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Clinical Trials

Date: 2017-06-23

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 3rd Congress of the European Academy of Neurology (EAN)

Company: Genentech, a member of Roche Group (USA - CA - Switzerland)

Product: Ocrevus® (ocrelizumab)

Action mechanism:

  • monoclonal antibody. Ocrelizumab is an investigational, humanized monoclonal antibody designed to selectively target CD20-positive B cells. CD20-positive B cells are a specific type of immune cell thought to be a key contributor to myelin (nerve cell insulation and support) and axonal (nerve cell) damage, which can result in disability in people with MS. Based on preclinical studies, ocrelizumab binds to CD20 cell surface proteins expressed on certain B cells, but not on stem cells or plasma cells, and therefore important functions of the immune system may be preserved.

Disease: relapsing multiple sclerosis (RMS) primary progressive multiple sclerosis (PPMS)

Therapeutic area: Autoimmune diseases - Neurodegenerative diseases

Country:

Trial details:

  • The Phase III clinical development program for ocrelizumab includes three studies: OPERA I, OPERA II and ORATORIO.
  • OPERA I and OPERA II are Phase III, randomized, double-blind, double-dummy, global multi-center studies evaluating the efficacy and safety of ocrelizumab (600 mg administered by intravenous infusion every six months) compared with interferon beta-1a (44 mcg administered by subcutaneous injection three times per week) in 1,656 people with relapsing forms of MS (i.e., relapsing-remitting MS and secondary-progressive MS with relapses).1
  • ORATORIO is a Phase III, randomized, double-blind, global multi-center study evaluating the efficacy and safety of ocrelizumab (600 mg administered by intravenous infusion every six months; given as two 300 mg infusions two weeks apart) compared with placebo in 732 people with PPMS. In contrast to the OPERA I and OPERA II studies, where the blinded treatment period was two years, the blinded treatment period of the ORATORIO study continued beyond that until all patients had received at least 120 weeks of either ocrelizumab or placebo and a predefined number of CDP events was reached overall in the study.

Latest news:

  • • On June 23, 2017, Roche announced that new post-hoc analyses from the Ocrevus® (ocrelizumab) Phase III clinical trial programme in people with relapsing and primary progressive forms of multiple sclerosis will be presented at the 3rd Congress of the European Academy of Neurology (EAN) from 24 June to 27 June in Amsterdam, Netherlands.
  • Ocrevus® significantly reduced disease activity and disability progression in patients with RMS and PPMS, as measured by No Evidence of Progression or Active Disease (NEPAD). In RMS, Ocrevus®  significantly increased the proportion of patients maintaining NEPAD by 82 percent compared with Rebif® (interferon beta-1a) at 96 weeks in a pooled exploratory analysis of the Phase III OPERA I and II studies. In PPMS patients, Ocrevus® more than tripled the proportion of those who maintained NEPAD compared with placebo at 120 weeks in an exploratory analysis of the Phase III ORATORIO study (29.9 percent with Ocrevus®  versus 9.4 percent with placebo).
  • In separate post-hoc analyses of the OPERA I and II studies, Ocrevus® significantly reduced the risk of patients with RMS losing the ability to walk long distances unassisted (EDSS ?4) or requiring a cane or crutch (EDSS ?6) compared with interferon beta-1a at 96 weeks. In the ORATORIO study, Ocrevus® significantly reduced the risk of becoming wheelchair-bound (EDSS ?7) compared with placebo at 120 weeks in PPMS patients with baseline EDSS ?6.
  • In a post-hoc analysis of the placebo-controlled ORATORIO study, Ocrevus® consistently reduced the risk of 12- and 24-week confirmed disability progression (CDP) across three different definitions of the measure meant to capture more severe disability worsening than traditionally assessed in PPMS patients.
  • • On April 26, 2017, Roche announced that new data from the Ocrevus™ (ocrelizumab) clinical trial programmes will be presented during the 69th American Academy of Neurology (AAN) Annual Meeting in Boston, Massachusetts. The presentations will highlight new efficacy and safety analyses from Phase II and Phase III trials, as well as from the open-label extensions.
  • Within the first eight weeks of treatment,Ocrevus™ reduced the relapse rate by 55 percent compared with Rebif® (interferon beta-1a), in a pooled exploratory analysis of the Phase III OPERA I and OPERA II studies in RMS.
  • In a separate Phase II study in relapsing-remitting MS (RRMS) patients, Ocrevus™ demonstrated rapid and near-complete suppression of brain MRI activity at eight weeks, including new active areas of damage (T1 gadolinium-enhancing lesions) and new or newly enlarging areas of damage (hyperintense T2 lesions), compared with placebo.
  • Additional analyses of the Phase III OPERA I and II studies demonstrated the efficacy of Ocrevus™ in people with early RMS (recently diagnosed and without previous treatment). Ocrevus™ suppressed more than 90 percent of active MRI lesions over two years compared with interferon beta-1a in these patients. In the same early RMS patients, Ocrevus™ also increased the proportion who achieved No Evidence of Disease Activity (NEDA) by 76 percent compared with interferon beta-1a over two years. These data were consistent with NEDA results observed in the overall Ocrevus™ -treated population.
  • In an analysis of pooled data from the Phase III RMS open-label extension (OLE) studies, patients who switched from interferon beta-1a to Ocrevus™ experienced reductions in relapse rates (unadjusted annualised relapse rate of 0.102 after switching) and MRI brain lesions (0.01 mean number of active lesions (T1 gadolinium-enhancing) and 0.37 new or enlarging T2 lesions after switching). Furthermore, patients who were treated with Ocrevus™ from the start of the studies showed a sustained benefit after three years.
  • In the ORATORIO study, PPMS patients with confirmed disability progression (CDP) had a greater increase in fatigue, underlining the importance of preventing disease progression in people with PPMS. Furthermore, patients treated with Ocrevus™ who didn’t experience disability progression reported a significant reduction in fatigue compared to those taking placebo.
  • Additionally, in open-label extension studies of over 2,200 patients with RMS and PPMS, Ocrevus™ safety was consistent with the controlled treatment periods.
  • The most common side effects associated with Ocrevus® in all Phase III studies were infusion reactions and upper respiratory tract infections, which were mostly mild to moderate in severity.
  • • On December 21, 2016, Roche announced that data from three Phase III studies of Ocrevus® (ocrelizumab)– the OPERA I and OPERA II studies in relapsing multiple sclerosis (RMS) and the ORATORIO study in primary progressive multiple sclerosis (PPMS) – were published in the 21 December 2016 online issue of the New England Journal of Medicine (NEJM). Data from the OCREVUS Phase III studies showed consistent and clinically meaningful reductions in major markers of disease activity and progression compared with Rebif® (interferon beta-1a) in RMS and with placebo in PPMS. The primary endpoint was met in all three studies, which includes relative reduction of annualised relapse rate in the RMS studies and relative reduction in the progression of clinical disability sustained for at least 12 weeks in the PPMS study. Key secondary endpoints in all three studies were also met, including multiple measures of disability progression and brain lesion activity.
  • • On September 14, 2016, Roche announced new analyses from the three Ocrevus® (ocrelizumab) Phase III studies in relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) will be presented during the 32nd congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), from 14th to 17th September in London, England. Ocrevus® increased disease control in patients with RMS and PPMS in separate post-hoc analyses.
  • In these analyses, two composite endpoints measured disease control using a combination of clinical and MRI outcomes:
  • - No Evidence of Disease Activity (NEDA) in patients with RMS and No Evidence of Progression (NEP) in patients with PPMS. These composite endpoints are emerging as new treatment targets. A NEDA analysis of pooled data from the Phase III OPERA I and OPERA II studies compared no evidence of disease activity during different time periods over two years of study. NEDA is achieved when a patient has no relapses, no confirmed disability progression, no gadolinium-enhancing MRI lesions and no new or enlarging MRI lesions. The data showed that Ocrevus® significantly increased the proportion of RMS patients achieving NEDA by 75 percent compared with interferon beta-1a over 96 weeks (0-96 weeks). Additionally, compared with interferon beta-1a, Ocrevus® treatment significantly increased the relative proportion of patients achieving NEDA by 33 percent in weeks 0-24 and by 72 percent in weeks 24-96. A majority of patients achieved NEDA in the first 24 weeks of Ocrevus® treatment (60.8 percent) and this proportion increased during weeks 24-96 of the study (72.2 percent).
  • New post-hoc analyses of the ORATORIO study in PPMS patients measured NEP, which includes three measures of physical disability (confirmed disability progression, walking speed and upper extremity function) and reflects no evidence of worsening of a person’s physical disability. Patients who achieved NEP had no evidence of confirmed disability progression sustained for at least 12 weeks and less than 20 percent worsening of performance on the timed 25-foot walk and 9-hole peg test. Ocrevus® treatment significantly increased the proportion of PPMS patients with NEP by 47 percent at week 120 compared with placebo (p=0.0006).
  • In addition, new patient-reported outcomes data from the ORATORIO study highlighting the unmet need of people with PPMS, including the effect Ocrevus® had on fatigue measures, will be presented.
  • • On October 8, 2015, Genentech announced data from three Phase III studies of ocrelizumab in people with relapsing multiple sclerosis and primary progressive multiple sclerosis. Data from two identical studies (called OPERA I and OPERA II) showed ocrelizumab was superior to interferon beta-1a (Rebif®) in reducing the three major markers of disease activity over the two-year controlled treatment period.
  • In a separate study called ORATORIO), ocrelizumab significantly reduced the progression of clinical disability sustained for at least 12 weeks (the primary endpoint) and 24 weeks (a secondary endpoint) compared with placebo.
  • Additionally, the study met other secondary endpoints of reducing the time required to walk 25 feet, the volume of chronic inflammatory brain lesions, and brain volume loss.
  • In the OPERA I and OPERA II studies, ocrelizumab significantly reduced the annualized relapse rate (ARR) – the primary endpoint of both studies – by nearly 50 percent compared with interferon beta-1a over the two-year period ((Abstract #246 - Dr. Hauser). Additionally, ocrelizumab met secondary endpoints of the study, significantly delaying confirmed disability progression (CDP; loss of physical abilities, measured by the Expanded Disability Status Scale, or EDSS) by approximately 40 percent sustained for both 12 and 24 weeks compared with interferon beta-1a in pre-specified, pooled analyses of the two studies (p=0.0006 and p=0.0025, respectively). Ocrelizumab also significantly reduced acute MS-related inflammation and brain injury (total number of T1-gadolinium-enhancing lesions measured by magnetic resonance imaging, or MRI) at 24, 48 and 96 weeks by more than 90 percent and the emergence of more chronic or growing areas of MS-related brain injury (T2 hyperintense lesions) at 24, 48 and 96 weeks by around 80 percent compared with interferon beta-1a.
  • Data from the Phase III studies in patients with relapsing MS showed:
  • - A 46-percent and 47-percent reduction in the ARR compared with interferon beta-1a over the two-year period in OPERA I and OPERA II,
  • - A 43-percent and 37-percent risk reduction in CDP sustained for 12 weeks compared with interferon beta-1a in OPERA I and OPERA II
  • - A 43-percent and 37-percent risk reduction in CDP sustained for 24 weeks compared with interferon beta-1a in OPERA I and OPERA II
  • - A 94-percent and 95-percent reduction in the total number of T1 gadolinium-enhancing lesions compared with interferon beta-1a in OPERA I and OPERA II
  • - A 77-percent and 83-percent reduction in the total number of new and/or enlarging hyperintense T2 lesions compared with interferon beta-1a in OPERA I and OPERA II.
  • Overall, the proportion of patients in the ocrelizumab group with adverse events was similar to interferon beta-1a in a pooled analysis of both studies (83.3 percent in each treatment group); the most common adverse event associated with ocrelizumab was infusion-related reactions (34.3 percent of patients who received ocrelizumab experienced at least one infusion-related reaction vs. 9.7 percent for interferon beta-1a). The proportion of patients in the ocrelizumab group with serious adverse events, including serious infections, was also similar to interferon beta-1a (6.9 percent vs. 8.7 percent, respectively).
  • The ORATORIO study met its primary endpoint, showing treatment with ocrelizumab significantly reduced the risk of progression of clinical disability sustained for at least 12 weeks by 24 percent compared with placebo. (Abstract #2368, Professor Montalban). Additionally, ocrelizumab was superior to placebo in significantly reducing the risk of progression of clinical disability for at least 24 weeks by 25 percent (p=0.0365) and the time required to walk 25 feet (Timed 25-Foot Walk, or T25-FW) over 120 weeks by 29 percent. Ocrelizumab decreased the volume of hyperintense T2 lesions by 3.4 percent over 120 weeks, compared to placebo which increased T2 volume by 7.4 percent. Ocrelizumab reduced the rate of whole brain volume loss over 120 weeks by 17.5 percent compared to placebo.
  • Overall, the proportion of patients in the ocrelizumab group with adverse events was similar to placebo (95.1 percent vs. 90.0 percent, respectively); the most common adverse event associated with ocrelizumab was infusion-related reactions (39.9 percent vs. 25.5 percent for placebo). The proportion of patients in the ocrelizumab group with serious adverse events, including serious infections, was also similar to placebo (20.4 percent vs. 22.2 percent, respectively).

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