AstraZeneca today announced top-line results of OSKIRA-1, a Phase III study to assess the efficacy and safety of fostamatinib, the first oral spleen tyrosine kinase (SYK) inhibitor in development for rheumatoid arthritis (RA). OSKIRA-1 had two primary endpoints: assessing signs and symptoms of RA as measured by ACR20 response rates, and an X-ray endpoint known as mTSS (modified Total Sharp Score).

In the OSKIRA-1 study, fostamatinib achieved a statistically significant improvement in ACR20 response rate at 24 weeks in both the 100 mg twice daily group and the group that received 100 mg twice daily for four weeks followed by 150 mg once daily (49%, p<0.001 and 44%, p=0.006 respectively) compared to placebo (34%). Fostamatinib did not demonstrate a statistically significant difference in mTSS compared to placebo at 24 weeks for either dose (p=0.252 and p=0.170, respectively).

The safety and tolerability findings for fostamatinib observed in the OSKIRA-1 study were generally consistent with those previously reported for the TASKi Phase II programme. 
The most commonly reported adverse events were typical of those seen in earlier studies, including hypertension, diarrhoea, nausea, headache and nasopharyngitis (common cold).

Briggs W. Morrison, MD, Executive Vice President of Global Medicines Development and Chief Medical Officer, said: “These top-line results provide important information on the efficacy and safety of fostamatinib and demonstrate that the compound has an effect on the signs and symptoms of rheumatoid arthritis. We will await the results of the remaining Phase III studies, OSKIRA-2 and OSKIRA-3, to further evaluate and characterise the profile of fostamatinib as a potential treatment for rheumatoid arthritis.”

OSKIRA-1 randomised 923 patients who had experienced an inadequate response to methotrexate (MTX) and, over a 24 week period, evaluated the effectiveness of two dosing regimens of fostamatinib (100 mg twice daily or fostamatinib 100 mg twice daily for four weeks followed by 150 mg once daily) in combination with MTX versus placebo in combination with MTX. Patients on fostamatinib remained on treatment in OSKIRA-1 for 12 months.

The OSKIRA-2 and OSKIRA-3 results are expected later in the second quarter of 2013.

Source: AstraZeneca

Last Updated: 4/5/13; 12:15PM EST

February 26, 2013- Chugai Pharmaceutical Co., Ltd. [Head Office: Chuo-ku, Tokyo; Chairman and CEO: Osamu Nagayama (hereafter, Chugai)] and F. Hoffmann-La Roche Ltd. [Head Office: Basel, Switzerland. CEO: Severin Schwan] announced today that the U.S. Food and Drug Administration (FDA) accepted the biologics license application (BLA) which Genentech, Inc. [Head Office: California, U.S., CEO: Ian T. Clark], a member of the Roche Group, submitted to the FDA in December 2012, for the subcutaneous formulation of the humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody, Actemra® [generic name: tocilizumab (genetical recombination)] for adult rheumatoid arthritis(RA). The review period is scheduled to be ten months, based on the Prescription Drug User Fee Act (PDUFA) and the anticipated action date comes in October 2013.

This BLA is based on two phase III studies, SUMMACTA study and BREVACTA study. The SUMMACTA study is a non-inferiority study which was conducted in patients with moderate to severe, active RA who have had an inadequate response to DMARDs therapy that may have included (in up to 20% of patients) one or more anti-TNFs. Patients received either ACTEMRA®162 mg SC weekly or ACTEMRA® 8 mg/kg IV every 4 weeks. As a result, a similar proportion of RA patients in each group achieved an ACR20 response at Week 24.

The BREVACTA study was conducted in patients with moderate to severe, active RA who had an inadequate response to DMARDs therapy. Patients received either ACTEMRA® 162 mg SC given every 2 weeks versus placebo given every 2 weeks, both in combination with DMARDs. As a result, more patients who received ACTEMRA® 162mg achieved ACR20 response at Week 24, compared to those who received placebo.

In both studies, the safety profile was consistent with the previous findings.

RA is a systemic inflammatory disease, with the main symptoms of multiple joint inflammation and progressive joint damage, and millions of patients are suffering from the pain and debilitating effects of the disease in the United States. Actemra®, created by Chugai in collaboration with Osaka University, utilizes genetic recombinant technology to produce monoclonal antibody from mouse anti-IL-6 receptor monoclonal antibody. It works by inhibiting IL-6 biological activity through competitively blocking the binding of IL-6 to its receptor.

In Japan, Actemra® was first launched in intravenous formulation in June 2005 by Chugai for Castleman's disease, following approval in April 2005. Subsequently, it was approved for the additional indications of RA (including prevention of structural damage of joints), polyarticular-course juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis (sJIA) in April 2008. In the EU, approval was granted as brand name RoActemra® in January 2009 for the treatment of adult RA in people who have either responded inadequately to, or who were intolerant to, previous therapy with one or more DMARDs or TNF inhibitors. In the US, in January 2010, Actemra® was approved as the treatment of adult patients with moderately to severely active RA who have had an inadequate response to one or more TNF antagonist therapies, and the indication was expanded in October 2012 to “the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more DMARDs”. Currently Actemra® is approved in more than 100 countries including India, Brazil, Switzerland and Australia. It was also approved in US in April 2011 and in EU in August 2011, for the treatment of active sJIA in patients two years of age and older.

The subcutaneous formulation was submitted in Japan in March 2012, and in Europe in December 2012 at the same timing as the US.

Today, Eli Lilly and Company announced that the company will discontinue the Phase III rheumatoid arthritis (RA) program for tabalumab, due to the lack of efficacy evidence. This decision will cost the company’s research and development $50 million.

Tabalumab is an anti-BAFF (B cell activating factor) monoclonal antibody. According to the company, the decision was not based on safety concerns, and the drug is currently in an ongoing Phase III program, ILLUMINATE, for systemic lupus erthematosus and will continue as planned.

Lilly discontinued the Phase 3 RA registration study for FLEX-M for lack of treatment effect in December 2012. The study was investigating the drug in patients with moderate-to-severe- RA who had an inadequate response to methotrexate therapy. After reviewing the lack of treatment effect results in the FLEX-M study, the company conducted an interim futility analysis of the FLEX-V study, which was investigating the drug for the treatment of patients with moderate-to-severe RA who had an inadequate response to one or more tumor necrosis factor (TNF) inhibitors. The company has decided to discontinue development of the tabalumab in the current program based on the outcomes of these two separate interim futility analyses.

“While we are obviously disappointed by these results in rheumatoid arthritis, we continue to believe that tabalumab could have significant potential for patients in other disease areas,” Eiry Roberts, MD, vice president of autoimmune product development at Lilly said in a statement. “Autoimmune disorders are highly individualized. We believe that targeting BAFF with a molecule such as tabalumab may still represent an important advance for patients, and therefore we will continue the ongoing Phase 3 tabalumab lupus program.”

Source: Eli Lilly and Company

Last Updated: 2/7/13; 2:35PM EST

The regenerative medicine company Mesoblast Limited announced that it has received clearance by the US Food and Drug Administration (FDA) to start a phase II clinical trial to evaluate a single intravenous infusion of allogeneic, or “off-the-shelf”, Mesenchymal Percursor Cells (MPCs) for patients with active rheumatoid arthritis (RA).

The trial is designed to compare the effects of single intravenous infusion of allogeneic MPCs dosed at 1 or 2 million cells/kg compared with placebo. It will consist of 48 patients who have had an incomplete or inadequate response to a biologic inhibitor of the TNF-alpha pathway for active rheumatoid arthritis across multiple sites in the United States and Australia. According to the company, the trial is expected to commence during the second quarter of 2013 and will assess the safety, tolerability, and effectiveness of the MPC therapy over an initial period of three months.

In preclinical studies, Mesoblast’s MPCs have shown to have a broad immunomodulatory mechanism of action (MOA), simultaneously inhibiting T cells and monocytes involved in autoimmunity and inflammation, suggesting that they may be useful agents for reducing the inflammation and permanent damage of the joints associated with progression of RA.

Currently, existing biologic treatments for RA only target single immune pathways, resulting in incomplete responses and the need for chronic administration. Additionally, these treatments can lead to infectious adverse events.

The company conducted a placebo-controlled study in thirty sheep with collagen-induced arthritis, which is a model that manifests characteristics of RA in humans. They found that when treated with Mesoblast’s MPCs, the sheep had significantly reduced TNF-alpha, IL-6 and IL-17 in the diseased joint as well as reduced tissue pathology. Based on these results, the company formed a rationale for their potential as both a first-line biologic treatment in those who do not respond to conventional anti-rheumatic agents and those with incomplete responses to biologic inhibitors of the TNF-alpha pathway alone.

“We believe that the broad immunomodulatory effects of our MPCs could provide a tangible benefit to patients with debilitating autoimmune diseases, including RA. This is the first in a series of programs designed to establish the credentials of our intravenous product formulation for a broad-based spectrum of inflammatory and immunologic conditions,” Silviu Itescu, Chief Executive Professor at Mesoblast stated.

Source: Mesoblast Limited

Last Updated: 2/1/13; 11:30AM EST