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Addressing Antibiotic Resistance With Combination Therapies for Acne
Published Tuesday, February 23, 2016 by Fred Zucker
Antibiotic resistance is the phenomenon where microorganisms adapt to antibiotic drugs, rendering the drugs ineffective in destroying the bacteria they were designed to kill.  The World Health Organization has called antibiotic resistance a “global health crisis” and “one of the greatest challenges for public health today.”  In November, WHO launched the first World Antibiotic Awareness Week in a bid to better educate people worldwide on how to best slow the growth of antibiotic resistance.

Antibiotics are used to treat a vast array of bacterial infections, such as skin/wound infections, pneumonia, strep throat, urinary infections and meningitis.  For more than 50 years, antibiotics have also been used to treat skin conditions like acne and rosacea, perhaps more than people realize.  In fact, even though dermatologists make up only one percent of U.S. physicians, they account for five percent of all antibiotic prescriptions.  This lengthy exposure, in combination with overuse and misuse, has the potential to contribute to the antibiotic resistance problem, a fact dermatologists are much more mindful of today.

Acne, For Example

A known cause of acne is the bacteria Propionibacterium acnes (P. acnes), an anaerobic, gram-positive bacterium that is part of the skin flora.  In a ten-year study in England, researchers discovered that the percent of patients carrying P. acnes strains that were resistant to commonly used anti-acne antibiotics, such as erythromycin and clindamycin, rose from 34.5 percent in 1991 to 55.5 percent in 2000.  The implications can run deep, considering that anti-acne drugs like clindamycin and doxycycline are also used to treat serious forms of Methicillin-resistant Staphylococcus aureus (MRSA) infections.

As noted in a recent article in Dermatology Today, antibiotics remain a staple in skin care, but dermatologists are also employing alternatives and combination therapies, a proactive approach to improve outcomes and help limit the development of antibiotic resistance.  Combinations often involve topical and systemic treatments that leverage both antibiotic and anti-inflammatory properties of products to treat skin conditions.  Long-standing drugs like erythromycin and clindamycin are available in topical formulations and are known to be effective acne treatments.  However, as noted in the Acne Guidance of the American Academy of Dermatology, “the use of these agents alone can be associated with the development of bacterial resistance.”

Studies show that resistant strains of P. acnes can emerge in as little as eight weeks of topical antibiotic monotherapy.  Utilizing complementary drugs with different mechanisms of action can deliver a clinically meaningful effect on slowing resistance development.  Ideally, it makes sense for dermatologists to use a multimodal approach, prescribing different drugs initially and then transitioning to non-antibiotic topicals.

Retinoids

Topical retinoids, drugs that are related to Vitamin A, are important as a front-line treatment for acne.  They work by unplugging clogged hair follicles that are at the root of acne, which also allows other medicines, such as topical antibiotics, to be more effective.   Topical retinoids include Nestle subsidiary Galderma’s Differin (adapalene), Allergan’s (NYSE: AGN) Tazorac (tazarotene) and tretinoin, which is marketed under many brand names and listed on the World Health Organization's List of Essential Medicines.

Retinoids, as an oral therapy for severe acne, came under scrutiny through isotretinoin, an effective, albeit sometimes controversial, drug. The drug was developed by Roche Pharmaceuticals (OTC: RHHBY) and eventually marketed as Accutane before Roche pulled it from the market over safety concerns in 2009, namely related to birth defects and inflammatory bowel disease.  However, follow-on studies painted a clearer picture as to the potential side effects and led to increasing usage today.  Roche’s patents on isotretinoin expired in 2002 and the drug is now available under multiple brand names, including Absorica by Mylan (NASDAQ: MYL) and Claravis by Teva (NYSE: TEVA).  Because of systemic toxicity and potential side effects, isotretinoin is still only meant to be used once other treatment options have been exhausted.

New Approaches

New medicines are available, or coming down the pipeline, that take a different route in treating acne.  Derm companies in this space are looking to provide better and safer treatment options and take a piece of a market forecast by Research and Markets to reach $3.02 billion in 2016.

Oculus Innovative Sciences (NASDAQ: OCLS) has built a portfolio of dermatology products founded upon its Microcyn® Technology to treat conditions by reducing infections, itch, pain, scarring and harmful inflammatory responses.  These are all responses that need to be addressed in many skin conditions, including acne.  The science of Microcyn centers on manufacturing a pH neutral solution of hypochlorous acid (HOCl), a natural bactericidal acid created on demand by the body’s white blood cells or neutrophils.  Published research shows that in an 89-patient clinical study Microcyn outperformed the commonly used acne treatment benzyl peroxide in reducing inflammation of lesions, although the improvement was not considered statistically significant and a larger trial is needed.

Importantly, HOCl has demonstrated to be potent and fast acting through targeting non-specific biomolecules on bacterial cell membrane. It is widely documented that HOCl readily reacts with a wide range of biomolecules including DNA strands, RNA strands, fatty acid groups, cholesterol and proteins amongst others. It is a highly reactive compound and upon reaction it is completely rendered neutral. Unlike antibiotics, and specifically the use of topical antibiotics, the potency of HOCl and the damage delivered to bacterial cell membranes without specificity, as reported by McKenna in 1988, infer a lack of resistance. Oculus strongly believes HOCl's mechanism of action, as opposed to the mechanism for antibiotics, drastically reduces the potential for emergence of new superbugs.

Oculus’ GramaDerm Solution and GramaDerm Hydrogel have been approved for use in Europe, with both products commercialized overseas in November as a new topical treatment of mild-to-moderate acne.  GramaDerm's marketing literature hammers three messages: (1) terrific kill times against P. acne, (2) reduction of inflammation with solid supporting clinical evidence and (3) no resistance issues due to HOCl's unique mechanism of action.

Stateside, the FDA has so far given its blessing to Oculus products for atopic dermatitis (eczema), scar and advanced wound management and animal healthcare applications.  Oculus also markets doxycycline monohydrate capsules, indicated “to reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline capsules (commonly used for moderate-to-severe acne) and other antibacterial drugs” used to treat bacterial infections.

Oculus and Maxim Group are teaming up to host a conference call with dermatology experts on Thursday, Feb. 25 to discuss these and other derm treatment issues. Details can be found here. One of the experts, Dr. Adam Friedman, recently penned an interesting piece in The Lancet, further discussing the drug resistance issue.

Dermira (NASDAQ: DERM) has in its pipeline DRM01, a novel, topical sebum production inhibitor currently in clinical development for the treatment of acne.  Sebum is an oily matter produced by sebaceous glands in the skin that when overproduced are known to play a key role in the pathogenesis of acne.  Sebum inhibition is known to improve acne, but the only approved drug that does this is the aforementioned oral version of isotretinoin.  DRM01 targets acetyl coenzyme-A carboxylase, an enzyme that plays an important role in the synthesis of fatty acids, which represent an essential component of sebum.  Because the drug acts in a dose-dependent manner, Dermira is attempting to determine the optimal dosing level in a Phase 2b trial currently.

Also in this space, the company has completed early clinical research on a topical PDE4 inhibitor dubbed DRM02 for the treatment of inflammatory skin diseases, such as atopic dermatitis, psoriasis and rosacea.  DRM05 is Dermira’s novel, topical photodynamic therapy in preclinical development for the treatment of acne.

One of the lead products of Foamix Pharmaceuticals (NASDAQ: FOMX) is FMX101, a novel topical foam formulation of minocycline for treating moderate-to-severe acne.  FMX101 delivers minocycline directly to the acne-infected sebaceous glands in the skin.  A 150-patient, 12-week Phase 2 trial showed clinically and statistically significant efficacy for patients taking FMX101 compared to the control group (taking either Solodyn, Epiduo or Aczone).  The data on FMX101-treated patients showed sharp improvements in both inflammatory and non-inflammatory lesions at six and 12 weeks, respectively, without any drug-related systemic side effects.  Larger, Phase 3 trials are expected in 2016.

In October, a Phase 2 trial began evaluating FMX103 in people with moderate-to-severe papulopustular rosacea.  Israel-based Foamix is also planning to initiate Phase 3 research of FMX102 as a new treatment for impetigo, a contagious bacterial skin infection that primarily affects young children and is typically caused by staphylococcus aureus, including MRSA.

Acne is a convenient example to demonstrate the importance of developing new drugs to avoid a post-antibiotic world, as even a common condition like acne highlights how often used drugs become ineffective.  Because it is not life-threatening like cancer or heart diseases, it is a condition that most probably don’t consider when pondering the problem of antibiotic resistance.  It also serves to show the changing dynamic to tackle the issue through innovation and combination therapies that utilize different pathways to lessen the dependence on antibiotics, a tactic that needs to make its way into other dermatological conditions.

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