Giant cell arteritis treatment expedited

The US Food and Drug Administration (FDA) is expediting its review of a new potential treatment for giant cell arteritis, a rare inflammatory disease that can cause permanent vision loss, Roche has announced.

The FDA and the European Medicines Agency have already approved tocilizumab (Actemra/RoActemra, Roche, Basel, Switzerland) for rheumatoid arthritis. Roche is seeking to add giant cell arteritis as an indication.

Under breakthrough status, the FDA will provide intensive guidance on efficient drug development, rolling reviews of aspects of an application and other support aimed at smoothing the path toward approval.

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The breakthrough designation follows on from Roche’s June announcement of positive results in GiACTA, a phase III clinical trial in 251 patients at 76 sites in 14 countries including Austria, Belgium, Denmark, France, Germany, Italy, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, and the UK.

Although researchers have not released any details of their results, in a June press release Roche reported that tocilizumab, initially combined with a 6-month glucocorticoid regimen, more effectively sustained remission through 1 year compared with a 6 or 12 month steroid-only regimen in people with newly diagnosed and relapsing giant cell arteritis.

They identified “no new safety signals” in the study, and adverse events were similar to those seen in previous Actemra/RoActemra clinical studies.

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The most common adverse events reported for tocilizumab include upper respiratory tract infections, nasopharyngitis, headache, hypertension, and abnormal liver function tests. The most serious adverse events are serious infections, complications of diverticulitis, and hypersensitivity reactions.

"The results of Genentech's GiACTA trial are encouraging for giant cell arteritis patients and the physicians who treat them," said Philip R Rizzuto, clinical associate professor of ophthalmic surgery at Brown University, Warren Alpert Medical School, in a Roche statement. "Long-term, high-dose steroid use can be problematic for many people. Having an alternative treatment would be welcome news."

If approved, tocilizumab would be the first new therapy available for giant cell arteritis in more than 50 years, according to Roche.

Disease symptoms

The most common primary vasculitis in adults, giant cell arteritis causes a generalised granulomatous inflammation of medium-sized to large-sized vessels mostly in people over 50 years of age. It is also known as temporal arteritis. 

Patients often present first with vision loss, and may visit ophthalmologists before they see other specialists.

The pathogenesis of giant cell arteritis is still under investigation. So far researchers have determined that some unknown stimulus causes T-cells to activate macrophages which use metalloproteinases and reactive oxygen intermediates to destroy blood vessel walls.

The healing response includes intimal thickening, myofibroblast proliferation, and extraceullular matrix deposition, which contribute to vascular stenosis and occlusion leading to arteritic anterior ischemic optic neuropathy (AAION).

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The superficial temporal artery, the ophthalmic artery, the posterior ciliary arteries, and the vertebral arteries are among those most often affected.

In addition to vision loss, patients commonly report headache, jaw claudication, diplopia, myalgias, and constitutional symptoms.

The standard of care for the initial treatment of giant cell arteritis is corticosteroids, sometimes in combination with methotrexate. 

Giant cell arteritis "causes blindness,” said Alan L Wagner, retina specialist and founder of Wagner Macula & Retina Center, in a Roche statement. “Steroids are an essential sight saving tool, but can be as harmful long term at moderate to high doses systemically as they are helpful to saving sight. The phase III tocilizumab study is a large step forward for our patients with this chronic autoimmune disorder."

A monoclonal antibody, tocilizumab competitively inhibits the binding of interleukin-6 (IL-6) to its receptor (IL-6R). This prevents IL-6 signal transduction to inflammatory mediators that summon B and T cells.

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According to ClinicalTrials.gov, in the GiACTA trial researchers randomly assigned patients to receive either tocilizumab 162 mg subcutaneously weekly or every 2 weeks or placebo for 52 weeks, with tapering oral daily doses of prednisone.

After week 52, patients in remission entered long-term follow-up, while patients with disease activity or flares received open-label tocilizumab 162 mg subcutaneously weekly for a maximum period of 104 weeks at the discretion of the investigator. 

Roche said GiACTA data will be submitted for presentation “at an upcoming medical conference and to regulatory authorities around the world for approval consideration.”