Rituximab for PV Granted Breakthrough Therapy Designation

March 28, 2017

Designated a breakthrough therapy for pemphigus vulgaris, rituximab has been shown to work better than prednisone alone and with fewer adverse events, researchers report in The Lancet.

The Food and Drug Administration has granted rituximab (Rituxan, Genentech) breakthrough therapy designation for the treatment of pemphigus vulgaris (PV). 

Rituximab, a chimeric monoclonal antibody directed at the CD20 molecule on the surfaces of some B cells, is approved in the U.S. for the treatment of rheumatoid arthritis in combination with methotrexate, but only in cases when TNFi therapy has failed. It is also approved for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It is currently under study for systemic lupus erythematosus (SLE).

As a breakthrough therapy, the FDA will expedite the development and review of rituximab for pemphigus vulgaris.

An autoimmune disease characterized by progressive blistering of the mouth, throat, nose, eyes, genitals, lungs and the surface of the skin, PV is potentially fatal and affects three in every 100,000 people.

The current standard of care includes high doses of corticosteroids taken for several weeks and corticosteroids in combination with the off-label use of corticosteroid-sparing immunosuppressive drugs for many months, which can cause significant, long-term side effects. 

Lancet study

recent study published in the March 22 issue of The Lancet showed that the first-line use of rituximab with short-term prednisone for patients with pemphigus was more effective than using prednisone alone, and with fewer adverse events.

This was a prospective, multi-center, parallel-group, open-label, randomized trial of 90 adult patients with newly diagnosed pemphigus. Patients were randomly assigned participants to receive either oral prednisone alone, 1.0 or 1.5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1,000 mg of intravenous rituximab on days zero and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0.5 or 1.0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group).

Patients were followed for three years with check-ins weekly in month one, then monthly for two years and at 36 months. The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis).

At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 patients assigned to prednisone alone.

More severe adverse events of grade 3–4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 [SD 1·25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 [1·15]; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]).

Ongoing clinical trials

Hoffmann-La Roche and Genentech are collaborating on a multi-center phase III, randomized, double-blind, study to evaluate the efficacy and safety of rituximab compared with mycophenolate mofetil (MMF) in patients with moderate-to-severely active PV requiring 60-120 milligrams per day (mg/day) oral prednisone or equivalent. Participants must have a confirmed diagnosis of PV within the previous 24 months (by skin or mucosal biopsy and immunohistochemistry) and evidence of active disease at screening. (For more information about this trial:  PEMPHIX, NCT02383589.

 

References:

Genentech news release, “FDA Grants Breakthrough Therapy Designation for Rituxan (Rituximab) in Pemphigus Vulgaris,” March 23, 2017.

Joly P, et al. “First-Line Rituximab Combined with Short-Term Prednisone Versus Prednisone Alone for the Treatment of Pemphigus (Ritux 3): A Prospective, Multicentre, Parallel-Group, Open-Label Randomised Trial,” The Lancet. March 22, 2017