, who should wear nitrile, not latex gloves, applies the patch. This is important as the capsaicin penetrates latex. Patients are given a local anesthetic prior to its application. Up to four patches can be applied over painful areas for 60 minutes. When removing the patch, healthcare providers should wipe the area with the supplied cleanser. The patch can be used once every 3 months, as need. The most common adverse event seen with the patch is pain at application site (42%). An uncommon but notable AE is an increase in blood pressure; therefore, clinicians should use caution when utilizing this drug in patients with unstable hypertension. The site may be sensitive to heat for several hours after patch removal, and it is Pregnancy category B.

Ketorolac trolamine is a new intranasal spray analgesic used for post-surgery or herpes zoster. It is a metered dose, one spray in each nostril every six hours and is dispensed as a “five pack” for five days of use. One of the major benefits of ketorolac trolamine is that is provides an analgesic effect similar to an opiate without accompanying sedation. (If patients are old or thin, the dose is decreased)

This treatment can facilitate GI ulcer/bleeding and should not be used in patients with a duodenal ulcer or gastric perforation, or patients with a history of GI bleeding. It shouldn’t be used in patients with advanced renal sufficiency or in the third trimester of pregnancy. The most common AE (15%) is transient nasal irritation, which lasts about five minutes; the next most common AE is transient lacrimation (5%).

New Hepatitis C Medications

Dr Rosen points out that, as a dermatologist, one may not administer the medications for HCV; however, a dermatologist may be the one who diagnoses hepatitis C as it is associated with PCT and LP. There are two new oral drugs available, telaprevir and boceprevir. Both of these drugs inhibit NSE-4A, the protease required for viral replication. They are not used as monotherapy (used with ribavirin and peginterferon-alpha). 60-88% of patients on these drugs achieved viral clearance, i.e., no viral RNA detectable 6 months after the last dose. One of the side effects of these products is anal itching and/or anal pain; therefore, as a result these patients may be back in your office.

HPV Vaccinations

Healthcare providers should be aware that HPV affects males as well.  The quadrivalent HPV vaccine has shown to be effective (per protocol) in 90+% of boys and men age nine through twenty-six. It is effective (per protocol) in 74% at preventing anal cancer in MSM when vaccinated at ages 16-26. The vaccine is FDA approved for use in males, ages 9-26 and the Advisory Committee on Immunization Practices now recommends the use of this vaccine in males, as does the American Academy of Pediatrics.

The standard dosing of the quadrivalent HPV vaccine-dosing regimen is 0, 2, and 6 months. It turns out; however, that 0, 3, and 9 months as well as 0, 6 and 12 months was equally effective which is important because many patients tend to miss follow-up dosing.

Anti-IL12/23p40 Antibodies in the Treatment of Psoriasis and Psoriatic Arthritis

Craig Leonardi, MD

The much anticipated introduction ustekinumab (Stelara®) for the treatment of moderate to severe psoriasis came about in 2010.  This fully humanized monoclonal antibody directed against the p40 subunit of IL 12 and 23 has demonstrated in phase II and III studies that it is a “high performance” drug: fast acting, long duration of action and great efficacy.  However, according to Craig Leonardi, MD, a principal investigator for ustekinumab, there appears to be a potential cardiovascular safety signal which came in the form of MACE events (Major Adverse Cardiovascular Events ie myocardial infarction, stroke and sudden death).  These MACE events appear to be a “class effect” as it is also found in the other anti p40 antibody briakinumab, which is in phase III development.  When both phase II and III data were analyzed for both anti-IL12/23 blockers there were 10 MACE events in the 3,100 drug treated patients and none in the 1,400 placebo treated control group. Because these studies are not powered to demonstrate statistical significance of this small but finite signal none was found.   It should be noted that MACE events do not encompass other cardiovascular signals such as angina, coronary bypass surgery or TIAs. The incidence of these non-MACE events is unknown.  This MACE safety signal has not found in the numerous trials involving thousands of moderate to severe psoriasis patients who received anti-TNF therapies who presumably have the same metabolic risk factors for MACE events.  Comparator groups such as those found in the Framingham study population really do not apply. Drug study populations preselect for healthy patients.  The placebo-controlled group is still the best comparator group and there were at least 1,400 patients in that group for both.

Dr Leonardi pointed out that MACE events occur early in the course of the drug therapy, usually within the first 8 months and level off.  Speculation regarding a mechanism for the MACE events would likely involve some form of plaque disruption. There is some independent investigational data that demonstrate a significant rise (a 13-fold increase) in serum p40 levels at week 12 which decrease back to baseline by 8 months after injection of these anti- p40 molecules.  This finding seems counter intuitive to what one would expect after introducing an antibody against p40 cytokines.   The elevation likely comes from an intracellular reservoir that enters into the serum over a period of time. Interestingly, the course of p40 subunits in the serum roughly parallels the development of MACE events. It is known that p40 can dimerize and become pro-inflammatory which if we continue on our speculator path could lead to plaque disruption and a MACE event.

Briakinumab’s application to the FDA for approval has been pulled and in July of 2011 Abbott halted all clinical trials involving briakinumab pending further evaluation of MACE events. Additionally there are many questions to be answered including regarding briakinumab’s early SAE’s such as infections  cutaneous and systemic squamous cell carcinomas reported in the first 28 weeks following the introduction of the drug in study patients.

Unlike the history behind TNF inhibitors which had long-term safety profile in the rheumatology and gastrointestinal field the IL 12/23 blockers are new and dermatology specific. In light of the current cardiovascular signal where does ustekinumab fit in our therapeutic tool box for psoriasis patients?

Dr. Leonardi’s Recommendations:  It should be understood that this is a “class effect” of the IL 12/23 blockers not observed in analysis of TNF inhibitor safety data.  Consider all options when selecting a biologic therapy.  Patients with moderate to severe psoriasis typically have cardiac risk factors.  Consider starting with a low dose regardless of the patient’s weight.  Although there is not data to support its use consider starting a patient on 81 mg of ASA.  Await further analysis of the safety data. Unlike the anti TNF therapies that came to us from rheumatology and gastroenterology, the IL 12/23 blockers have no point of reference.  Scientific analysis of the p40, IL 12 and IL 23 serum levels during long term treatment.

To add to Dr. Leonardi’s recommendations, in my patients with early signs of psoriatic arthritis such as enthesitis (inflammation of the insertions of ligaments and tendons into bone) with possible early join involvement I still favor the use of anti-TNF therapy when considering a biologic agent because of their longstanding efficacy in psoriasis patients with early signs of psoriatic arthritis.

Post Maui Derm Footnotes:

Since Dr. Leonardi’s presentation a paper co-authored by Dr. Leonardi discussing this potential safety signal among antii-IL 12/23 antibodies was published in JAMA (JAMA Aug 24/31 Vol 306 No. 8 (864 -871).  The article concluded: “Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti–IL-12/IL-23 antibodies or anti–TNF treatments. This study may have been underpowered to identify a significant difference.”

Centocor recently released Stelara’s 4-year safety data, which did not demonstrate any new safety signals. This comes as good news particularly when one considers that the appearance of Raptiva’s (efalizumab) safety signal (PML) occurred at year 4.