Investor Update

Basel and London, 01 October 2013

Roche presents late-stage pipeline highlights at investor event

Upcoming decision points underscore commitment to personalised healthcare

  • Promising results outside oncology: etrolizumab in inflammatory bowel disease and lampalizumab (anti-factor D) in geographic atrophy, an advanced form of dry AMD
  • Expanding in HER2: TH3RESA study in advanced HER2-positive breast cancer confirmed Kadcyla’s clinical benefit
  • Anti-PDL1 in cancer immunotherapy: durable response rate in non-small cell lung cancer

Roche (SIX: RO, ROG; OTCQX: RHHBY) today will provide an update from its leading late-stage pipeline comprising ten new molecular entities in key therapeutic areas: oncology, immunology & ophthalmology and neuroscience. The London investor event will focus on major progress that has been achieved in recent months as well as on further development plans for these potential breakthrough medicines.

“We are constantly pushing frontiers to improve treatments for patients in areas with high unmet medical needs,” said Hal Barron, M.D., Chief Medical Officer and Head, Global Product Development at Roche. “In oncology, our broad pipeline allows us to combine medicines with complementary actions to target and potentially eliminate tumor cells via several cancer growth pathways. We are also building on scientific knowledge to make progress in our other established disease areas including immunology and ophthalmology.”

Expanding the success of existing franchises in oncology

HER2 franchise: Kadcyla

Results from the phase III TH3RESA study confirmed Kadcyla’s clinical benefit for people with HER2-positive metastatic breast cancer (mBC) whose disease worsened despite prior treatment with at least two other HER2-targeted medicines. TH3RESA met its co-primary endpoint of progression-free survival (PFS) extending the time people with HER2-positive mBC lived without their disease worsening compared to physician’s choice of treatment. About 80% of patients in the comparator arm of TH3RESA who were treated according to physician’s choice received a Herceptin-containing regimen. The study showed that the risk of disease worsening or death was reduced by 48 percent for people who received Kadcyla (PFS 6.2 vs. 3.3 months; HR=0.528, P<0.0001). Although early in the study and data are not mature, there was a strong trend seen in improving survival (overall survival; OS, the other co-primary endpoint of the study) for people who received Kadcyla as compared to the physician’s choice of treatment.

Kadcyla was approved in the US in February 2013 and recently received positive opinion from the European Union’s Committee for Medicinal Products for Human Use (CHMP) as a single agent for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic  breast cancer who previously received trastuzumab and a taxane, separately or in combination. A European Commission decision is expected by the end of the year.

A phase III study (MARIANNE) testing the combination of Kadcyla with Perjeta vs. standard of care in first-line HER2-positive mBC is ongoing. The trial is expected to read out in the second half of 2014.

Hematology franchise: GA101 and combinations with complementary mode of action

GA101 (obinutuzumab) is the first type II anti-CD20 medicine that is glycoengineered with the goal of improving efficacy as compared to MabThera/Rituxan, the current standard of care, in many hematological cancers. GA101 is a unique anti-CD20 antibody that acts as an immunotherapy, engaging the patient’s own immune system to help attack the cancerous cells. In addition, GA101 binds directly to CD20 with the aim of inducing direct cell death.

Recently, top-line results from the phase III CLL11 study showed GA101 plus chlorambucil, a chemotherapy, was superior to MabThera/Rituxan plus chlorambucil in helping people with previously untreated chronic lymphocytic leukemia (CLL), one of the most common forms of blood cancer, live longer without their disease worsening. Data from the stage II of the CLL11 study have been submitted to the American Society of Hematology’s 55th Annual Meeting in December, 2013.

Based on an earlier analysis (stage I) of the CLL11 study, GA101 was granted priority review and Breakthrough Therapy designation by the FDA in the treatment of CLL and is expected to be approved by the end of this year. Marketing applications have also been submitted to other regulatory authorities, including the European Medicines Association (EMA) in April 2013.

GA101 is currently being investigated in a large clinical program, including multiple head-to-head phase III studies versus MabThera/Rituxan in indolent non-Hodgkin lymphoma and diffuse large B-cell lymphoma.

Anti-CD20 targeted agents remain the mainstay in the treatment of B cell hematological cancers. The goal of future therapies is to achieve a deep response followed by long remission as measured by the absence of minimal residual disease.

In CLL, minimal residual disease (MRD) is used to assess the quality of the response in clinical trials. If a patient becomes MRD negative this means that there are no detectable cancer cells left in the blood or bone marrow which is associated in most cases with a long lasting remission. In the CLL11 study, the addition of GA101 to chlorambucil induced MRD negativity in the blood of 31% of patients, compared to 2% of patients who received MabThera/Rituxan and chlorambucil.

In order to further increase the number of patients who are MRD negative, combination partners with complementary actions to anti-CD20 backbone therapies such as the Bcl-2 inhibitor GDC-0199 are being evaluated. Additionally, combination partners such as the antibody-drug conjugates anti-CD22 and anti-CD79b have the potential to eliminate chemotherapy and improve tolerability.

GDC-0199 (RG7601) is designed to work by interfering with the process by which some cancer cells survive, thereby promoting a natural death process known as apoptosis. Phase 1 data from a study of GDC-0199 in patients with R/R CLL showed that GDC-0199 is highly active achieving an 84% overall response rate. 18% of patients achieved a complete remission. Of those patients, 35-50% showed MRD negativity. A phase I study in relapsed/refractory (R/R) CLL combining GDC-0199 and GA101 is ongoing. A phase III study in RR CLL combining MabThera/Rituxan and GDC-0199 is expected to start enrolment in Q1 2014.

Antibody–drug  conjugates  anti-CD22  (RG7593) and anti-CD79b (RG7596): The antibody–drug conjugates humanised IgG1 anti-CD22 and anti-CD79b monoclonal antibodies both conjugated to a potent anti-mitotic agent, are currently being tested in combination with MabThera/Rituxan in a head-to-head comparison phase II study in people with Non-Hodgkin’s Lymphoma.

This demonstrates that Roche has a strong set of assets in its development pipeline with the potential to further improve on the anti-CD20 backbone therapy MabThera/Rituxan, the current standard of care in fighting hematological tumors.

Anti-PDL1 immunotherapy: Enabling immune cells to attack tumors

The anti-PDL1 antibody MPDL3280A (RG7446) is an investigational medicine designed to make cancer cells more vulnerable to the body’s own immune system by interfering with a protein called PD-L1. Anti-PDL1 has shown promising early data in various cancer types. At the recent European Cancer Congress in Amsterdam, updated results for patients enrolled in a phase I study in advanced non-small cell lung cancer (NSCLC) were presented. Among the 53 patients evaluated for efficacy in this analysis of the study of MPDL3280A as a single agent (those receiving their first dose by 1 Oct 2012), 23% (12 of 53 patients) achieved a confirmed objective response as measured by RECIST 1.1 criteria. 11 of 12 responding patients continued to respond as of the data cutoff date, and the 24-week PFS rate was 44.7% (95% CI: 31.2%:58.3 %). The association between PD-L1 expression and treatment benefit was analysed: objective response was particularly pronounced in the PD-L1 IHC3 population at 83.3% (5 of 6 patients). Disease control rate (DCR), a measure which combines best objective response of complete response, partial response and stable disease, suggests a relationship between PD-L1 expression and treatment benefit. Patients with high levels of PD-L1 expression (IHC 2/3; defined as tumors containing ≥5% PD-L1-positive tumor-infiltrating immune cells) achieved a DCR of 69% compared to a DCR of 48% in the IHC 0/1 population (IHC 0/1; defined as tumors containing <5% PD-L1-positive tumor-infiltrating immune cells).

A randomized phase III study (OAK) in 2nd/3rd line mNSCLC comparing anti-PDL1 with docetaxel is expected to start in Q1 2014.

Further development will include combination studies. Currently ongoing are one phase I study combining anti-PDL1 and Zelboraf in people with metastatic melanoma and one phase I study in combination with Avastin in solid tumors. Further studies with other combinations, and in other tumor types, are planned.

Late-stage enabling milestones

Etrolizumab in inflammatory bowel disease

Etrolizumab demonstrated encouraging results in the phase II EUCALYPTUS study in patients with moderate-to-severely active ulcerative colitis (UC), a type of inflammatory bowel disease (IBD). Ulcerative Colitis is a chronic inflammatory condition of the colon, characterized by mucosal ulceration, rectal bleeding, diarrhea and abdominal pain that in complicated cases may require major and sometimes urgent surgery. Despite available treatment options, there is still a high unmet need for safer treatments that offer higher rates of sustained remission in newly diagnosed patients and patients previously treated with anti-TNFs who no longer respond.

Etrolizumab is a gut-selective monoclonal antibody targeting the anti-β7 integrin, inhibiting both the alpha4-beta7 and alphaE-beta7 integrins. Other gut selective anti-integrins in clinical development inhibit only alpha4-β7 integrin.

EUCALYPTUS phase II results showed that in the anti-TNF naïve subgroup the rates of clinical remission at week 10 were significantly higher in the 100 mg treatment group compared with placebo (43.8% vs 0%, p=0.007). These data showed that placebo-corrected remission rates achieved with etrolizumab were among the highest compared to current treatment options. A phase III program in inflammatory bowel disease investigating etrolizumab in ulcerative colitis and also in Crohn’s disease comprising more than 3000 patients is expected to start in the first half of 2014. AlphaE-beta7, a potential biomarker predicting which subgroup of patients will respond best to etrolizumab has been identified. It will be tested for its capacity as a companion diagnostic in Phase 3.

Lampalizumab: Potentially first treatment in geographic atrophy, an advanced form of dry AMD

Recently, compelling phase II data for lampalizumab (also referred to as anti-factor D) in patients with geographic atrophy (GA) were presented with a strong effect observed in a subset identified by exploratory biomarkers. GA is characterized by the irreversible loss of retinal tissue in the macula that results in permanent blind spots in a patient’s visual field; GA affects more than 8 million people worldwide representing a high unmet need as no approved treatments currently exist.

Results from the phase II MAHALO study demonstrated a reduction in the progression rate of GA lesions by 44 percent (p<0.005) at 18 months in a sub-population of GA patients that were identified using pre-specified exploratory biomarkers when treated with monthly lampalizumab. In patients positive for these exploratory biomarkers who presented with better vision (20/50 to 20/100), progression of the GA area was reduced by 54 percent (p<0.005) at 18 months when treated with monthly lampalizumab. From the patient samples collected in the MAHALO study, 57 percent of patients were positive for the exploratory biomarkers. More information on the exploratory biomarkers will be shared at a future medical congress.

Lampalizumab is an antigen-binding fragment (Fab) of a humanised, monoclonal antibody directed against complement factor D. Complement factor D is a rate-limiting enzyme involved in the activation of the alternative complement pathway , a component of the immune system's natural defense against infections. Genetic polymorphisms as well as hyperactivity of the alternative complement pathway have been implicated in the development of AMD including GA. Discussions with health authorities regarding a phase III development program for lampalizumab in GA are planned this year.

Partners & collaborations

  • Kadcyla (trastuzumab emtansine): In collaboration with ImmunoGen, Inc.
  • GA101 (obinutuzumab): In collaboration with Biogen Idec
  • Bcl-2 inhibitor GDC-0199, RG7601: Joint project with AbbVie in collaboration with WEHI (The Walter and Eliza Hall Institute)
  • Antibody–drug  conjugates  anti-CD22  (RG7593) and anti-CD79b (RG7596):  In collaboration with Seattle Genetics

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, infectious diseases, inflammation, metabolism and neuroscience. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner 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 2012 Roche had over 82,000 employees worldwide and invested over 8 billion Swiss francs in R&D. The Group posted sales of 45.5 billion Swiss francs. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com.

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