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.

Cutaneous Oncology: Recent Drug Approvals Part 2

Keith Flaherty, MD & George Martin, MD

Vismodegib (ErivedgeTM) for the Treatment of Advanced Basal Cell Carcinoma (BCC)

Dr Keith Flaherty, an oncologist at MGH, spoke on ErivedgeTM for the treatment of advanced and metastatic BCC.   Historically,  the treatment of patients with advanced BCC with either metastatic or locally advanced disease employed standard chemotherapeutic regimens using agents such as cis-platinum. Reports of success were few and generally limited to individual case reports until the recent FDA approval of Erivedge® a hedgehog pathway inhibitor.

The “hedgehog pathway” (Hh pathway: Figures 1 & 2) and its role in the development of basal cell carcinomas (BCC) has been the subject of intense research over the last decade.  Aberrant activation of the Hh pathway (Figures 3 & 4) has been identified in both hereditary BCC syndrome ie Gorlin syndrome (Basal Cell Nevus Syndrome) as well as sporadic BCCs.  Gorlin syndrome patients carry a germ-line heterozygous mutation in the PTCH gene and are highly predisposed to developing multiple BCCs. Mutations in the PTCH gene (Figure 3), remove its ability to inhibit the Hh pathway through its inhibition of SMO (Smoothened protein).  Approximately 90% of sporadic BCCs have a PTCH gene mutation and an additional 10% of sporadic BCC have activating mutations in the SMO gene (Figure 4), which is downstream of PTCH, and this mutation leads to overstimulation of the Hh pathway.

Vismodegib (Erivedge®) is a hedgehog pathway inhibitor (figure 5), which binds to and inactivates SMO.  Its use is indicated for the treatment of adults with metastatic basal cell carcinoma (mBCC), or with locally advanced basal cell carcinoma (laBCC) that has recurred following surgery or who are not candidates for surgery or radiation.

Dr Flaherty presented data evaluating the safety and efficacy of Erivedge in mBCC and laBCC obtained from an international, single-arm, multi-center, open-label, 2-cohort phase II study involving 104 patients (Erivance BCC/SHH447g). Patients with laBCC either had histologically-confirmed BCC that was unresectable or were not appropriate candidates for surgery: >1 cm or 2 or more recurrences after surgery; curative resection unlikely; anticipated substantial morbidity and/or deformity after surgery.  mBCC patients had histologic confirmation of mBCC and radiographically measurable tumors. The patient demographics are listed in figure 6. Patients received vismodegib 150 mg/day orally until tumor progression or intolerable drug toxicity.

The objective response rates (ORR) were assessed by an independent review facility (IRF) and were 42.9% for laBCC and 30.3% for mBCC.  The median duration of response was 7.6 months and the median progression-free survival was 9.5 months for both cohorts.

The rate of severe toxicities (grade III + IV) for vismodegib is quite low. Mild to moderate toxicity (grades I + II toxicity) seen with vismodegib included fatigue, muscle spasms and dysgeusia (altered taste).

In summary, vismodegib is dramatically effective for BCC treatment in patients with advanced.  Approximately 80% of patients with advanced BCC have regression of disease with 30 – 60% of patients having objective responses.  Now FDA approved for patients with advanced BCC, it will be interesting to see how this drug will be used both therapeutically and in an adjuvant setting in combination with other surgical and non-surgical modalities.

 

 

Cutaneous Oncology: Recent Drug Approvals Part 1

Keith Flaherty, MD & George Martin, MD

The hot topics of discussion at Maui Derm 2012 were January’s FDA approval of two innovative products in the cutaneous oncology arena: (Picato®), ingenol mebutate 0.015% gel and 0.05% gel for the treatment of actinic keratoses (AKs) and Erivedge®  (vismodegib) for the treatment of advanced basal cell carcinoma.  At Maui Derm, Dr Martin discussed the data on Picato® and Dr. Keith Flaherty, an oncologist from MGH, discussed ErivedgeTM.

Ingenol Mebutate (Picato®): 0.015% and 0.05% gel

Ingenol Mebutate is derived from the sap of the plant Euphorbia peplus, a commonly found plant whose sap has been used in traditional medicine for the treatment of a wide variety of skin lesions ranging from warts to skin cancer. The active pharmacologic ingredient, ingenol mebutate (ingenol‐3‐angelate), has been formulated as a field therapy for the treatment of AKs.

Mechanism of Action

Extensive work has been done to determine the mechanism of action of ingenol mebutate.  In high concentrations it induces tumor cell necrosis. It also up-regulates keratinocyte and endothelial cell cytokine and chemokine production presumably via the protein kinase C (PKC) pathway.  In response to ingenol mebutate, IL-8 a neutrophil chemo-attractant is produced in significant quantities by rapidly proliferating keratinocytes and endothelial cells following exposure to ingenol mebutate.  Also upregulated in response to ingenol mebutate is the expression of adhesion molecules ICAM-1 and E-selectin by endothelial cells, which in turn promotes neutrophil migration into the treatment area. In mouse models ingenol mebutate was show to reduce mutated p53 patches of skin in UV irradiated mice compared to placebo.

Two Strengths/Two Dosing Regimens

Ingenol mebutate was approved for the treatment of AKs using two different concentrations employing different dosing regimens. Ingenol mebutate 0.015% gel applied daily for 3 consecutive days was approved for treatment of AKs of the face and scalp. Ingenol mebutate 0.05% gel applied daily for 2 consecutive days was approved for treatment of AKs on the trunk and extremities.

In two multicenter, randomized, parallel-group, double-blind, vehicle controlled pivotal phase III trials the efficacy and safety of ingenol mebutate 0.015% gel applied daily for 3 consecutive days to the face and scalp was evaluated as a field therapy (4-8 AKs in a 25 cm2 area).  Of the treated patients completing both studies, 37% and 47% of drug treated patients achieved 100% clearance compared to 2% and 5% for vehicle controls.  Partial clearance (≥ 75% lesions cleared) was achieved in 60% and 68% of drug treated patients compared to 7% and 8% for vehicle controls.  Median percent lesion reduction for drug treated side were (83.3%) and (86.6%) compared to (0%) and (0%) for vehicle controls.  These clearance rates are comparable or better than currently FDA approved AK field therapies used on the face and scalp. Hypopigmentation and hyperpigmentation were ≤ 1%.  No scarring was reported.  There was no systemic absorption of ingenol mebutate above the limit of quantification in blood samples of subjects evaluated.

The efficacy and safety of ingenol mebutate 0.05% gel applied daily for 2 consecutive days (4 – 8 AKs in a 25 cm2 area) to trunk and extremity lesions (arm, back of hand, chest, back, shoulder and leg) was evaluated in two multicenter, randomized, parallel-group, double-blind, vehicle controlled pivotal phase III trials. Of the treated patients completing both studies, 28% and 42% of drug treated patients achieved 100% clearance compared to 5% and 5% for vehicle controls.  Partial clearance ( ≥ 75% lesions cleared) was achieved in 44% and 55% of drug treated patients compared to 7% and 7% for vehicle controls.  Median lesion percent reduction for drug treated side were (69%) and (75%) compared to (0%) and (0%) for vehicle controls. Hypopigmentation and hyperpigmentation were ≤1 %. There was no systemic absorption of ingenol mebutate above the limit of quantification in the blood samples of subjects evaluated.

A 12-month follow-up study was performed evaluating patients who completely cleared their lesions during the phase III studies. No recurrent lesions were observed in 46.1% of patients treated on the face or scalp and in 44% of patients treated for trunk and extremity lesions.  The overall reduction in AKs from baseline to 12 months was 87.2% for face and scalp lesions and 86.8% for trunk and extremity lesions

Clinical Pearls

The take home points on both 0.015% and 0.05% gel is that they have comparable or better efficacy in clearing AKs in comparison to currently FDA approved field therapies, produce sustained clearance in 12 month follow-up studies, cause limited downtime (peak inflammation on day 4 for the face/scalp with resolution of scabbing by day 8; peak inflammation on the trunk and extremities by day 4 – 8 with resolution by day 15), achieve excellent patient compliance with the 3 and 2 day application regimens and induce minimal side-effects post therapy in terms of hypopigmentation, hyperpigmentation and scarring.

Immunogenicity

Bruce Strober, MD, PhD

In this presentation, Dr Strober discusses the important concept of immunogenicity as it relates to the management of psoriasis and the use of biologic therapy. There are several factors that lead to the loss of therapeutic response. These factors include drug level reduction, specifically immunogenicity, suboptimal dosing schedules (e.g. etanercept step-down dosing, infliximab every eight weeks and ustekinumab given every 84 days)  and poor patient adherence. Another issue is that of altered pathophysiology of the disease in the face of the therapy applied, i.e., one can see a loss of therapeutic response without immunogenicity.

What is Immunogenicity?

By definition, foreign proteins are immunogenic. Biologic therapies for the treatment of psoriasis are all foreign, even though they are based on natural forming molecules. Immunogenicity requires that a protein has to be more than just “foreign”, i.e., different biologic drugs exhibit different degrees of immunogenicity. Immunogenicity inhibits therapeutic response and may increase risk.

Do Biologic Medications Lose Efficacy When Treating Psoriasis?

Infliximab begins with very high efficacy, PASI 75 scores are nearly 80%; however, after about one year of Q 8 week dosing, one loses about one third of patients who initially achieved a PASI 75. This could be due to pharmacokinetics; however, in part, it is probably due to immunogenicity.

Initially, 100 % of adalimumab responders achieved a score of PASI 75, but after about two years, only three quarters of those patients were still at a PASI 75.

At week 48, 61% and 63% of patients on etanercept achieved a PASI 75; however, at week 96, that number had fallen by 18%.

Ustekinumab also demonstrated a drop-off regarding therapeutic efficacy.

Clinical Pearl-Loss of therapeutic response is part of the issue when treating psoriasis patients with biologic therapies

The Manufacturers of Biologics Acknowledge Immunogencity

 Infliximab

In psoriasis clinical trials, antibodies were observed in 20-36% of patients treated with 5 mg/kg every eight weeks for one year. A higher incidence of antibodies to infliximab was observed in Crohn’s disease patients receiving infliximab after drug free intervals for more than 16 weeks. In psoriatic arthritis studies, patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and infusion reactions, which is an important safety issue. Antibody development was lower among RA and Crohn’s disease patients receiving immunosuppressant therapies such as 6-MP/azathioprine or methotrexate.

Adalimumab

Approximately 5% of RA patients developed low-titer antibodies to adalimumab at least once during one year of treatment, which were neutralizing in vitro. Patients who were treated with concomitant methotrexate had a lower rate of antibody development than patients on adalimumab monotherapy (1% versus 12%). With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. ACR 20 responses are lower among antibody-positive patients than among those patients who are anti-body negative.

Etanercept

Antibodies to the TNF receptor portion or other protein components of etanercept were detected at least once in sera of approximately 6% of adult patients with RA, PsA, AS, or PsO. Antibodies were all non-neutralizing. The percentage of patients testing positive increases with an increase in the duration of study. There was not a correlation of antibody development to clinical response nor were there any adverse events. There was no effect with methotrexate.

Ustekinumab

In Study 1 and Study 2 looking at ustekinumab and immunogenicity, 3-5% of patients, respectively, showed antibodies against drug. 48% to 90% of patients studied were inconclusive. Data presented at a recent EADV meeting demonstrates that immunogenicity against ustekinumab correlates with reduction in response long-term.

Clinical Pearl-More frequent administration of a biologic tends to reduce immunogenicity

Should we care about “neutralizing” vs. “non-neutralizing” antibodies?

Dr Strober feels that dermatologists should really care about whether or not a drug has an antibody raised against it and if so, does the body remove the drug from circulation…?

In patients, antibodies against adalimumab and infliximab usually bind to the antigen (TNF) binding domain; therefore, they “neutralize” the ability of the drug to bind to TNF. Antibodies that are raised against etanercept fall into what’s referred to as the hinge domain that really mediates the linkage between the Fc domain and the TNF receptor domain. So, while they bind to the molecule, they do not neutralize its ability to block TNF, i.e. “non-neutralizing”.

Open Label Studies

Switching to Etanercept after Failure to either Adalimumab or Infliximab for Treatment of RA

This study evaluated 292 patients with rheumatoid arthritis. 203 patients were anti-TNF naïve. 89 of the patients had been previously treated with either infliximab (n=30) or adalimumab (n=59), and then switched to etanercept. 32% of the patients were non-responders since the start of the treatment with either infliximab or adalimumab and 68% of the patients had lost the initial response. Out of the 89 patients who switched to etanercept, 47 patients (53%) had antibodies against adalimumab or infliximab as measured at baseline prior to the start of etanercept treatment. Patients with detectable anti-drug antibodies had significantly lower doses of methotrexate at baseline compared to patients without antibodies (p=0.031).

Patients who were anti-TNF naive were compared to switchers without antibodies and a DAS28 improvement was significantly larger in patients who were anti-TNF naïve after 28 weeks of etanercept treatment. There was no significant difference in the improvement in DAS28 between patients who were TNF naïve compared to switchers with antibodies. The improvement in DAS28 was significantly larger in switchers with anti-drug antibodies compared to switchers without antibodies. This study concludes that altered disease pathophysiology may play a greater role in patients who lose response without showing immunogenicity. Immunogenicity is only part of the equation.

Anti-adalimumab Antibodies are Associated with Lower Adalimumab Concentrations and Treatment Non-response

This was a prospective observational cohort study looking at 121 consecutive RA patients treated with adalimumab and a concomitant DMARD or adalimumab alone. During 28 weeks of follow-up, antibodies were detected in 21 (17%) of patients. Serum adalimumab concentrations in patients with anti-adalimumab antibodies were significantly lower than in patients without these antibodies (median 1.2 mg/l, range 0.0–5.6 vs median 11.0 mg/ l, range 2.0–33.0; p,0.001). Non-responders had anti-adalimumab antibodies significantly more often than good responders (p=0.006).

Higher concentrations correlate with better clinical response

Extent and Clinical Consequences of Antibody Formation Against Adalimumab in Patients with Plaque Psoriasis

This was a prospective observational cohort study looking at 29 psoriasis patients, 17% (5 of 29) also had psoriatic arthritis. Patients were given standard adalimumab dosing (40 mg) every other week after an initial dose of 80 mg and a dose of 40 mg the week thereafter. Adalimumab trough concentration was measured 12 and 24 weeks after the initiation of treatment. This study correlates with the data presented above (RA) in that the lower the concentration of drug, the lower the response and low antibodies to drug demonstrates better clinical response. Three patients used concomitant methotrexate and none of these patients developed antibodies to adalimumab.

There are a lot of data that suggest that methotrexate blocks immunogenicity. There should be no doubt regarding methotrexate and therapeutic efficacy.

Patients Not Responding to Etanercept Show Lower Trough Etanercept Concentrations Compared to Responding Patients

This was a prospective, single center observational cohort study from Amsterdam. The study looked at 292 consecutive patients with active RA who were given a new etanercept prescription. Clinical response and etanercept levels were collected at baseline and after 1, 4 and 6 months of etanercept treatment. Trough serum etanercept levels were measured by ELISA.

The study showed that patients with good clinical response display significantly higher levels of etanercept than patients who were not responding. Anti-etanercept antibodies were measured by 4 different assays and no anti-etanercept antibodies were detected which is a different response from that of infliximab and adalimumab. The absolute differences in etanercept levels between responding and non-responding patients were small. Immunogenicity may not explain the lack of response in RA patients treated with etanercept.

Effect of MTX on Efficacy with Etanercept

When looking at patients who are methotrexate non-responders and who were either given methotrexate with etanercept and then tapered off the methotrexate or continued the methotrexate, it is clear that those who tapered off the methotrexate did not respond as well; therefore, demonstrating that methotrexate has some effect on etanercept response.

A Basic Approach to Moderate to Severe Psoriasis or Psoriatic Arthritis

Healthcare providers should initiate therapy with methotrexate and allow 12 weeks to demonstrate a response. If methotrexate monotherapy is inadequate, a biologic should be added. Dr Strober continues the methotrexate indefinitely because of the data that demonstrates a better clinical response.

Conclusions

  • Biologics should be dosed without interruption and at intervals that make sense with regard to the drug’s half-life.
  • Concomitant MTX (or, possibly, azathioprine) blunts immunogenicity
  • When given with MTX, biologic agents invariably show greater and more durable efficacy, even when MTX is ineffective as monotherapy
  • A sensible practice is to add a biologic therapy to MTX, not vice versa, as once immunogenicity occurs it may be difficult to reverse