Biological Cross Fire: Takeaways from the Biologic Therapies Summit

Highlights of Cleveland Clinic’s recent Biologic Therapies VI Summit included an unprecedented session titled “Biological Cross Fire: What Can We Learn From Each Other?” It brought together six expert physicians from diverse disciplines to spotlight how biologics are being used or studied in interesting ways in their specialties.

Free CME-certified webcasts of all six presentations from this unique session are available at ccfcme.org/BioVIOnline. For a taste of what’s in store there, below is a recap of key points from two of the talks.

Biologics in RA: A focus on Tregs

Leonard Calabrese, DO, the R.J. Fasenmyer Chair of Clinical Immunology at Cleveland Clinic, outlined new approaches for augmenting peripheral regulatory mechanisms in the treatment of autoimmune diseases, or “diseases of faulty tolerance,” including rheumatoid arthritis (RA).

In normal immune systems, attacks from self-specific effector T cells are held in check by regulatory T cells (Tregs). “Every one of us has autoreactive T cells to central and native proteins, but for some reason we keep them under control,” Dr. Calabrese explained.

An imbalance resulting in underexpression of Tregs — whether they’re deficient or defective — is postulated to cause an imbalance leading to autoimmunity or chronic graft vs. host disease. One therapeutic approach aims to control autoimmune disease and inflammation with low doses of the cytokine interleukin 2 (IL-2), a T cell growth factor required for initiating clonal expansion of T cells in response to antigen.

“Knowing that humans have these cells that bear the IL-2 receptor and are very susceptible to the presence of IL-2, there has been a paradigm created that these cells may not only be responsible for autoimmunity, but might be manipulated,” Dr. Calabrese noted.

Various approaches being studied

One such effort is an ongoing protocol called TRANSREG, in which French researchers are using low-dose IL-2 to induce Tregs in a set of 11 autoimmune and autoinflammatory diseases including RA, spondyloarthritis and systemic lupus erythematosus.

Another approach involves selective Treg activation to strengthen the body’s natural ability to prevent excessive autoinflammatory reactions, as with the investigational humanized monoclonal anti-CD4 antibody tregalizumab. In contrast to other monoclonal antibodies, tregalizumab activates the suppressive properties of Tregs without activating effector T cells, and does not induce cytotoxicity.

Although the phase 2 TREAT 2b study of tregalizumab for methotrexate-refractory active RA failed to meet its primary end point, “this remains an enticing pathway,” Dr. Calabrese said.

Biologics in psoriasis: All about options

Five biologics are currently approved by the FDA for treating moderate-to-severe psoriasis vulgaris, and they all offer significant efficacy. In that context, two issues loom especially large, according to Anthony Fernandez, MD, PhD, Director of Medical Dermatology at Cleveland Clinic:

• Adequately assessing which patients qualify for treatment
• Carefully tailoring choice of agent to the patient’s profile and preferences

Psoriasis severity is typically defined by how much body surface area is affected: Less than 3 percent is considered mild; 3 to 10 percent is moderate; and more than 10 percent is severe.

But it’s increasingly clear that other aspects of the disease, including physical symptoms and psychological impact, must be taken into account. “Some patients with mild overall body surface area involvement have overall moderate-to-severe disease when physical and/or psychological impact is assessed,” said Dr. Fernandez.

He noted that 83 percent of patients in a recent survey reported skin pain that interfered with their daily activities, particularly when lesions were present on the palms and/or soles. Nearly all patients (93 percent) reported pruritus, with more than half reporting that it interfered with their sleep. Moreover, when psoriasis involves sensitive areas such as the groin, the disease can affect patients’ sex lives and relationships. In studies, up to 87 percent of patients have feelings of embarrassment or helplessness and 60 percent qualify as clinically depressed.

“Those of us who treat patients with psoriasis realize that its effects go far beyond the skin and the joints,” said Dr. Fernandez. “Psoriasis is associated with a tremendous negative impact on quality of life.”

Practical considerations for clinical use

He pointed out that while the five FDA-approved biologics — the TNF-α inhibitors infliximab, etanercept and adalimumab; the IL-12/23 inhibitor ustekinumab; and the IL-17 inhibitor secukinumab — all work well, infliximab is less convenient than the others because it requires infusion. The TNF-α agents are contraindicated in patients with concurrent demyelinating diseases, and the IL-17 agent is contraindicated in Crohn’s disease because it can cause flares.

Patient preference is important too, he noted, in terms of both administration and dosing regimen.

Dr. Fernandez said he adds an adjunctive therapy to the biologic for every patient, typically a topical corticosteroid or methotrexate, to maximize response.

He sees patients three to four months after starting therapy and assesses progress objectively as well as subjectively by asking “Are you happy with the outcome?” If response is inadequate, options include adding further adjunctive treatment, switching to a different biologic class or reducing the time between doses. “This usually works,” he noted.

Two new IL-17 inhibitors have completed phase 3 trials and are expected to be approved soon. And two IL-23 inhibitors are in early clinical trials with promising results.

“There’s never been a time when we’ve gotten better efficacy,” Dr. Fernandez concluded. “It’s fun to see these patients come back so happy.”

The online webcast activities discussed above have been approved for AMA PRA Category 1 credit™.