Immune modulators offer promising outcomes

Immune system modulators are changing the ways in which dermatologists treat inflammatory skin diseases. But how best to use these medications and for which skin diseases isn’t always clear.

“Immunomodulation is a very generic term. In some cases you want to dampen or turn inflammation off; in others, you want to turn it on,” says Adam Friedman, M.D., associate professor of dermatology and director of translational research at George Washington School of Medicine and Health Sciences.

It’s important for dermatologists to have their fingers on the pulse of skin pathophysiology, according to Dr. Friedman, who co-directed the session, “Treating Tumors and Inflammatory Skin Diseases with Immunomodulators and Biologics,” at the February 2018 American Academy of Dermatology (AAD) annual meeting.

“Our understanding of how the immune system works, for example, enables us to utilize and even develop therapies that target the specific biological dysfunction,” Dr. Friedman says.

The potential for using medications that impact the immune system are vast, with new injectables, orals and topicals continuously entering the market, he says.

Starting with cancer

Dermatologists and others are using immunotherapies to augment immune response to better attack skin cancers. The FDA is helping by fast tracking many of the approvals for immunotherapies for melanoma, as well as approving combinations of immunotherapies to target melanoma, according to Dr. Friedman.

The FDA’s approval of combination immunotherapies makes it easier to get treatment for advanced melanoma covered by insurance, he says.
Among the drug classes taking aim at melanoma: anti PD1 (programmed death 1) antibodies or inhibitors, of which there are two approved, and T cell stimulating agents such as ipilimumab (Yervoy),  according to Dr. Friedman.

“So far, the lesson learned is that combination therapy is king. One of these drugs, alone, works, but isn’t perfect. Together or sequentially, they work much better,” he says.
Researchers also are utilizing immunomodulators for vitiligo and alopecia areata treatment. While these are clinically very different diseases, they’re actually quite similar from an immunology perspective, according to Dr. Friedman.

In this space, the focus is on janus kinase (JAK) inhibition, he says.

“It’s an extremely promising area that has been shown not only in animal models, but also in human trials,” Dr. Friedman says. “The nice thing is these are oral medications, versus injectables.”

Off-label uses for immunomodulators, biologics

There is considerable opportunity to use biologic agents to treat conditions that go beyond the FDA-approved indications, including for inflammatory dermatoses that may either be too rare to have gotten an indication or as another option in certain conditions where numerous first-line treatments have failed, according to George Han, M.D., Ph.D., dermatology chair at Mount Sinai Beth Israel, who co–directed the AAD session.

“Our armamentarium of immunomodulatory agents is still in relative infancy, and we're just at the tip of the iceberg with regards to the variety of conditions these medications can treat,” Dr. Han says. “Unfortunately, the FDA review process necessitates an investment and a certain number of patients with a disease process to test it on to obtain official clearance, which is often impractical for some of the conditions we regularly treat.”

Considering these medications, despite the hurdles, can transform patients’ quality of life, he says.

“For off-label use, there is always some amount of risk involved because there's less data about using the medication for indications other than what's approved. However, most of these patients that we're thinking about using biologics off-label for, have already failed the first-line and other therapies,” Dr. Han says. “I think that as long as the physician establishes a strong relationship with the patient, and underlines the risks of the medication (which are the same as if one were prescribing it on-label), along with the fact that it is being used off-label but with some evidence of success, the patient is usually on board.”

The big challenge, however, is the battle with insurance companies to get these medications covered for off-label use, he says.

“A strongly worded letter is often necessary to try to obtain coverage, along with evidence of success in other cases (i.e. literature references). Sometimes obtaining samples from the drug manufacturer is an option. The advice to avoid any problems is the same as the advice to avoid issues in any practice: document, document, document!” Dr. Han says.

Dermatologists should review the evidence in order to select rational off-label uses for biologics, according to Dr. Han.

“[By doing so,] we can greatly expand our repertoire of treatment for many inflammatory skin conditions, including immuno-bullous diseases,” he says.

cAMP, cannabinoid connections

There’s strong interest in dermatology for developing drugs to inhibit phosphodiesterase 4 (PDE4), a protein that breaks down cyclic adenosine monophosphate, or cAMP. Two such medications are approved: apremilast, for psoriasis, and crisoborole, for atopic dermatitis, according to Dr. Friedman.

“These drugs bind to certain elements of the PDE4 enzyme, which result in less breakdown of cAMP,” Dr. Friedman says. “I think certainly blocking this protein and increasing cAMP in the cells, in inflammatory diseases like eczema and psoriasis, has a benefit. And PDE4/cAMP biology is certainly important to a lot of inflammatory and neoplastic diseases.”

But questions remain, even with drugs in the class which are already approved, about how to optimize treatment, he says.

“These drugs are ok. They work. But they’re not amazing,” Dr. Friedman says. “So, is there a better way to do it? That research is ongoing, much of which is being pioneered by my friend and colleague Dr. Jonathan Zippin at Weil Cornell.”

Dr. Friedman, who addressed the potential of cannabinoids for the treatment of inflammatory and neoplastic skin diseases during the AAD session, says a lot of what researchers know today about the human endocannabinoid system is from studies on recreational drug use.

“We have two receptors in our bodies for cannabinoids: CB1r, which is heavily expressed in the central nervous system, and CB2R, which is expressed by numerous immune cells and organs,” he says. “If it wasn’t for the interest in things like THC [tetrahydrocannabinol], which is the psychoactive cannabinoid component from the cannabis plant, we would never have learned that we have this inherent endocannabinoid system.’’

Unlike the biological active molecule THC, which binds to CB1r, the molecule cannabidiol (CBD) binds to CB2r. which is expressed by immune cells, the spleen and lymph nodes to name a few, and therefore has no binding affinity for the central nervous system. Researchers, according to Dr. Friedman, are looking at how to make synthetic and other cannabinoids more bioavailable or bind better to specific CB receptors, according to Dr. Friedman.

“A great example is ajulemic acid, a synthetic cannabinoid made from THC but changed in a way that it predominately binds to CB2r and not CB1r. I think of all the things out there, this is the furthest along in terms of treating complex medical dermatologic diseases. Corbus Pharmaceutical has already executed several clinical trials in dermatomyositis and scleroderma using an oral form of ajulemic acid with very promising result,” he says.

There are in fact a good number of basic science papers looking at the mechanism by which cannabinoids can have utility in treating nonmelanoma and melanoma skin cancer and inflammatory skin diseases in major scientific journals, including the Journal of Clinical Investigation (JCI) and Journal of Investigative Dermatology, he says.

“For inflammatory diseases, there is some animal model data [cannabinoid treatment] for eczema. For acne, there’s one paper in the JCI using human sebocytes that highlights cannabidiol’s ability to inhibit sebum production and also key inflammatory signals such as IL-1b that are released from sebaceous glands which exposed to validated stimuli. There actually is nothing, short of oral retinoids, that can inhibit sebum production and inflammation, so there’s tremendous potential there,” Dr. Friedman says.

Dr. Friedman is conducting research on how to better deliver topical cannabinoids, which are highly lipophilic and poorly penetrate the skin barrier.

“You need a unique way to deliver them in order to capitalize on all of the preclinical we have to day. That’s where my work in nanotechnology comes in, which is the development of materials at the nano (1 billionth) meter scale, also known as the scale of cellular biology,” he says. “To overcome some limitations with topical cannabinoids, we encapsulated an endocannabinoid called AEA, or anandamide, and studied it in a validated mouse model of cutaneous lupus…. In this model, we allowed the animals to develop skin disease and then treated it with a topical nanoparticle formulation. It worked, clearing the lesions; whereas, the untreated group got worse and worse.”
The research is early, but promising, Dr. Friedman says.

“The nice thing about using an endocannabinoid is it’s not a controlled substance,” he says. “There is a lot of promise but a lot of controversy. If we allow the social and political hang-ups about the recreational use get in the way of really good science, it would be a shame.”

Disclosures:

Dr. Friedman is an investigator with Aclaris Therapeutics; a speaker and faculty member for Allergan; and advisor, speaker and educator for Amgen, Janssen Biotech and Regeneron; a speaker for Bayer; an advisor for La Roche-Posay Laboratorie Pharmaceutique; and a consultant for Dermira, Eli Lilly and Company, Encore Dermatology, Exeltis, Galderma USA, IntraDerm Pharmaceuticals, Johnson and Johnson Consumer Products Company, Oculus innovative Sciences, Pfizer and Sanova Works. He is an advisor for Menlo Therapeutics and Novartis. He is a speaker for Orlando Dermatology Aesthetic & Clinical; He is an advisor and speaker for Promius Pharma. He is an investigator for Valeant Pharmaceuticals International, and advisor for Valeant Pharmaceuticals North America. Dr. Friedman is co-inventor of the nanoparticle platform listed, which has been licensed to Zylö Therapeutics, a nanotechnology-based biopharmaceutical company.

Dr. Han is an investigator for Celgene and MC2 Therapeutics. He is a speaker for Pfizer, Regeneron Pharmaceuticals and Sanofi. And he is an investigator for Janssen and Eli Lilly.

References:

F003 “Treating Tumors and Inflammatory Skin Diseases with Immunomodulators and Biologics,” American Academy of Dermatology 2018 annual meeting. Adam J. Friedman, George Han, Edward W. Cowan, et al. 9-11 a.m., Friday, February 16.