New Data: Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis

New data on the long term benefits of Ocrelizumab for PPMS has recently been published 29 October 2020 on the Lancet

Ocrelizumab is currently funded for RRMS in New Zealand but not currently for PPMS. This new data, covering a 6.5 year follow up period, provides further long term evidence to demonstrate the sustained benefits of Ocrelizumab on disease progression when given earlier in the disease course. Halting and slowing progression in PPMS is a high unmet need.

732 participants were randomly assigned to receive either intravenous infusion of 600-mg ocrelizumab (two 300-mg infusions, 14 days apart) or placebo every 24 weeks for at least 120 weeks. 544 completed the double-blind phase, after which patients entered an extended controlled period, followed by an optional open-label extension where they could continue ocrelizumab or switch from placebo to the drug. 527 people entered the open-label extension phase, the last patient entering in April 2016.

MedPage Today have published a review of these results, copied below:

Long-Term Ocrelizumab Benefits Seen in PPMS:

by Judy George, Senior Staff Writer, MedPage Today November 2, 2020

Early, continuous treatment with ocrelizumab (Ocrevus) led to sustained slowing of disease progression in primary progressive multiple sclerosis (PPMS), long-term data from the ORATORIO extension study suggested.

Most measures of 6-month confirmed disability progression, including Expanded Disability Status Scale (EDSS) scores, were better in PPMS patients who started treatment early in ORATORIO compared with patients who started with placebo before joining the open-label extension, reported Jerry Wolinsky, MD, of the University of Texas McGovern Medical School in Houston, and co-authors. No new safety signals emerged compared with the double-blind phase of ORATORIO.

“Compared with patients switching from placebo, earlier and continuous ocrelizumab treatment provided sustained benefits on measures of disease progression over the 6.5 study years of follow-up,” the researchers wrote in Lancet Neurology.

“Although this study shows the benefit of earlier intervention with ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis,” they noted. “Further research should focus on how the potential benefits described in this study might be improved upon, particularly over longer time periods.”

PPMS is characterized by gradual disability accumulation from disease onset, sometimes with superimposed relapses or MRI lesion activity. Ocrelizumab, an anti-CD20 monoclonal antibody, is the only disease-modifying therapy approved to treat PPMS currently. The FDA’s decision was based on ORATORIO results, which showed that treatment with intravenous 600-mg ocrelizumab every 6 months reduced 3-month confirmed worsening of EDSS scores compared with placebo.

“The efficacy of ocrelizumab versus placebo shown in ORATORIO was recapitulated as participants switched from placebo to ocrelizumab upon entering the open-label extension,” noted Deja Rose, MD, and Jeffrey Cohen, MD, both of the Cleveland Clinic in Ohio, in an accompanying editorial.

But several questions remain, Rose and Cohen pointed out: “Can we extrapolate these results in primary progressive multiple sclerosis to secondary progressive multiple sclerosis (a more common form of progressive multiple sclerosis, which occurs after a relapsing-remitting course)? Are there rare or late adverse events that have not yet been seen?”

“Some studies, but not others, have suggested that the proportion of patients treated with anti-CD20 monoclonal antibodies is higher among patients with severe COVID-19 outcomes than among the overall population with multiple sclerosis,” they added. “Further research is needed to investigate whether anti-CD20 monoclonal antibodies reduce protective immunity after SARS-CoV-2 infection or, when available, vaccination.”

ORATORIO was a double-blind phase III trial of PPMS patients with an EDSS score of 3.0-6.5. Patients who had previous treatment with B cell-targeted therapies or other immunosuppressive medications were excluded.

Participants were randomly assigned to receive either intravenous infusion of 600-mg ocrelizumab (two 300-mg infusions, 14 days apart) or placebo every 24 weeks for at least 120 weeks. After the double-blind phase, patients entered an extended controlled period, followed by an optional open-label extension where they could continue ocrelizumab or switch from placebo to the drug. The last patient entered the open-label extension in April 2016.

Overall, 544 of 732 participants completed the double-blind period, and 527 people entered the open-label extension phase. Time to onset of disability progression was confirmed at 6 months with four measures — increase in EDSS score; 20% or more increase in time to complete the 9-Hole Peg Test (9HPT); 20% or more increase in time to perform the Timed 25-Foot Walk (T25FW); and composite progression, defined as the first confirmed occurrence of any of these three individual measures. Time to requiring a wheelchair (EDSS score 7 or higher) also was assessed.

After at least 6.5 study years of follow-up, the proportion of patients with progression on disability measures was lower in those who started ocrelizumab early compared with those who started with placebo in most measures of 6-month confirmed disability progression (T25FW showed a non-significant trend):

  • EDSS score: 51.7% vs 64.8%; difference 13.1%, 95% CI 4.9-21.3, P=0.0018
  • 9HPT: 30.6% vs 43.1%; difference 12.5%, 95% CI 4.1-20.9, P=0.0035
  • T25FW: 63.2% vs 70.7%; difference 7.5%, 95% CI -0.3 to 15.2, P=0.058
  • Composite progression: 73.2% vs 83.3%; difference 10.1%, 95% CI 3.6-16.6, P=0.0023
  • Confirmed time to requiring a wheelchair: 11.5% vs 18.9%; difference 7.4%, 95% CI 0.8-13.9, P=0.0274

Percent changes in T2 lesion volume (0.45% vs 13.00%, P<0.0001) and T1 hypointense lesion volume (36.68% vs 60.93%, P<0.0001) were lower among early ocrelizumab starters than in those who started with placebo.

In the all-ocrelizumab exposure population, adverse events were 238.09 (95% CI 232.71-243.57) per 100 patient-years. Serious adverse events were 12.63 (95% CI 11.41-13.94) per 100 patient-years, most commonly serious infections, at 4.13 (95% CI 3.45-4.91) per 100 patient-years. One potential serious opportunistic infection emerged in the open-label extension, a case of serious Candida sepsis that resolved in a patient who had stopped ocrelizumab 11 months earlier and was receiving cancer chemotherapy.

As of January 7, 2019, no cases of progressive multifocal leukoencephalopathy were identified in the overall ORATORIO study population. Also of that date, the rate of all malignancies per 100 patient-years in the all-exposure population was 0.91 (95% CI 0.61-1.32).

The study has several limitations, Wolinsky and co-authors said. As an open-label extension study, it lacked a control group. Survivor bias may have confounded results and open-label treatment may have led to bias. “It is important to note that, although there was a continued benefit for patients who initiated ocrelizumab 3-5 study years earlier, subgroup analyses were not done on patients who were earlier on in their multiple sclerosis disease course,” the researchers added.

Participants were randomly assigned to receive either intravenous infusion of 600-mg ocrelizumab (two 300-mg infusions, 14 days apart) or placebo every 24 weeks for at least 120 weeks. After the double-blind phase, patients entered an extended controlled period, followed by an optional open-label extension where they could continue ocrelizumab or switch from placebo to the drug. The last patient entered the open-label extension in April 2016.

Like this article?

Share on Facebook
Share on Twitter
Share on Linkdin
Share on Email

Andrew Cushen

Trustee

Andrew is an independent corporate affairs and strategy consultant, working and living in Auckland. He has previously held senior positions in a number of corporate and not-for-profit entities in New Zealand.

Across his career, Andrew has worked as a funder of research projects (albeit in different areas than medicine and health), served in a number of not-for-profit governance roles, and been successful in developing and implementing collaborative funding models to extend investment in research and community programmes.

Andrew’s interest in Multiple Sclerosis stems from his father’s diagnosis with progressive MS in the early 2000s, and he is keenly interested in research, treatment and management approaches that may lessen the impact of MS on those diagnosed and their families.

Julia Howell

Trustee

Julia is a qualified nurse and midwife, with a varied career including specialising in eating disorders, primary healthcare, and management.    

Julia, in partnership with a GP, set up an outpatient clinical trials unit (Southern Clinical Trials). Under her leadership this grew into a network of 6 sites across NZ. This network merged with another one in 2021 to form PCRN, NZ’s largest clinical trials network. Julia is currently working as joint COO for PCRN.

Julia’s daughter was diagnosed with MS aged 14 and she has been intimately involved with her management over the years.

 

Jan Campbell

Trustee

Born in Ōtautahi Jan trained as a nurse in Christchurch, as a midwife in Winchester, UK and has a degree in philosophy with particular interest in healthcare and business ethics.

After working in the public health system in the UK and NZ, Jan joined Roche Pharmaceuticals based in Auckland in 1999. As a respected senior leader and Medical Director, she established a medical division over the ensuing 20 years responsible for significant investment in clinical trials in NZ, developing a top-class global medicine information service, compassionate medicine supply for kiwis in need, pharmacovigilance oversight and a team working closely with patients, specialists, MEDSAFE and PHARMAC to support the safe and appropriate use of Roche medicines.

As a retiree Jan has volunteered for Mercy Hospice in Auckland and the WBoP Museum in Katikati. Now living in Ōtepoti, Jan sits on both the MS Research Trust and MSNZ executive committees with a keen interest to ensure people with MS get a fair go in NZ.

Dr Elza Cloete

Trustee

Elza is a Neonatal Paediatrician at Christchurch Women’s Hospital. Originally from South Africa, she moved to New Zealand in 2006 and completed her specialist training in Auckland.

Subsequent to that she embarked on doctoral studies at the University of Auckland’s Liggins Institute and obtained a PhD investigating congenital heart disease in new-born babies.

Elza received the Vice-Chancellor’s award for best doctoral thesis for her research and is the author of several research publications. She moved to Christchurch in 2020 for a work opportunity in clinical practice.

Elza was diagnosed with MS in 2012 and brings a consumer perspective and research experience to the Trust.

Dr Ernie Willoughby

Trustee

Dr Willoughby has been a consultant neurologist at Auckland City Hospital (1979 to 2021 – now retired, emeritus) and clinical associate professor at Auckland University School of Medicine.

He directed the MS clinic at Auckland Hospital, has had a long association with the Auckland and NZ MS Societies, and is a member of the International Medical and Scientific Board of the MS International Federation.

Dr Brian Linehan

Independent Trustee

Dr Brian Linehan is a retired pathologist who was previously Managing Director of Medlab Hamilton.

He is currently Chairman of the Tranmere group of investment companies and a Director of a number of other private companies. In 2014, he retired after 12 years on the Council of the University of Waikato where he was Pro-Chancellor.

He is a past Chairman of the New Zealand Medical Association, past Chairman of NZMA Ethics Committee, past President and Chairman of CMAAO (Combined Medical Associations of Asia and Oceania) and past Chairman of IANZ (International Accreditation NZ).

Brian was diagnosed with MS in 2007 but is still active and mobile.

Peter Wood - JP, BCom, AGNZ, ACIS, FNZTA

Treasurer

Peter gained his commerce degree at Victoria University of Wellington and has been practising as a Chartered Accountant initially in Wellington and then in Tauranga.

Peter was a respected and trusted advisor to many businesspeople.
He is now resident in Auckland and consultants to a limited number business clients.

He has also served his community through involvement with Jaycees, Lions and Rotary clubs and a number of charitable trusts.

Peter is currently the Treasurer of Multiple Sclerosis Auckland and a trustee of the Multiple Sclerosis Auckland Trust. Peter is a Justice of the Peace and a member Governance New Zealand and is a Fellow of the NZ Trustees’ Association.

Neil Woodhams

Trustee

Neil is an independent health management consultant who has had an extensive career in health management as a senior manager or consultant to government, DHBs, primary care and community providers. 

Neil is President of MS New Zealand and a trustee of the MS Auckland Region Trust. Neil was also President of MS Auckland until he stepped down from this role mid-2020 to concentrate on his national roles.

Neil’s wife was diagnosed with MS in 1994. One of his four sons was also diagnosed in 2010.

Neil strongly believes in the objectives of the NZ Multiple Sclerosis Research Trust and has advocated for the establishment of the Trust for over 10 years.

Sir William Gallagher

Trustee

Sir William is renowned as a motivational, pragmatic and hands-on businessman in and outside of New Zealand and has a reputation both as a dynamic leader and one of NZ’s most astute businessmen.

Still very involved in the daily operation, he maintains regular contact with customers in the 130 countries in which Gallagher products are sold spending up to 150 days a year on the road representing the company and its philosophies and emphasising the ethics and integrity of his professional and personal dealings.

His achievements have been officially recognised by a string of awards, the latest to mark his commitment to enterprise and leadership skills being his Knighthood in the 2010 New Year’s Honours List. He was also the 1996 winner of the prestigious Excellence in Communication Leadership award, the first time in its history that it had been awarded outside of North America. He also received an MBE in 1987 followed by a Companion of the New Zealand Order of Merit (CNZM) in 1998.

Sir William Gallagher - KNZM, MBE. HonD

Patron

Sir William is renowned as a motivational, pragmatic and hands-on businessman in and outside of New Zealand and has a reputation both as a dynamic leader and one of NZ’s most astute businessmen.

Still very involved in the daily operation, he maintains regular contact with customers in the 130 countries in which Gallagher products are sold spending up to 150 days a year on the road representing the company and its philosophies and emphasising the ethics and integrity of his professional and personal dealings.

His achievements have been officially recognised by a string of awards, the latest to mark his commitment to enterprise and leadership skills being his Knighthood in the 2010 New Year’s Honours List. He was also the 1996 winner of the prestigious Excellence in Communication Leadership award, the first time in its history that it had been awarded outside of North America. He also received an MBE in 1987 followed by a Companion of the New Zealand Order of Merit (CNZM) in 1998.