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Investor Update

Basel, 26 June 2009

Roche Files MabThera as a First-line Biologic Treatment for Rheumatoid Arthritis in Europe

Roche announced today that it has submitted a combined filing to the European health authorities (the European Medicines Agency) for three new indications to extend the label for MabThera to use as a first-line biologic therapy for patients with rheumatoid arthritis (RA).  The new filings are for patients who have not been treated with methotrexate (MTX), the current standard treatment option; those who have had an inadequate response to MTX; and for the prevention of joint damage across all RA patient populations.

Joint damage in RA often begins early in the disease, so it is critical to treat patients as early as possible to reduce symptoms and stop irreversible damage before it occurs. This damage can lead to permanent disability affecting patients’ ability to carry out normal everyday activities such as walking or dressing.

MabThera (administered as courses of two infusions of 1000mg, with repeat treatment determined by disease activity) is already a well established therapeutic option when used later in the treatment algorithm.  It is currently licensed for patients with moderate-to-severe disease who have not benefited from, or are intolerant to, one or more tumour necrosis factor (TNF) inhibitors.  In this population, MabThera is the only RA therapy that has proven to offer the preservation of joint structure for patients,1,2 providing additional improvements in the signs and symptoms of RA with each repeat course of treatment.3

“This filing represents a significant advance for patients with early rheumatoid arthritis” said Urs Schleuniger, Roche’s Global Product Strategy Head, Inflammation/Immunology.  “A successful regulatory outcome will mean that clinicians and patients have a new treatment option to tackle the disease early on, allowing patients to carry on with everyday tasks and activities without experiencing the detrimental effects of RA and irreversible damage to their joints.”

The combined filing follows positive results from three large clinical trials: IMAGE, SERENE and MIRROR.  The studies showed that MabThera, when used as the first biologic in combination with MTX, improves the signs and symptoms of RA in patients, compared to those patients treated with MTX alone.4,5,6  In addition, the IMAGE trial demonstrated that treatment with MabThera (two x 1000mg every 24 weeks), in combination with MTX, can significantly reduce the progression of joint damage including a reduction in bone erosions, where areas of the bone are destroyed.4

About the studies

SERENE

SERENE was a phase III international study treating 509 patients with active RA. The study was conducted at 102 study sites across 11 countries. In this randomized, placebo controlled, double blind, parallel group study, patients received either MabThera (500mg or 1000mg) or placebo by intravenous infusion on days 1 and 15, plus weekly MTX. A significantly greater proportion of patients treated with MabThera in combination with MTX achieved an improvement in disease signs and symptoms at week 24, compared to those treated with MTX alone. A preliminary analysis of the data did not reveal any unexpected safety signals and the overall safety profile was consistent with that reported in previous studies. The study also explored pharmacokinetics and the long-term efficacy and safety of further courses of MabThera in this patient population.

MIRROR

MIRROR was a phase III randomized, double-blind, international study to evaluate the efficacy and safety of three dosing regimens of MabThera in combination with MTX in 375 patients with active RA and an inadequate response to MTX. Patients were randomized to three groups with two courses of MabThera treatment at varying doses:

  • Group A: all courses 500 mg MabThera on days 1 and 15; repeat treatment at 24 weeks,
  • Group B: first course 500 mg MabThera on days 1 and 15; second course 1000 mg MabThera; repeat treatment at 24 weeks,
  • Group C: all courses 1000 mg on days 1 and 15; repeat treatment at 24 weeks.

The primary endpoint was the proportion of patients achieving ACR20 at week 48. Secondary endpoints included ACR50, ACR70 and EULAR responses. There was a trend towards better efficacy results with the regular 2 x 1000mg dose compared to low dose 2 x 500mg, and this reached statistical significance for EULAR good/moderate response (2x1000 mg = 88% vs. 2x500 mg = 72%, p < 0.05). Other endpoints although numerically superior at 48 weeks didn’t show any statistically significant difference between the three dosing regimens.

IMAGE

IMAGE was a Phase III, randomized, controlled, double-blind trial involving 748 patients to evaluate the safety and efficacy of MabThera in combination with MTX compared to MTX alone, in MTX-naïve patients with active RA. Patients in the MabThera arms were either treated with 2 x 1000mg or 2 x 500mg every 24 weeks. The primary endpoint was radiographic progression measured by total modified Sharp score at week 52.

In patients treated with 2 x 1000mg MabThera and MTX, the data show a significantly smaller change (0.359) in modified Total Sharp Score (mTSS) compared to patients on MTX alone (1.079; p=<0.001) - a lower progression of joint damage. Further, a significantly higher proportion of patients treated with MabThera and MTX had no progression in their joint damage over 1 year (64% vs 53% p=0.0309). By week 52, 65% of these patients achieved a 50% improvement in symptoms (ACR50), while 47% had achieved a 70% improvement (ACR70), compared to 42% and 25% on MTX alone (p<0.0001 for both ACR50 and ACR70 comparisons). Safety data from the study are consistent with results from previous MabThera clinical trials and further enhance the robust safety profile. Rates of serious adverse events and serious infections were similar between the two MabThera groups and the MTX only group.

MabThera also improved the physical function of patients, which was assessed at regular intervals during the study using a number of standard health-related quality of life tools, such as HAQ-DI, FACIT, and SF-36. Patients also reported significantly lower levels of fatigue, one of the most commonly reported debilitating symptoms experienced by people with rheumatoid arthritis.

About rheumatoid arthritis and MabThera

Rheumatoid arthritis (RA) is an autoimmune disease characterised by inflammation that leads to stiff, swollen and painful joints. This ultimately results in irreversible joint damage and disability. MabThera selectively targets B cells and represents a new highly effective therapeutic approach for RA in addition to existing treatments such as disease-modifying anti-rheumatic drugs (DMARDs) and tumour necrosis factor (TNF) inhibitors.

B cells are known to play a key role in the inflammation associated with RA. As the first and only selective B cell therapy available for the treatment of RA, MabThera represents a proven and truly different alternative for patients who have inadequate response or are not able to tolerate TNF inhibitor therapy. MabThera is the only RA treatment that has demonstrated the ability to preserve joint structure in this patient group and offers an unprecedented duration of response of at least six months with each course. Each course of MabThera also provides the opportunity of sustained or improved relief for patients from the signs and symptoms of their disease.

MabThera is marketed in the US by Genentech and Biogen Idec under the brand name Rituxan®.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2008, Roche had over 80,000 employees worldwide and invested almost 9 billion Swiss francs in R&D. The Group posted sales of 45.6 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.

All trademarks used or mentioned in this release are protected by law.

References
1) Cohen S et al.  Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.  Arthritis Rheum 2006; 54:2793–2806
2) Keystone E et al.  Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies.  Ann Rheum Dis; Feb 2009;68:216-221
3) Keystone E, Fleischmann R et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis. Arthritis Rheum 2007;56:3896-908
4) IMAGE refers to International study in Methotrexate-nAïve subjects investiGating Rituximabs Efficacy
5) SERENE refers to Study Evaluating Rituximab’s Efficacy in methotrexate iNadequate rEsponders
6) MIRROR refers to Methotrexate Inadequate Responders Randomised study Of Rituximab