Genentech’s Ocrelizumab First Investigational Medicine to Show Positive Pivotal Study Results in Both Relapsing and Primary Progressive Forms of Multiple Sclerosis

  • Ocrelizumab showed superiority to interferon beta-1a (Rebif®) in
    two identical Phase III studies in people with relapsing multiple
    sclerosis (MS), the most common form of the disease
  • Ocrelizumab is the first investigational medicine to show efficacy
    in people with primary progressive MS in a large Phase III study
  • Ocrelizumab Phase III data will be presented at the 31st congress
    of the European Committee for Treatment and Research in Multiple
    Sclerosis (ECTRIMS) from October 7-10 in Barcelona, Spain

SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE)–Genentech, a member of the Roche group (SIX: RO, ROG; OTCQX: RHHBY)
today announced data from three positive, pivotal Phase III studies of
ocrelizumab in people with relapsing multiple sclerosis (MS) and primary
progressive multiple sclerosis (PPMS). Data from two identical studies
(called OPERA I and OPERA II) in people with relapsing MS, which affects
approximately 85 percent of people with MS at the time of diagnosis,
showed ocrelizumab was superior to interferon beta-1a (Rebif®), a
well-established MS therapy, in reducing the three major markers of
disease activity over the two-year controlled treatment period.

In a separate study (called ORATORIO) in people with PPMS, a form of the
disease marked by steadily worsening symptoms and typically without
distinct relapses or periods of remission, 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.

“The results of these three pivotal trials have the potential to
transform the treatment of MS,” said Sandra Horning, M.D., chief medical
officer and head of Global Product Development. “Ocrelizumab is the
first investigational medicine to significantly reduce disability
progression in people with relapsing MS and people with primary
progressive MS – a form of MS with no approved treatments. We are eager
to work with regulatory authorities to bring this investigational
medicine to the MS community as soon as possible.”

“These results redefine our understanding of MS by highlighting the
central role of the B cell,” said Stephen Hauser, M.D., chair of the
Scientific Steering Committee of the OPERA studies and chair of the
Department of Neurology at the University of California San Francisco
School of Medicine. “The findings may also encourage the MS community to
look more closely at earlier treatment of the disease. Currently, many
doctors reserve what are considered highly effective MS medicines until
a patient’s disease becomes more advanced. Patients and their doctors
need new treatment options that offer the potential for greater efficacy
than a standard-of-care interferon with a similar safety profile.”

“This is an important moment for the MS community,” said Xavier
Montalban, M.D., Ph.D., chair of the Scientific Steering Committee of
the ORATORIO study and professor of Neurology and Neuroimmunology at
Vall d’Hebron University Hospital and Research Institute, Barcelona,
Spain. “For decades, trial after trial has failed to show the benefit of
any medicine for people with primary progressive MS. Now, for the first
time, we have a positive Phase III study result for people with this
debilitating form of the disease.”

Genentech plans to pursue marketing authorization for ocrelizumab in
relapsing MS and in PPMS. Data from the ocrelizumab OPERA I and OPERA II
studies and from the ORATORIO study will be submitted to the U.S. Food
and Drug Administration in early 2016.

About the OPERA I and OPERA II studies in relapsing MS

Results from the OPERA I and OPERA II studies will be presented by Dr.
Hauser on Friday, October 9 (Abstract #246, 2:40-2:52 PM CET). 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

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. 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,
    respectively (p<0.0001 and p<0.0001).
  • 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,
    respectively (p=0.0139 and p=0.0169).
  • 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,
    respectively (p=0.0278 and p=0.0370).
  • 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, respectively (p<0.0001 and p<0.0001).
  • 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, respectively (p<0.0001 and p<0.0001).

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).

About the ORATORIO study in PPMS

Results from the ORATORIO study will be presented as a late-breaking
abstract by Professor Montalban on Saturday, October 10 (Abstract #2368,
8:52-9:03 AM CET). 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.2 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.

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, as measured by the EDSS (p=0.0321). 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 (p=0.0404). 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 (p<0.0001).
Ocrelizumab reduced the rate of whole brain volume loss over 120 weeks
by 17.5 percent compared to placebo (p=0.0206).

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).

Follow Genentech on Twitter via @Genentech and keep up to date with 2015
congress of ECTRIMS news and updates by using the hashtag #ECTRIMS2015.

About ocrelizumab

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.

The Phase III clinical development program for ocrelizumab includes
three studies: OPERA I, OPERA II and ORATORIO.

About multiple sclerosis

Multiple sclerosis (MS) is a chronic disease that affects an estimated
2.3 million people around the world, for which there is currently no
cure.3,4 MS occurs when the immune system abnormally attacks
the insulation and support around nerve cells (myelin sheath) in the
brain, spinal cord and optic nerves, causing inflammation and consequent
damage. Damage to these nerves can cause a wide range of symptoms,
including muscle weakness, fatigue and difficulty seeing, and may
eventually lead to disability.5,6,7 Most people with MS
experience their first symptom between 20 and 40 years of age, making
the disease the leading cause of non-traumatic disability in younger
adults.8

Relapsing MS is the most common form of the disease. Disease activity
and progression can occur even when people do not show signs or symptoms
of MS, despite available relapsing MS treatments. Primary progressive MS
(PPMS) is a debilitating form of the disease marked by steadily
worsening symptoms but typically without distinct relapses or periods of
remission.9 Approximately one in 10 people with MS are
diagnosed with the primary progressive form of the disease. There are no
approved treatments for PPMS.

About Genentech in neuroscience

Neuroscience is a major focus of research and development at Genentech
and Roche. The company’s goal is to develop treatment options based on
the biology of the nervous system to help improve the lives of people
with chronic and potentially devastating diseases. Roche has more than a
dozen investigational medicines in clinical development for diseases
that include multiple sclerosis, Alzheimer’s disease, spinal muscular
atrophy, Parkinson’s disease, Down syndrome and autism.

About Genentech

Founded more than 35 years ago, Genentech is a leading biotechnology
company that discovers, develops, manufactures and commercializes
medicines to treat patients with serious or life-threatening medical
conditions. The company, a member of the Roche Group, has headquarters
in South San Francisco, California. For additional information about the
company, please visit http://www.gene.com.

All trademarks used or mentioned in this release are protected by law.
Rebif is a registered trademark of Merck KGaA and EMD Serono, Inc.

1 F. Hoffmann-La Roche. ClinicalTrials.gov NCT01247324 and
NCT01412333. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT01247324
and https://clinicaltrials.gov/ct2/show/NCT01412333.

2 F. Hoffmann-La Roche. ClinicalTrials.gov NCT01194570.
National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT01194570.

3 Multiple Sclerosis International Federation. (2013). Atlas
of MS 2013. Available at: http://www.msif.org/about-us/advocacy/atlas/.

4 National Institutes of Health-National Institute of
Neurological Disorders and Stroke. (2015). Multiple Sclerosis: Hope
Through Research. Available at: http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm#280373215.

5 Ziemssen T. (2005). Modulating processes within the central
nervous system is central to therapeutic control of multiple sclerosis. J
Neurol
, 252(Suppl 5), v38-v45.

6 Hauser S.L. et al. (2012). Multiple sclerosis and other
demyelinating diseases. In Harrison’s Principles of Internal Medicine
(pp.3395-3409). New York, NY: McGraw Hill Medical.

7 Hadjimichael O. et al. (2007). Persistent pain and
uncomfortable sensations in persons with multiple sclerosis. Pain, 127(1-2),
35-41.

8 Multiple Sclerosis International Federation. What is MS?
Available at http://www.msif.org/about-ms/what-is-ms/.
Last accessed January 2015.

9 MS International Federation. Types of MS. Available at: http://www.msif.org/about-ms/types-of-ms/.

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