Head-to-Head in Psoriasis: Brodalumab vs Ustekinumab

It has been unusual for companies to risk direct comparisons of new agents with recent vintage competitors, but that is beginning to happen in the crowded market for biologic agents in psoriasis.  It is also important to note that the trend toward a higher bar for efficacy assessment of treatments for this disease is continuing with a 100% reduction in the psoriasis area-and-severity index score (PASI 100) being used as the benchmark for efficacy.

In two phase III studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomized to brodalumab, ustekinumab, or placebo.

The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with the primary endpoint being the percent of patients achieving at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician’s global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to PASI 100.

At week 12, PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (AMAGINE-2, 44% vs 22%; AMAGINE-3, 37% vs 19%; P<0.001).

Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo and mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo (Lebwohl, 2015).

References

Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318-28.

Lasers: Red vs Blue in PDT

Its Blue

A study reported late last year was carried out to determine whether prior microneedling would enhance the penetration of topical aminolevulinic acid HCl (Levulan) and thus enhance photodynamic therapy (PDT) and possibly also result in a better cosmetic outcome vs PDT alone in patients with AKs.

In this trial, 20 patients each with ≥4 non-hyperkeratotic AKs on each side of their faces were randomized to receive multiple passes with a microneedling device on one side of their faces, followed by application of aminolevulinic acid HCl to the entire face.

The aminolevulinic acid HCl was allowed to incubate for 1 hour and this was followed by exposure to blue light (Blu U) for 1000 seconds.

For the 19 patients who completed 4 months of follow-up, the mean AK reduction on the microneedling side was 89.3% vs 69.5% on the PDT alone side. In addition, 13 of the 19 patients had a noticeable improved cosmetic appearance on the microneedled side of the face (Spencer, 2016).

No, Its Red

Aminolevulinic acid hydrochloride (BF-200 ALA, Ameluz) was recently approved by the United States Food and Drug Administration for PDT using the BF-RhodoLED lamp, a narrowband, red light illumination source, for lesion-directed and field-directed treatment of AKs of mild-to-moderate severity on the face and scalp.

This approval was based on results from 779 patients with 4-8 mild to moderate AK lesions. The results obtained from these studies demonstrated that BF-200 ALA was significantly superior to the standard of care, with a complete patient response rate of 91% when paired with BF-RhodoLED PDT lamp (CenterWatch, 2017).

In addition, BF-200 ALA showed positive long-term effects with low recurrence over the course of 12 months (Dirschka, 2013).

In a pivotal phase III trial performed on entire treatment fields, BF-200 ALA demonstrated long-lasting skin rejuvenation effects in sun-damaged, but asymptomatic, skin regions (CenterWatch, 2017; Reinhold, 2016).

References

CenterWatch. Ameluz (aminolevulinic acid hydrochloride). 2017. Available at: http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100150/ameluz-aminolevulinic-acid-hydrochloride

Dirschka T, Radny P, Dominicus R, et al. Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis. Br J Dermatol. 2013;168:825-36.

Reinhold U, Dirschka T, Ostendorf R, et al. A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz(®) ) vs. placebo in the field-directed treatment of mild-to-moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED lamp. Br J Dermatol. 2016;175:696-705.

Spencer JM, Freeman SA. Microneedling Prior to Levulan PDT for the Treatment of Actinic Keratoses: A Split-Face, Blinded Trial. J Drugs Dermatol. 2016;15:1072-4.

5-Fluorouracil (5-FU): 4% vs 5% for the Treatment of Actinic Keratosis

While oxymetazoline HCl cream, 1% and bromocriptine gel, 0.33% were not compared in a head-to-head trial, this has been done for 4% 5-FU in an aqueous vehicle cream containing peanut oil (Tolak) vs 5% 5-FU in a vanishing cream (Efudex) in patients with actinic keratosis (AKs).

In a 4-week, double-blind, multicenter non-inferiority study that included 841 subjects, 4% 5-FU cream administered once daily was compared with 5% 5-FU cream twice daily with 100% and 75% clinical clearance of AK’s assessed as the study endpoint.

4% 5-FU achieved 100% clearance in 80% of patients and 75% clearance in 100% of patients compared with 75% and 95%, respectively, with 5% 5-FU.

Skin irritation occurred in 30% of patients treated with 4% 5-FU vs 60% with 5% 5-FU.

It was also noted that the peanut oil component of the 4% 5-FU preparation is safe even in peanut-allergic patients.

Thus, 4% 5-FU is non-inferior to 5% 5-FU with better tolerability and permits once-daily administration which may result in better adherence to therapy (Dohil, 2016).

References

Dohil MA. Efficacy, safety, and tolerability of 4% 5-fluorouracil cream in a novel patented aqueous cream containing peanut oil once daily compared with 5% 5-fluorouracil cream twice daily: meeting the challenge in the treatment of actinic keratosis. J Drugs Dermatol. 2016;15:1218-1224.

Oxymetazoline Hydrochloride 1% Cream for Rosacea

Oxymetazoline hydrochloride (HCl) cream, 1% (RHOFADE), an alpha-1A-adrenoceptor agonist and a partial agonist at the alpha-2 receptor, was approved in January of 2017 and is indicated for the treatment of persistent facial erythema associated with rosacea in adults. Nasal sprays containing a lower concentration of oxymetazoline HCl have been used off-label to treat rosacea for many years, and oxymetazoline hydrochloride (HCl) cream, 1% is the first approved treatment using this compound (Smith, 2017).

In two clinical trials, once-daily application of oxymetazoline hydrochloride (HCl) cream, 1% reduced persistent facial erythema associated with rosacea through 12 hours.  After 29 days of treatment, patients achieving clinical success at 12 hours were 15% vs 6% for placebo in one study and 12% vs 6% in the second trial (RHOFADE PI, 2017).

Oxymetazoline HCl cream, 1% is not the first adrenergic agent approved for the treatment of rosacea. Brimonidine topical gel, 0.33% (MIRVASO) is an alpha-adrenergic agonist indicated for the topical treatment of persistent facial erythema of rosacea in adults that has been available since 2013 (MIRVASO PI, 2016).

Which of these two preparations is a better choice for your patient?  There is no head-to-head comparison of these treatments, so it is hard to know. Combined assessment of results from different studies (for example, with network meta-analyses) has now become a fairly common approach for comparing treatments that have never been tested vs each other, but that has not been accomplished for these drugs.  A look at the labels for the two agents suggests that effect sizes for oxymetazoline HCl cream, 1% and bromocriptine gel, 0.33% are very similar, but that application site erythema may occur more often with bromocriptine gel, 0.33% than with oxymetazoline HCl cream, 1% (RHOFADE PI, 2017; MIRVASO PI, 2016).

References

MIRVASO (brimonidine) topical gel. 2016. Available at: http://www.galdermausa.com/PI/MirvasoPI.pdf

RHOFADE (oxymetazoline hydrochloride) cream, for topical use. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208552s000lbl.pdf

Obiltoxaximab: A Monoclonal Antibody for Cutaneous Anthrax

You should certainly hope that you will never have to use it, but it is still important to know about obiltoxaximab (Anthim), a monoclonal antibody administered by injection, that has been approved for treating inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs in adult and pediatric patients.

It is also approved for prophylaxis of inhalational anthrax when alternatives are not available or appropriate (Kaufman, 2016).

Why should dermatologists care? Because the most common type of human anthrax is the cutaneous form. Other forms of human anthrax (gastrointestinal, inhalational, or injectional) are rare (Kajfasz, 2014).

It is expected that the main use of obiltoxaximab is likely to be in the setting of bioterrorism, but it might also be effective for the rare patient in your practice with cutaneous anthrax.

References

Kaufman MB. Pharmaceutical Approval Update. P T. 2016;41:355-6.

Kajfasz P, Bartoszcze M, Borkowski PK, Basiak W. Retrospective review of the case of cutaneous anthrax-malignant pustule from 1995 in 15-year old girl. Przegl Epidemiol. 2014;68:657-9.

Crisaborole: New Treatment for Atopic Dermatitis

Crisaborole (EUCRISA) is a novel non-steroidal topical ointment for mild to moderate atopic dermatitis (AD, eczema) that was approved in December of 2016. Topical agents are the mainstay of AD therapy and current guidelines recommend both corticosteroids, and topical calcineurin inhibitors (Eichenfield, 2014).

Agents in both of these classes are effective, but may be limited by application reactions and safety concerns with extended use.  Crisaborole is a phosphodiesterase 4 inhibitor (PDE-4) inhibitor with a mechanism of action that has been described for apremilast (Otezla), the oral drug used to treat psoriasis (Moustafa, 2014).

Two identical, vehicle-controlled, double-blind studies showed that crisaborole was significantly more effective than vehicle in achieving ≥2-grade improvements in Investigator’s Static Global Assessment (ISGA) scores in patients with AD (P<0.05 for both studies).

Crisaborole also provided significantly more rapid relief from itch than vehicle. As you know, this is a very important consideration for patients with AD since itch is generally the most bothersome symptom in this common disease.  In addition, itch typically results in scratching which can promote lesion formation and/or transformation to a chronic lichenified state (Turner, 2014).

The majority of treatment-related adverse events with crisaborole were application site pain, primarily reported as burning or stinging. This pain was the only treatment-related adverse events that occurred in ≥1% of patients (Paller, 2016).  Perhaps the main advantage of crisaborole over available topical therapies is avoidance of the potential long-term risks associated with these agents (Zane, 2016).

References

Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71:116-32.

Moustafa F, Feldman SR. A review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4-inhibitors in clinical dermatology. Dermatol Online J. 2014;20:22608.

Turner MJ, Zhou B. A new itch to scratch for TSLP. Trends Immunol. 2014;35:49-50.