2016 Genentech Rheumatology Pipeline Summarized

The monoclonal antibody drug obinutuzumab shows promise for treating rheumatoid arthritis, systemic lupus erythematous and potentially other autoimmune disorders, according to new studies presented in November at the American College of Rheumatology annual meeting in San Francisco.  The pharmaceutical, a product of Genentech, is one of several the company highlighted for rheumatoid arthritis at the meeting. Other research pointed to the promise of rituximab as a second-line option for patients who do not respond to anti-TNF agents, and to tocilizumab as a monotherapy for rheumatoid arthritis. [[{"type":"media","view_mode":"media_crop","fid":"44444","attributes":{"alt":"©Guschenkova/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_4199809127021","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4975","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"©Guschenkova/Shutterstock.com","typeof":"foaf:Image"}}]] Obinutuzumab is approved for the treatment of chronic lymphocytic leukemia. It attaches to the membrane protein CD20, targeting B cells for death.  More recently, researchers have become interested in testing whether obinutuzumab might outstrip rituximab in the treatment of rheumatoid arthritis.  Using whole-blood assays from patients with rheumatoid arthritis and systemic lupus erythematous, Genentech researchers compared B cell depletion by obinutuzumab and rituximab. They found that obinutuzumab is more than twice as efficient than rituximab at inducing cytotoxicity in B cells in both sets of patients. It was also twice as efficient at inducing natural killer cell activation than rituximab. The researchers also reported reduced CD20 internalization and reduced complement-mediated cytotoxicity.  Obinutuzumab is glycol-engineered, meaning the sugar molecules on the surface of the antibody are designed to enhance cell-mediated cytotoxicity on B cells. As a result, the drug relies less on complement-mediated cytotoxicity than rituximab, said Jeffrey Siegel, the senior group medical director in immunology at Genentech. "Studies on nonhuman primates indicate that (obinutuzumab) is particularly good at depleting B cells in tissues, something that was not seen as well in these non-human primates with rituximab," Siegel said. "So we think that it may have the unique ability do deplete B cells in tissue, where that is important for clinical benefit." The company is also investigating the use of obinutuzumab in lupus nephritis and in patients who are candidates for kidney transplant but have high levels of alloantibodies that would make rejection of a donor kidney likely, Siegel said. The drug might be able to reduce those alloantibodies to make more donor kidneys available to these patients.  Other research at the conference focused on the use of more established drugs, including rituximab. One study compared ritixumab as a second- or third-line therapy compared to alternative anti-TNF agents in patients with rheumatoid arthritis. There are few studies pitting ritixumab as a second-line therapy head-to-head with choosing another anti-TNF agent instead, the researchers wrote. The research team led by Denis Choquette of the Institut de recherché en rhumatologie de Montreal, conducted a prospective study on patients who were treated with rituximab or anti-TNF agents after a first-line TNF agent failed. Of 231 patients total, 80.1 percent who received rituximab as a second-line treatment continued with the drug at a six-year follow-up, compared to only 19.1 percent of patients who received a second anti-TNF agent after the failure of a first. For patients who took rituximab as a third-line therapy, six-year persistence with the drug was 53.6 percent, compared with 37.2 percent for a third-line anti-TNF agent.  In short, the researchers reported, rituximab may be a better second choice than another anti-TNF agent once a first anti-TNF agent has failed.  A final study looked at whether tocilizumab should be used as a monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis. Using the U.S.-based Corrona network of rheumatoid arthritis patients, researchers identified 1,001 who began tocilizumab either as a monotherapy or in combination. They found that the median time before switching to another drug was comparable in both circumstances: 36.4 months in the monotherapy condition versus 28 months in the combination condition (95 percent confidence interval).  The research examined only persistency, not direct clinical benefit, Siegel warned. But it's consistent with clinical trials suggesting that tocilizumab alone is an effective treatment, he said.  What these data indicate is that tocilizumab monotherapy seems to provide efficacy that allows long-term retention on tocilizumab similarly for monotherapy and for combination with methotrexate," Siegel said.   

References:

1. Reddy V, Klein C, Isenberg DA, Cambridge G, Glennie M, Cragg M, Leandro MJ.

Obinutuzumab Outperforms Rituximab at Inducing B-Cell Cytotoxicity in Vitro through Fc-Mediated Effector Mechanisms in Rheumatoid Arthritis and Systemic Lupus Erythematosus

[abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/obinutuzumab-outperforms- rituximab-at-inducing-b-cell-cytotoxicity-in-vitro-through-fc-mediated-effector-mechanisms- in-rheumatoid-arthritis-and-systemic-lupus-erythematosus/.  2. Choquette D, Bessette L, Haraoui B, Massicotte F, Pelletier JP, Raynauld JP, Rémillard MA, Sauvageau D, Villeneuve , Coupal L, Brown J, Turcotte A.

Use of Rituximab Compared to Anti- TNF Agents As Second and Third Line Therapy in Patients with Rheumatoid Arthritis: 6-Year Follow-up Report from the Rhumadata® Clinical Database and Registry

[abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/use-of-rituximab-compared- to-anti-tnf-agents-as-second-and-third-line-therapy-in-patients-with-rheumatoid-arthritis-6- year-follow-up-report-from-the-rhumadata-clinical-database-and-registry/  3. Pappas DA, John A, Etzel CJ, Karki C, Li Y, Kremer JM, Haselkorn T, Greenberg JD.

Persistency of Tocilizumab As Monotherapy or Combination Therapy in Patients with Rheumatoid Arthritis– Real-World Analyses from the US Corrona Registry

[abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/persistency-of-tocilizumab-as-monotherapy-or- combination-therapy-in-patients-with-rheumatoid-arthritis-real-world-analyses-from-the-us- corrona-registry/.