Novartis announces new late-breaking ofatumumab data at EAN demonstrating robust efficacy and safety in the treatment of relapsing forms of multiple sclerosis (RMS)

• Rapid and profound depletion of B-cells contributed to a halt in disease activity in RMS patients¹
   
• A post hoc analysis showed 47.0% and 87.8% of patients treated with ofatumumab achieved no evidence of disease activity (NEDA-3) within the first (0–12 months) and second year (12–24 months) of treatment, respectively¹
   
• Regulatory action for ofatumumab in RMS in the US is expected in June 2020
   
• If approved, ofatumumab has the potential to become a first-choice treatment for RMS patients and the first B-cell therapy that can be self-administered at home using an autoinjector pen

Basel, May 27, 2020 — Novartis announced today that new ofatumumab data from the Phase III ASCLEPIOS trials and the Phase II APLIOS trial were presented virtually at the 6^th Congress of the European Academy of Neurology (EAN). The data continue to demonstrate ofatumumab (OMB157) as a potential novel treatment option for patients with RMS. The safety profile was comparable to teriflunomide².

Ofatumumab is a targeted B-cell therapy that, if approved, addresses a clinical unmet need as the first B-cell therapy that can be self-administered at home through an autoinjector pen². In addition to being presented virtually, the data were also published in the European Journal of Neurology, Volume 27, Supplement 1, May 2020.

A post hoc analysis from the Phase III ASCLEPIOS I and II trials (n=1882) assessed the odds of patients achieving NEDA-3 with ofatumumab versus teriflunomide within the first (Month 0–12) and second year (Month 12–24) of treatment¹. NEDA-3 is a comprehensive composite measure commonly used to assess treatment outcomes in patients with RMS. It is defined as an absence of three measures of disease activity: relapses; disease progression, measured as 6-month confirmed disability worsening (CDW), and gadolinium enhancing (Gd+) T1 lesions³. The study results showed that compared with teriflunomide, a greater proportion of patients treated with ofatumumab achieved NEDA-3 in year 1 (47.0% vs 24.5%; P<.001) and in year 2 (87.8% vs 48.2%; P<.001)¹.

“Achieving no evidence of disease activity is widely recognized as an important treatment goal for multiple sclerosis therapies,” said Professor Ludwig Kappos, University Hospital Basel. “These data suggest that halting new disease activity is possible by targeted B-cell therapy in RMS.”

A separate analysis from the APLIOS trial (n=284) showed ofatumumab treatment led to rapid and sustained depletion of both CD20+ B- and T-cells in patients with RMS. Ofatumumab depleted different B- and T-cell subsets including memory B-cells and naïve B-cells, as well as a subset of T-cells that are known to exhibit an activated phenotype. However, CD3+ T-cells that do not express the CD20 receptor, were largely unaffected⁴.

“These results are encouraging and support our belief that, if approved, ofatumumab could have the potential to significantly improve the lives of people with RMS,” said Krishnan Ramanathan, Neuroscience Global Program Head at Novartis. “These data are a testament to our commitment to reimagining medicine and advancing innovative treatments that help people with this serious and progressive disease.”

Regulatory action for ofatumumab in the US is expected in June 2020. Novartis is committed to bringing ofatumumab to patients around the world, and additional regulatory filings are currently under way.

About ofatumumab
Ofatumumab (OMB157) is a fully human anti-CD20 monoclonal antibody (mAb) in development for RMS that is self-adminstered by a once-monthly injection, delivered subcutaneously^2,5. 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 depletion⁶. The selective mechanism of action and subcutaneous administration of ofatumumab allows precise delivery to the lymph nodes, where B-cell depletion in MS is needed, and may preserve the B-cells in the spleen, as shown in preclinical studies⁷. Once-monthly dosing of ofatumumab also allows fast repletion of B-cells and offers more flexibility⁸. Ofatumumab was originated by Genmab and licensed to GlaxoSmithKline; Novartis obtained rights for ofatumumab from GlaxoSmithKline in all indications, including RMS, in December 2015⁹.

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-center Phase III studies evaluating the safety and efficacy of ofatumumab 20 mg monthly subcutaneous injections versus teriflunomide 14 mg oral tablets taken once daily in adults with RMS. The ASCLEPIOS I and II studies enrolled 1882 patients with MS, between the ages of 18 and 55 years, with an Expanded Disability Status Scale (EDSS) score between 0 and 5.5². The studies were conducted in over 350 sites in 37 countries¹⁰. 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 (P<.001 in both studies) in ASCLEPIOS I and II respectively (primary endpoint). Ofatumumab showed significant reduction of both Gd+T1 lesions and new or enlarging T2 lesions. It significantly reduced the mean number of both Gd+ T1 lesions (97.5% and 93.8% relative reduction in ASCLEPIOS I and II, respectively, both P<.001) and new or enlarging T2 lesions (82.0% and 84.5% relative reduction in ASCLEPIOS I and II, respectively, (both P<.001).

Ofatumumab also showed a relative risk reduction of 34.4% (P=.002) in 3-month CDW and 32.5% (P=.012) in 6-month CDW compared with teriflunomide in pre-specified meta-analysis, as defined in ASCLEPIOS. Ofatumumab demonstrated that it lowered neurofilament light levels in serum at the first assessment at Month 3 compared with teriflunomide. There was no difference in slope of brain volume change from baseline between treatments. In a measure of 6-month confirmed disability improvement events, a favorable trend was seen but this did not reach significance. The frequency of serious infections and malignancies was similar across both treatment groups, and overall, ofatumumab had a similar safety profile to teriflunomide. Injection-related reactions, injection-site reactions and upper respiratory tract infection were the most commonly observed adverse events across both treatment groups, occurring in ≥10% of patients².

A separate post hoc analysis demonstrated ofatumumab may halt new disease activity in RMS patients. It showed the odds of achieving NEDA-3 (no relapses, no MRI lesions, and no disability worsening combined) with ofatumumab versus teriflunomide were >3-fold higher at Month (M) 0–12 (47.0% vs 24.5% of patients; P<.001) and >8-fold higher at M12–24 (87.8% vs 48.2% of patients; P<.001)¹. Overall ofatumumab, a fully human antibody targeting CD20+ B-cells, delivered superior efficacy and demonstrated a safety and tolerability profile with infection rates similar to teriflunomide².

About APLIOS study
The APLIOS study is a 12-week, open-label, Phase II bioequivalence study to determine the onset of B-cell depletion with ofatumumab subcutaneous monthly injections and the bioequivalence of subcutaneous administration of ofatumumab via a pre-filled syringe—as used in ASCLEPIOS I and II—and an autoinjector pen in patients with RMS. Patients were randomized according to injection device and site including the abdomen and the thigh. B-cell depletion was measured nine times over 12 weeks and Gd+ lesion counts were assessed at baseline and at Weeks 4, 8 and 12. Regardless of injection device or site, ofatumumab 20 mg subcutaneous monthly injections resulted in rapid, close to complete and sustained B-cell depletion. The proportion of patients with B-cell concentrations of <10 cells/μL was >65% after the first injection by Day 7, 94% by Week 4 and sustained >95% at all following injections. Ofatumumab treatment reduced the mean number of Gd+ lesions from baseline (1.5) to 0.8, 0.3 and 0.1 by Weeks 4, 8 and 12, respectively. The proportion of patients free from Gd+ lesions at the corresponding time points were 66.5%, 86.7%, and 94.1%, respectively^4,5.

About Multiple Sclerosis
MS disrupts the normal functioning of the brain, optic nerves and spinal cord through inflammation and tissue loss¹¹. MS, which affects approximately 2.3 million people worldwide¹², is often characterized into three forms: primary progressive MS (PPMS)¹³, relapsing remitting MS (RRMS), and secondary progressive MS (SPMS), which follows from an initial RRMS course and is characterized by physical and cognitive changes over time, in presence or absence of relapses, leading to a progressive accumulation of neurological disability¹⁴. Approximately 85% of patients initially present with relapsing forms of MS¹².

Novartis in Neuroscience
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. We are committed to supporting patients and physicians in multiple disease areas, including MS, migraine, Alzheimer's disease, Parkinson's disease, epilepsy and attention deficit hyperactivity disorder, and have a promising pipeline in MS, Alzheimer's disease, spinal muscular atrophy and specialty neurology.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “seek,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

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 nearly 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 109,000 people of more than 145 nationalities work at Novartis around the world. Find out more at https://www.novartis.com.

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References
1.    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.
2.    Hauser S. Efficacy and safety of ofatumumab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ASCLEPIOS I and II trials. Presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Annual Conference; September 11–13, 2019; Stockholm, Sweden.
3.    MS Trust. NEDA (no evidence of disease activity) [online]. Available from: https://www.mstrust.org.uk/a-z/neda-no-evidence-disease-activity [Last accessed: May 2020].
4.    Wiendl H, Fox E, Goodyear A, et al. Effect of Subcutaneous Ofatumumab on Lymphocyte Subsets in Patients with RMS: Analysis from the APLIOS Study. Eur J Neurol. 2020;27(1).
5.    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.
6.    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.
7.    Smith P, Huck C, Wegert V, et al. Low-dose, subcutaneous anti-CD20 therapy effectively depletes B-cells and ameliorates CNS autoimmunity. Poster presented at ECTRIMS; September 14–17, 2016; London, UK.
8.    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.
9.    GSK press release. GSK completes divestment of rights to ofatumumab for auto-immune indications to Novartis. December 21, 2015. Available from: https://www.gsk.com/en-gb/media/press-releases/gsk-completes-divestment-of-rights-to-ofatumumab-for-auto-immune-indications-to-novartis/ [Last accessed: May 2020].
10.  Kappos L, Bar-Or A, Comi G, et al. Ofatumumab Versus Teriflunomide in Relapsing Multiple Sclerosis: Baseline Characteristics of Two Pivotal Phase 3 Trials (ASCLEPIOS I and ASCLEPIOS II). Poster presented at ECTRIMS; October 10–12, 2018; Berlin, Germany.
11.  National Multiple Sclerosis Society. Definition of MS. Available from: https://www.nationalmssociety.org/What-is-MS/Definition-of-MS [Last accessed: May 2020].
12.  Multiple Sclerosis International Federation. Atlas of MS 2013. Mapping Multiple Sclerosis Around the World. Available from: http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf [Last accessed: May 2020].
13.  MS Society. Types of MS. Available from: https://www.mssociety.org.uk/about-ms/types-of-ms [Last accessed: May 2020].
14.  National Multiple Sclerosis Society. Secondary Progressive MS (SPMS). Available from: https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS [Last accessed: May 2020].

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