Novartis announces publication of Phase III ASCLEPIOS trials data in NEJM demonstrating efficacy of the ofatumumab in patients with relapsing multiple sclerosis

·         Ofatumumab, an investigational product, demonstrated superiority versus teriflunomide in clinical measures of disease activity and in slowing worsening of disability in patients with relapsing forms of multiple sclerosis (RMS)[i]

 

·         Post-hoc analysis showed ofatumumab may suspend new disease activity, with 47.0% and 87.8% of patients treated with ofatumumab achieving no evidence of disease activity (NEDA-3) within the first (n=841) and second year (n=833) of treatment, respectively^[ii]

 

·         Ofatumumab is a targeted B-cell therapy with a similar safety and tolerability profile to teriflunomide as demonstrated in Phase III ASCLEPIOS I and II trials¹

London, UK, August 06, 2020 – Novartis today announced that the New England Journal of Medicine (NEJM) has published results from the ASCLEPIOS I and II studies of ofatumumab (OMB157) versus teriflunomide in adult patients with relapsing forms of multiple sclerosis (RMS). The data demonstrate the superiority of ofatumumab in reducing the rates of disease activity and progression compared with teriflunomide, a commonly prescribed oral disease modifying therapy (DMT) for relapsing MS^1,[iii]. If licensed, ofatumumab will be the first B-cell therapy that can be self-administered at home using an autoinjector pen.

In the ASCLEPIOS I and II studies, ofatumumab showed a significant reduction in the frequency of confirmed relapses versus teriflunomide, as evaluated by the annualised relapse rate (ARR)¹. Results also demonstrated suppression of new inflammatory activity evidenced on MRI scans, showing a significant reduction of both gadolinium enhancing (Gd+) T1 lesions and new or enlarging T2 lesions compared with teriflunomide¹.

Additionally, ofatumumab was shown to reduce the risk of three- and six-month confirmed disability worsening (CDW) compared with teriflunomide¹. Gradual disability worsening independent of relapse activity is now recognised to occur throughout the course of RMS, highlighting the importance of both controlling disease activity and slowing down disability progression in the management of RMS[iv]^,[v].

“It is increasingly clear that early initiation of disease modifying treatments can improve long-term outcomes for patients with RMS, and there is a need for effective, well tolerated and convenient treatment options that can be used early in the development of the condition,” said Dr Martin Duddy, Clinical Director and Consultant Neurologist at Newcastle upon Tyne Hospitals NHS Foundation Trust. “The ASCLEPIOS results are positive news for patients and physicians seeking to meaningfully reduce the chance of relapses and worsening disability.”

 

 

“Ofatumumab appears to be effective and well tolerated in the ASCLEPIOS I and II studies which support its potential to become a new treatment option that offers RMS patients flexibility and control in managing their disease,” said Dr Mark Toms, Chief Scientific Officer, Novartis UK. “These results are a testament to our commitment to reimagine treatment in the MS journey and represent another step towards addressing the unmet needs of people living with RMS in the UK.”

There are approximately 130,000 people living with MS in the UK, of which approximately 85% are considered to have relapsing remitting MS (RRMS) at the point of diagnosis[vi]^,[vii]. Despite the availability of a range of DMTs for RMS, there are significant needs that are not fully met by current treatment options. While MS progression is different for each person and influenced by multiple factors, studies have shown that between 24% and 40% of people with RRMS progress to secondary progressive MS (SPMS) within 10 years of diagnosis^{[viii],[ix],[x]}. SPMS is characterised by a progressive accumulation of disability over time[xi].

A separate post-hoc analysis from the ASCLEPIOS I and II trials, presented virtually at the 6^th Congress of the European Academy of Neurology (May 2020), found that ofatumumab suspended several measures of new disease activity in RMS patients². Results showed that compared with teriflunomide, a greater proportion of patients treated with ofatumumab achieved no evidence of disease activity – as measured by NEDA-3, defined as the absence of relapses, MRI lesions, and disability worsening combined – in the first and second year of treatment².

The marketing authorisation application for ofatumumab is currently under review by the European Medicines Agency (EMA), with decisions anticipated in Q2 2021.

About ASCLEPIOS I and II studies

The ASCLEPIOS I and II studies are twin, identical design, flexible duration (up to 30 months), double-blind, randomized, multi-centre Phase III trials evaluating the safety and efficacy of ofatumumab versus teriflunomide in adults with RMS¹. The studies were conducted in 37 countries and enrolled 1,882 patients between the ages of 18 and 55 years, with an Expanded Disability Status Scale (EDSS) score between 0 and 5.5¹. Ofatumumab demonstrated a significant reduction in annualized relapse rate (ARR) by 50.5% (0.11 vs. 0.22) and 58.5% (0.10 vs. 0.25) compared with teriflunomide in ASCLEPIOS I and II, respectively (P<0.001 in both studies; primary endpoint)¹.

 

Ofatumumab significantly reduced the mean number of both Gd+ T1 lesions in ASCLEPIOS I and II. In ASCLEPIOS I, the mean number of GD+ T1 lesions per MRI scan was 0.012 with ofatumumab and 0.452 with teriflunomide. In ASCLEPIOS II, the corresponding numbers were 0.032 and 0.514 (97.5% and 93.8% relative reduction in ASCLEPIOS I and II, respectively, both P<0.001) ¹.

 

In ASCLEPIOS I, the mean number of new or enlarging T2 lesions per year was 0.72 with ofatumumab and 4.00 with teriflunomide, corresponding values in ASCLEPIOS II were 0.64 and 4.15 (82.0% and 84.5% relative reduction in ASCLEPIOS I and II, respectively, both P<0.001)¹.

 

Ofatumumab also showed a relative risk reduction of 34.4% (P=0.002) in three-month confirmed disability worsening (CDW) (9.3% for ofatumumab and 13.4% for teriflunomide) and 32.5% (P=0.012) in six-month CDW (7.5% for ofatumumab and 10.6% for teriflunomide) compared with teriflunomide in pre-specified analyses meta-analysis, as defined in ASCLEPIOS¹. The frequency of serious infections and malignancies was similar across both treatment groups, and overall, ofatumumab has a similar safety profile to teriflunomide¹.

 

A separate post hoc analysis from the ASCLEPIOS I and II trials showed that compared with teriflunomide, a greater proportion of patients treated with ofatumumab achieved no evidence of disease activity (NEDA-3; no relapses, no MRI lesions, and no disability worsening combined) in the first (47.0% (n=841) vs 24.5% (n=854); P<0.001) and second year of treatment (87.8% (n=833) vs 48.2% (n=821); P<0.001) ².

 

About ofatumumab (OMB157)

Ofatumumab is a fully human anti-CD20 monoclonal antibody (mAb) in development for RMS that is self-administered by a once-monthly injection, delivered subcutaneously^1,[xii]. As shown in preclinical studies, ofatumumab is thought to work by binding to a distinct epitope on the CD20 molecule, inducing potent B-cell lysis and depletion[xiii]. Once-monthly dosing of ofatumumab allows faster repletion of B-cells versus other anti-CD20 monoclonal antibodies, and offers flexibility in the management of RMS[xiv].

 

About Multiple Sclerosis
There are approximately 130,000 people with multiple sclerosis (MS) in the UK, and each year around 7,000 people are newly diagnosed with the condition⁶. MS is a chronic disorder of the central nervous system (CNS) that disrupts the normal functioning of the brain, optic nerves and spinal cord through inflammation and tissue loss^[xv]. The evolution of MS results in an increasing loss of both physical and cognitive functions (e.g. mobility problems, numbness, bladder and bowel problems, and problems with thinking, learning and planning)^[xvi]. There are three types of MS: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)^[xvii]. Patients with relapsing forms of MS – including RRMS and SPMS with active disease – experience distinct attacks of symptoms, known as relapses^11,[xviii]. Around 85% of people are considered to have RRMS at their point of diagnosis⁷. SPMS, which typically follows from an initial RRMS course, is characterised by a gradual worsening of neurological function over time, and can be described as active (with relapses and/or evidence of new MRI activity) or not active (no evidence of current activity)^11,[xix].

 

About Novartis in Multiple Sclerosis 

Novartis has a strong ongoing commitment to neuroscience and to bringing innovative treatments to patients suffering from neurological conditions where there is a high unmet need. The Novartis multiple sclerosis (MS) portfolio includes Gilenya^®▼ (fingolimod, an S1P modulator), which is licenced in Europe for the treatment of adults and children aged 10 and older with highly active relapsing remitting forms of MS. Mayzent^®▼ (siponimod) is licenced in Europe for the treatment of adult patients with SPMS with active disease evidenced by relapses or imaging features of inflammatory activity. Extavia^® (interferon beta-1b for subcutaneous injection) is approved in Europe to treat people with RRMS, people with SPMS with active disease (evidenced by relapses), and people who have had a single clinical event suggestive of MS.

 

About Novartis

Novartis is reimagining medicine to improve and extend people’s lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world’s top companies investing in research and development. Novartis products reach more than 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 130,000 people of nearly 150 nationalities work at Novartis around the world. Find out more at www.novartis.com.

 

In the UK, we employ approximately 1,500 people to serve healthcare needs across the whole of the UK, as well as supporting the global operations of Novartis. Since 2014, Novartis has invested over £200 million in R&D and is a leading sponsor of clinical trials, in the UK. For more information, please visit www.novartis.co.uk.

 

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[i] Hauser S, Bar-Or A, Cohen J, et al. Ofatumumab versus teriflunomide in relapsing multiple sclerosis. New Engl J Med. 2020;383:546-57.

[ii] Hauser S, Bar-Or A, Cohen J, et al. Ofatumumab versus teriflunomide in relapsing multiple sclerosis: Analysis of no evidence of disease activity (NEDA-3) from ASCLEPIOS I and II trials. Eur J Neurol. 2020;27(1):261–263.

[iii] MS Trust. Aubagio (teriflunomide). Available at: https://www.mstrust.org.uk/a-z/aubagio-teriflunomide. Accessed July 2020.

[iv] Winkelmann A, Loebermann M, Reisinger E, Hartung H, Zettl U. Disease-modifying therapies and infectious risks in multiple sclerosis. Nat Rev Neurol. 2016 Apr;12(4):217-33.

[v] The Multiple Sclerosis Coalition. The use of disease-modifying therapies in multiple sclerosis: principles and current evidence. Available at: http://ms-coalition.org/the-use-of-disease-modifying-therapies-in-multiple-sclerosis-updated/. Accessed July 2020.

[vi] MS Society. MS in the UK. Available at: https://www.mssociety.org.uk/what-we-do/our-work/our-evidence/ms-in-the-uk. Accessed July 2020.

[vii] Multiple Sclerosis International Federation. Atlas of MS 2013. Available at: http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf. Accessed July 2020.

[viii] Tremlett H, Yinshan Z, Devonshire V. Natural history of secondary-progressive multiple sclerosis. Mult Scler. 2008; 14: 314-324.

[ix] Scalfari A, Neuhaus A, Daumer M, Muraro PA, Ebers GC. Onset of secondary progressive phase and long-term evolution of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85:67-75.

[x] Rovaris M, Confavreux C, Furlan R, Kappos L, Comi G, Filippi M. Secondary progressive multiple sclerosis: current knowledge and future challenges. Lancet Neurol. 2006;5:343-354.

[xi] National Multiple Sclerosis Society. Secondary Progressive MS (SPMS). https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS. Accessed July 2020.

[xii] Bar-Or A, Fox E, Goodyear A, et al. Onset of B-cell Depletion with Subcutaneous Administration of Ofatumumab in Relapsing Multiple Sclerosis: Results from the APLIOS Bioequivalence Study. Presented at Americas Committee for Treatment and Research in Multiple Sclerosis Forum; February 27–29, 2020.

[xiii] Smith P, Kakarieka A, Wallstroem E. Ofatumumab is a fully human anti-CD20 antibody achieving potent B-cell depletion through binding a distinct epitope. Poster presented at ECTRIMS; September 2016; London, UK.

[xiv] Savelieva M, Kahn J, Bagger M, et al. Comparison of the B-Cell Recovery Time Following Discontinuation of Anti-CD20 Therapies. ePoster presented at ECTRIMS; October 25–28, 2017; Paris, France.

[xv] National Multiple Sclerosis Society. Definition of MS. Available at: https://www.nationalmssociety.org/What-is-MS/Definition-of-MS. Accessed July 2020.

[xvi] NHS. Multiple sclerosis – Symptoms. Available at: https://www.nhs.uk/conditions/multiple-sclerosis/symptoms/. Accessed July 2020.

[xvii] MS Society. Types of MS. Available at: https://www.mssociety.org.uk/what-is-ms/types-of-ms. Accessed July 2020.

[xviii] MS Society. Relapsing remitting MS. https://www.mssociety.org.uk/about-ms/types-of-ms/relapsing-remitting-ms. Accessed July 2020.

[xix] MS Society. Secondary Progressive MS (SPMS). Available at: https://www.mssociety.org.uk/about-ms/types-of-ms/secondary-progressive-ms. Accessed July 2020.