Sage Therapeutics presents promising results from LUMINARY Study
Data presented during the Emerging Science Session at the American Academy of Neurology’s Annual Meeting, April 2022
The LUMINARY Study is a Phase 2, open-label study evaluating the safety, tolerability and efficacy of SAGE-718 once daily in individuals with mild cognitive impairment and mild dementia due to Alzheimer’s disease
SAGE-718 demonstrated improvement across multiple tests of executive performance as well as improvement on key tests of learning and memory in the LUMINARY Study.
Sage Therapeutics, Inc., presented data from the Phase 2 LUMINARY Study that showed SAGE-718, a first-in-class, oral, positive allosteric modulator of the NMDA receptor, was generally well-tolerated and associated with improvement on multiple tests of executive performance and learning and memory in patients with mild cognitive impairment (MCI) and mild dementia due to Alzheimer’s disease (AD). The LUMINARY Study is part of CogNEXT, Sage’s early-stage trial platform designed to evaluate the therapeutic potential of SAGE-718 to treat cognitive deficits across a range of brain health disorders. The data was presented during the Emerging Science Session on Tuesday, April 5, at the 74th Annual Meeting of the American Academy of Neurology (AAN) in Seattle, US.
“Alzheimer’s disease is one of the greatest areas of unmet patient need, with an estimated global prevalence of more than 134 million people and few, if any, treatment options to specifically address mild cognitive impairment and mild dementia,” said Jim Doherty, Ph.D., Chief Development Officer at Sage.
We are encouraged by the positive results shared from the LUMINARY Study, which are consistent with signals suggesting improvement in cognitive performance seen across the SAGE-718 programme, including in people with Parkinson’s and Huntington’s disease. We look forward to learning more about the potential of SAGE-718 as we continue to advance our programme with multiple ongoing or planned Phase 2 studies.
Jim Doherty, Ph.D., Chief Development Officer at Sage
In the LUMINARY Study, a comprehensive battery of tests was used to assess multiple domains of cognitive performance in 26 patients receiving SAGE-718 3 mg once daily for 14 days. At Day 14, improvements from baseline were observed on multiple tests of executive functioning (Digit Symbol Substitution, Multitasking, One Touch Stockings, Spatial Working Memory, and 2-Back tests) and learning and memory (Pattern Recognition Memory and Verbal Recognition Memory tests).
Statistically significant improvement in the Montreal Cognitive Assessment (MoCA) (+2.3 points vs baseline) was observed at Day 28. As expected, no appreciable effect was observed on measures of simple attention/psychomotor speed, in keeping with the profile of SAGE-718 based on data to date. Functional assessments also captured notable improvement in some patients (Clinical Global Impressions Scales and Amsterdam Instrumental Activities of Daily Living Questionnaire), particularly on items measuring aspects of complex/higher order activities.
SAGE-718 was generally well-tolerated in the LUMINARY Study. Eight mild/moderate treatment-emergent adverse events (TEAE) were reported in seven patients. No serious adverse events or deaths were reported.
About the LUMINARY Study
The LUMINARY Study was an open-label, Phase 2 study evaluating SAGE-718, 3mg once daily for 14 days in patients with mild cognitive impairment and mild dementia due to AD. Patients aged 50–80 years with MoCA scores of 15-24 were included. Treatment-emergent adverse event incidence through Day 28 (primary endpoint), other safety outcomes (secondary endpoints) and cognitive and functional assessments were analysed.
About SAGE-718
SAGE-718, Sage’s first-in-class NMDA receptor PAM and lead neuropsychiatric drug candidate, is in development as a potential oral therapy for cognitive disorders associated with NMDA receptor dysfunction, potentially including Huntington’s disease, Parkinson’s disease and Alzheimer’s disease. Ongoing studies aim to evaluate whether SAGE-718 may have the potential to improve cognitive symptoms for these difficult-to-treat disorders. SAGE-718 is currently being studied in the ongoing Phase 2 DIMENSION Study, a double-blind placebo-controlled study in people with early to moderate cognitive impairment due to Huntington’s disease that is designed to evaluate the efficacy of once-daily dosed SAGE-718 over three months. Sage expects to initiate additional Phase 2 studies evaluating SAGE-718 in Huntington’s, Parkinson’s and Alzheimer’s diseases in 2022. In 2021, SAGE-718 received Fast Track Designation from the FDA for development of SAGE-718 as a potential treatment for Huntington’s disease.
Abstract of poster presented at the AAN 2022, by Michele Tagliati, MD, FAAN
Treatment with liraglutide improves critical features of PD, including non-motor symptoms and activities of daily living. These results validate similar outcomes reported with other GLP-1 agonists in PD and offer new strategies to treat the constellation of PD symptoms.
Background Insulin resistance (IR) is a promising therapeutic target in Parkinson’s disease (PD). Currently, receptor agonists of glucagon-like peptide 1 (GLP-1) are the safest and most reliable means of reducing IR. Liraglutide is a powerful GLP-1 agonist currently approved for treatment of diabetes and obesity.
Objective To test the therapeutic efficacy and safety of the GLP-1 agonist liraglutide in patients with idiopathic PD.
Design Methods In this single-center, randomized, double-blind, placebo-controlled trial, PD patients received, in addition to regular medications, once-daily self-administered injections of liraglutide (1.2 or 1.8 mg, as tolerated) or placebo in a 2:1 study design for 52 weeks after titration. Primary outcomes included the adjusted difference in the OFF-state Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) part III, non-motor symptoms scale (NMSS) and Mattis Dementia Rating Scale (MDRS-2) at week 54. Efficacy analyses included patients who completed any post-randomization follow-up assessment.
Results 63 patients were enrolled and randomized to liraglutide (n=42) or placebo (n=21). Twelve patients were early withdrawals, 4 of whom completed week 28 evaluation. Primary analysis included 37 active and 18 placebo subjects. At 54 weeks, NMSS scores had improved by 6.6 points in the liraglutide group and worsened by 6.5 points in the placebo group, a 13.1 point adjusted mean difference (p=0.07). MDS-UPDRS part III and MDRS-2 score changes from baseline did not significantly differ between active and placebo. Secondary outcome analysis revealed a significant improvement in MDS-UPDRS part-II scores in the treatment group (-4.1 points, p=0.001). Injection site reactions and gastrointestinal symptoms were common AEs. Eleven serious AEs were reported, none of which related to the study intervention.
Conclusions Treatment with liraglutide improves critical features of PD, including non-motor symptoms and activities of daily living. These results validate similar outcomes reported with other GLP-1 agonists in PD and offer new strategies to treat the constellation of PD symptoms.
Angelini Pharma, an international pharmaceutical company part of the privately held Italian Angelini Group announced on 4 April 2022 that ONTOZRY® (cenobamate) is now available in the Netherlands for the adjunctive treatment of focal-onset seizures with or without secondary generalisation in adults patients who have not been adequately controlled despite an history of treatment with at least two anti-epileptic medicinal products. The product obtained approval from The European Medicines Agency in March ’21.2
There are an estimated 84 000 people in the Netherlands with epilepsy. Approximately 40% of adult patients with focal epilepsy have inadequate control of seizures after treatment with two anti-seizure medications (ASMs).3
Safety and efficacy of this product has been evaluated in three key trials involving over 1,900 patients.1,4,5 The pivotal trial (study 017) published in The Lancet Neurology1is a multicenter, double-blind, randomised, placebo-controlled trial has demonstrated that cenobamate at doses of 100 mg, 200 mg, and 400 mg/day significantly improved seizure control versus placebo for adult patients with focal-onset seizures taking 1-3 ASMs. 1
The product demonstrated significantly higher responder rates (percentage of patients achieving ≥50% reduction in seizures) across all doses during the 12-week maintenance phase compared to placebo. The responder rates were 40% (p=0.036), 56% (p<0.001), and 64% (p<0.001), for the 100 mg, 200 mg, and 400 mg groups, respectively, compared to 25% in the placebo arm. Furthermore, 4% (not significant), 11% (p=0.002), and 21% (p<0.001), of patients treated with this product 100 mg, 200 mg and 400 mg per day, respectively, reported zero focal-onset seizures (100% seizure freedom) compared with only 1% of placebo treated patients during the maintenance phase.1
The global disease burden of epilepsy is high.6,7 A diagnosis of epilepsy confers significant disability on the individual, including physical, psychological, and social issues that negatively impact self-esteem, family environment, relationships, leisure and working life .6,8
In addition, people with epilepsy whose seizures are poorly controlled have higher morbidity and mortality rates, and often experience comorbid illnesses, social stigmatization, and an impaired quality of life.9,10
The product, which was discovered by SK Biopharmaceuticals and SK life science that have partnered with Angelini Pharma for the European market, marks a therapeutic breakthrough in managing the disease, and bringing hope to patients living with epilepsy.11
References
Krauss GL et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicenter, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurol. 2020 Apr;19(4):288-289.
ONTOZRY SmPC
Chen Z, et al. JAMA Neurol. 2018;75(3):279–286.
Chung SS et al. Neurology. 2020;94(22):e2311–e2322.
Sperling MR et al. Epilepsia. 2020;61(6):1099–1108
Epilepsy: a public health imperative. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO.
ILAE/IBE/WHO. Global Campaign Against Epilepsy: Out of the Shadows. 2003.
Kaiser S, et al. Long-term follow-up of topiramate and lamotrigine: a perspective on quality of life. Seizure. 2002;11:356–360.
Engel J. Bringing epilepsy out of the shadows. Neurol. 2003;60(9):1412.
Engel J. Approaches to refractory epilepsy. Ann Indian Acad Neurol. 2014;17(Suppl 1):S12–7.
Specchio N, et al. Int. J. Mol. Sci. 2021, 22, 9339.
Guignet Met al, Epilepsia. 2020 Oct 16. doi: 10.1111/epi.16718.
Anderson LL et al., Epilepsia 2014; 55(8):1274-1283.
Stafstrom CE, Epilepsy Curr 2007; 7(1):15-22.
Vreugdenhil M et al., Eur J Neurosci., 2004; 19: 2769-2778.
White HS et al, Epilepsy Res. 1997;28(3):167-79. 18 ClinicalTrials.gov. NCT03678753
About Angelini Pharma
Angelini Pharma is an international pharmaceutical company, part of the Italian privately-owned Angelini Group with a UK affiliate established in 2021. Angelini Pharma is committed to helping patients in the therapeutic areas of Mental Health (including Pain), Rare Diseases and Consumer Healthcare. In particular, Angelini Pharma is committed to brain health – working every day to reduce and mitigate neurological disorders, while restoring and protecting mental health and cognitive function.
Over the past 50 years, in the field of mental health, Angelini Pharma has gained international recognition for its substantial efforts to improve the management of patients with mental health disorders thanks to important, internally developed molecules (such as trazodone) and its commitment to fighting mental-health stigma.
Angelini Pharma operates directly in 15 countries employing almost 3,000 people and commercialises its products in more than 50 countries through strategic alliances with leading international pharmaceutical groups.
In January 2021, Angelini Pharma announced that they concluded a definitive merger agreement under which Angelini Pharma acquired Arvelle Therapeutics. As a result, Angelini Pharma has the exclusive license to commercialise cenobamate in the European Union and other countries in the European Economic Area (Switzerland and the UK).
About Cenobamate
Cenobamate was discovered and developed by SK Biopharmaceuticals and SK life science and is an FDA and EMA-approved ASM for the treatment of partial-onset seizures in adults (also known as focal-onset seizures). Cenobamate is commercially available in the US under the trademark XCOPRI®.12
Cenobamate is a novel small molecule that provides a dual, complementary mechanism of action aimed at treatment of seizures.13,14 Cenobamate at clinically relevant concentrations, acts both as a positive allosteric modulator of GABAA receptors at a non-benzodiazepine binding site and preferentially blocks the persistent sodium current.9,14 The dual mechanism of action of cenobamate suggests that it has the potential to both prevent seizure initiation and limit seizure spread.15;16,17
Long-term data of cenobamate is being studied in the open-label extensions of the double-blind placebo control trials as well as the open-label safety study in adults with uncontrolled focal-onset seizures.5 Additionally, the product is being assessed in an ongoing randomised, double-blind, placebo-controlled trial evaluating its safety and efficacy as adjunctive therapy in patients with primary generalised tonic-clonic seizures. (NCT03678753)18
Cenobamate has recently gained recognition by healthcare regulatory bodies in the United Kingdom and Germany given its potential use in treatment resistant focal-onset seizures in epilepsy. The drug is available in Europe including Germany, Sweden, Denmark, UK and the Netherlands under the trademark ONTOZRY®.
Horizon Therapeutics plc announced on 31 March, 2022 the presentation of a post-hoc analysis from the N-MOmentum Phase 3 pivotal trial of UPLIZNA, showing that the medicine was safe and effective in NMOSD patients who were treated with UPLIZNA after having only one attack. These data were presented during a poster session at the American Academy of Neurology (AAN) 2022 Annual Meeting in Seattle April 2-7 and virtually April 24-26, 2022. UPLIZNA is the first and only FDA-approved CD19+ B-cell-depleting monotherapy proven to reduce the risk of attacks in adults with NMOSD who are anti-aquaporin-4 (AQP4) antibody positive.
This analysis aimed to clarify how prior history of attacks might affect the response to UPLIZNA by evaluating the medicine’s effect among individuals with newly-presenting NMOSD who were enrolled in the 28-week randomized, placebo-controlled period of the trial after their first attack compared to individuals with a history of two or more attacks.
Key analysis findings:
Of the 37 study participants who had experienced only one attack before joining the study, 4.2% (1/24) of those who were treated with UPLIZNA experienced an attack compared to 23.1% (3/13) of those who were treated with placebo.
Of the 176 study participants who had experienced more than one attack before joining the study, 12.4% (17/137) of those who were treated with UPLIZNA experienced an attack compared to 48.7% (19/39) of those who were treated with placebo.
No significant differences in attacks or Expanded Disability Status Scale (EDSS) worsening were found between participants with one pre-study attack and those with two or more pre-study attacks.
Treatment-emergent adverse events among those enrolled after their first attack were consistent with pivotal trial outcomes.
“These data are important because physicians see NMOSD patients at varying stages of their illness and it is helpful to understand how UPLIZNA might benefit patients at disease onset as well as those who have had more than one attack,” said Bruce Cree, MD, PhD, MAS, professor of clinical neurology at the University of California San Francisco Weill Institute for Neurosciences and primary study investigator. “In this sub-analysis of the N-MOmentum pivotal trial, which is the largest clinical trial conducted in NMOSD, UPLIZNA shows comparable efficacy in patients who had only one attack to those who have had two or more attacks. With this information, physicians can feel confident that patients may stop experiencing attacks after being treated with UPLIZNA regardless of how many previous attacks they experienced.”
In addition, an analysis from the N-MOmentum trial was presented showing long-term treatment with UPLIZNA improved pain outcomes in patients with NMOSD. Pain is a common, debilitating symptom of NMOSD that can dramatically impact daily activities. Previously presented data demonstrated improvements in pain scores after treatment with UPLIZNA. The new analysis builds on those findings by showing a durable, long-term benefit in managing pain, with year-over-year improvements from baseline (average of 6.57 points after one year, 7.08 after two years and 7.96 after three years) as measured by the 36-item short-form survey body pain subscore (SF36-BPS).
These rigorous analyses from the UPLIZNA pivotal trial provide compelling insights into the real value that UPLIZNA may provide as a novel option for people living with NMOSD. As physicians gain more experience with UPLIZNA, they can see how these clinical data translate into outcomes within their practices and potentially help more patients gain greater control over this challenging disease.”
Kristina Patterson, MD, PhD, medical director, neuroimmunology, Horizon.
References
Ajmera MR, Boscoe A, Mauskopf J, Candrilli SD, Levy M. Evaluation of comorbidities and health care resource use among patients with highly active neuromyelitis optica. J Neurol Sci. 2018;384:96-103.
Liu Y, et al. A tract-based diffusion study of cerebral white matter in neuromyelitis optica reveals widespread pathological alterations. Mult Scler. 2011;18(7):1013-1021.
Chihara N, et al. Interleukin 6 signaling promotes anti-aquaporin-4 autoantibody production from plasmablasts in neuromyelitis optica. PNAS. 2011;108(9):3701-3706.
Duan T, Smith AJ, Verkamn AS. Complement-independent bystander injury in AQP4-IgG seropositive neuromyelitis optica produced by antibody dependent cellular cytotoxicity. Acta Neuropathologica Comm. 2019;7(112).
Beekman J, et al. Neuromyelitis optica spectrum disorder: patient experience and quality of life. Neural Neuroimmunol Neuroinflamm. 2019;6(4):e580.
Kimbrough DJ, et al. Treatment of neuromyelitis optica: review and recommendations. Mult Scler Relat Disord. 2012;1(4):180-187.
Baranello RJ, Avasarala, JR. Neuromyelitis optica spectrum disorders with and without aquaporin 4 antibody: Characterization, differential diagnosis, and recent advances. J Neuro Ther. 2015;1(1):9-14.
Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol. 2016;79(5):775-783.
About Neuromyelitis Optica Spectrum Disorder (NMOSD)
NMOSD is a unifying term for neuromyelitis optica (NMO) and related syndromes. NMOSD is a rare, severe, relapsing, neuroinflammatory autoimmune disease that attacks the optic nerve, spinal cord, brain and brain stem.1,2 Approximately 80 percent of all patients with NMOSD test positive for anti-AQP4 antibodies.3 AQP4-IgG binds primarily to astrocytes in the central nervous system and triggers an escalating immune response that results in lesion formation and astrocyte death.4
Anti-AQP4 autoantibodies are produced by plasmablasts and plasma cells. These B-cell populations are central to NMOSD disease pathogenesis, and a large proportion of these cells express CD19.5 Depletion of these CD19+ B cells is thought to remove an important contributor to inflammation, lesion formation and astrocyte damage. Clinically, this damage presents as an NMOSD attack, which can involve the optic nerve, spinal cord and brain.4,6 Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.7 Each NMOSD attack can lead to further cumulative damage and disability.8,9 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.10,11
About UPLIZNA
INDICATION
UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.
IMPORTANT SAFETY INFORMATION
UPLIZNA is contraindicated in patients with:
A history of life-threatening infusion reaction to UPLIZNA
Active hepatitis B infection
Active or untreated latent tuberculosis
WARNINGS AND PRECAUTIONS
Infusion Reactions: UPLIZNA can cause infusion reactions, which can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash or other symptoms. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions. Administer pre-medication with a corticosteroid, an antihistamine and an anti-pyretic.
Infections: The most common infections reported by UPLIZNA-treated patients in the randomized and open-label periods included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%) and influenza (7%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.
Increased immunosuppressive effects are possible if combining UPLIZNA with another immunosuppressive therapy.
The risk of hepatitis B virus (HBV) reactivation has been observed with other B-cell-depleting antibodies. Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer to patients with active hepatitis.
Although no confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies and other therapies that affect immune competence. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation.
Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA.
Vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation, until B-cell repletion.
Reduction in Immunoglobulins: There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment. Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with UPLIZNA until B-cell repletion especially in patients with opportunistic or recurrent infections.
Fetal Risk: May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping UPLIZNA.
Adverse Reactions: The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were urinary tract infection and arthralgia.
For additional information on UPLIZNA, please see Prescribing Information at http://www.UPLIZNA.com.
About Horizon
Horizon is focused on the discovery, development and commercialisation of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. http://www.horizontherapeutics.com
• Novartis announces that the peer-reviewed journal Neurology and Therapy1 has published new data on COVID-19 infections in people living with relapsing remitting multiple sclerosis (RRMS) treated with Kesimpta®(ofatumumab)
• A very small proportion (1.5%) of those fully vaccinated and treated with ofatumumab developed COVID-19. Despite being fully or partially vaccinated all patients with breakthrough COVID-19 recovered
• At the time of data cut-off (September 25, 2021), no cases of COVID-19 were reported after the booster vaccination
• Novartis is committed to generating evidence to better understand the severity and outcomes of COVID-19 in people receiving ofatumumab to help support informed decision making in relapsing remitting (RRMS) treatment selection
Novartis announced on March 23 2022 that the peer-reviewed journal Neurology and Therapy1 has published new data on COVID-19 infections in people living with relapsing remitting multiple sclerosis (RRMS) treated with Kesimpta® (ofatumumab). This data was compiled from the ongoing, single-arm, open-label, long-term extension phase 3b ALITHIOS study and from post-marketing reports submitted through the Novartis Global Safety Database.
Of the 1703 participants in ALITHIOS, 245 (14.4%) reported COVID-19, most cases were mild (44.1%) or moderate (46.5%) and the vast majority of patients had either recovered or were recovering or recovered with sequelae (98.4%).1 The overall fatal outcome (0.8%) and hospitalisation rates (9.4%) due to COVID-19 in ofatumumab-treated patients1 were lower than the rates reported in the general MS population (1.97% fatal outcome2 and 15.5%-21.5% hospitalisation2,3,4,5). Breakthrough COVID-19 infections occurred in 1.5% of fully vaccinated participants (n = 7/476), from which all recovered. No cases of COVID-19 were reported after receiving a booster vaccination (n = 27) as per the data cut-off. The current data does not suggest any evidence of increased risk of severe COVID-19 in ofatumumab-treated patients compared to the reported data from the general population or other MS patients treated with or without disease-modifying therapies (DMTs).1,2,3
Access to a range of different treatment options is important for people living with MS to manage their condition in a way that is best for them and their lifestyle. This data gives reassurance to the MS community that the risk of severe COVID-19 infection in those vaccinated is in line with that reported currently in the general population.
David Martin, Chief Executive Officer, Multiple Sclerosis Trust
Dr David Paling, Consultant Neurologist at the Royal Hallamshire Hospital: “COVID-19 has had a huge impact on people living with MS and has complicated decisions about treatment. This study of the outcomes of people who developed COVID-19 whilst on ofatumumab from the ALITHIOS study will allow my colleagues and I to reassure people with MS about their risks, and have informed discussions about treatment choices based on really accurate evidence.”
Chinmay Bhatt, Managing Director, UK, Ireland & Nordics for Novartis Pharmaceuticals: “The last couple of years have been a challenge for people living with MS as they have had to make important decisions with their doctor or nurse on how best to manage their condition during the COVID-19 pandemic. At Novartis, we are committed to conducting research to understand the impact of the COVID-19 vaccines and related clinical outcomes in patients treated with our medicines to ensure no person with MS is left behind. We are very pleased with the results of this study which provide reassurance to the healthcare professionals involved in managing MS.”
About Multiple Sclerosis (MS)
There are approximately 130,000 people with MS in the UK, and each year around 7,000 people are newly diagnosed with the condition.6 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.7 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.8 There are three types of MS: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS).9 Patients with relapsing forms of MS (RMS) – including RRMS and SPMS with active disease – experience distinct attacks of symptoms, known as relapses.10,11 Around 85% of people are considered to have RRMS at their point of diagnosis.12 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 magnetic resonance imaging [MRI] activity) or not active (no evidence of current activity).11,13
Ofatumumab is a fully human anti-CD20 monoclonal antibody (mAb) for adults with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features, which is intended to be self-administered by a once monthly injection, delivered subcutaneously.14,15 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.16,17 Ofatumumab allows faster repletion of B-cells upon discontinuation versus other anti-CD20 mAbs, and therefore may offer flexibility in the management of RRMS.18
Ofatumumab has been approved for the treatment of relapsing forms of multiple sclerosis with active disease defined by clinical or imaging features in both the European Union and United Kingdom.19,20
About ALITHIOS study
The ALITHIOS study is an ongoing open-label, single-arm, multi-center extension Phase IIIb study evaluating the long-term safety, tolerability and effectiveness of ofatumumab in subjects with RMS who have participated in a Novartis ofatumumab clinical MS study. The primary endpoint is the number of patients that experience an adverse event or abnormal laboratory, vital and/or ECG results and positive suicidality outcomes. Secondary endpoints include number of relapse rates per year, 3- and 6-month confirmed disability worsening (CDW), 6-, 12- and 24-month confirmed disability improvement and improvement until end of study. This study includes a vaccination sub-study investigating the effects of ofatumumab on the development of antibody responses to selected vaccines and keyhole limpet hemocyanin (KLH) neo-antigen in subjects with RMS.21
References
1. Cross AH, Delgado S, Habek M, et al. COVID-19 Outcomes and Vaccination in People with Relapsing Multiple Sclerosis Treated with Ofatumumab. Neurol Ther. 2022;https://doi.org/10.1007/s40120-022-00341-z.
2. Prosperini L, Tortorella C, Haggiag S, Ruggieri S, Galgani S, Gasperini C. Increased risk of death from COVID-19 in multiple sclerosis: a pooled analysis of observational studies. J Neurol. 2021; 1-7.
3. Barzegar M, Mirmosayyeb O, Gajarzadeh M, Afshari-Safavi A, Nehzat N, Vaheb S, et al. COVID-19 among patients with multiple sclerosis: A systematic review. Neurol Neuroimmunol Neuroinflamm. 2021;8(4):e1001.
4. Reder AT, Centonze D, Naylor ML, et al. COVID-19 in Patients with Multiple Sclerosis: Associations with Disease-Modifying Therapies. CNS Drugs. 2021;35(3):317-330. doi:10.1007/s40263-021-00804-1
5. Möhn N, Konen FF, Pul R, et al. Experience in Multiple Sclerosis Patients with COVID-19 and Disease-Modifying Therapies: A Review of 873 Published Cases. J Clin Med. 2020;9(12):4067. Published 2020 Dec 16. doi:10.3390/jcm9124067
14. Hauser S, Bar-Or A, Cohen J, et al. Ofatumumab versus teriflunomide in relapsing multiple sclerosis. N Engl J Med. 2020;383(6):546–557)
15. 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. Poster presentated at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS); 27-29 February 2020; West Palm Beach, FL).
17. 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; 14–17 September 2016; London, UK).
18. 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.
21. U.S. National Library of Medicine. Long-term safety, tolerability and effectiveness study of ofatumumab in patients with relapsing MS. https://clinicaltrials.gov/ct2/show/NCT03650114. [Accessed March 2022].
New Data for Genentech’s Ocrevus (ocrelizumab) show benefit in disability progression and cognitive decline in both Secondary Progressive and Primary Progressive Multiple Sclerosis
– 75% of patients with secondary progressive multiple sclerosis (SPMS) and primary progressive MS (PPMS) achieved no evidence of progression (NEP) in a one-year interim analysis of CONSONANCE study
– 70% of patients with SPMS and PPMS demonstrated stable or improved cognition after one year of Ocrevus treatment in CONSONANCE
–Separate analysis on treatment disparities showed fewer Black and Hispanic patients with MS initiate high-efficacy treatments within two years of diagnosis
–Data at AAN support the body of evidence for Ocrevus more than 450,000 patient years and more than 225,000 patients treated globally
Genentech, a member of the Roche Group announced on 4 April 2022 that new Ocrevus® (ocrelizumab) data show its benefit on disease progression and cognitive outcomes in primary progressive multiple sclerosis (PPMS) and secondary progressive MS (SPMS). Separate analyses on treatment disparities among newly diagnosed patients with MS by race and ethnicity were a platform presentation at the 74th American Academy of Neurology (#AAN2022) Annual Meeting April 2-7, 2022 in Seattle. CONSONANCE data will be presented virtually at AAN April 24-26, 2022.
We continue to work on closing treatment gaps for all people impacted by MS, as everyone living with this neurodegenerative condition experiences disease progression from the start. For people with progressive forms of MS and in some Black and Hispanic subpopulations, the disease may progress faster. We are encouraged by the low levels of disability progression and cognitive decline in Ocrevus-treated patients seen across the complete spectrum of progressive MS for the first time, since SPMS and PPMS often bring a substantial quality of life burden.”
Levi Garraway, M.D., Ph.D. chief medical officer and head of Global Product Development
CONSONANCE interim analysis: low levels of disease progression in SPMS and PPMS
Treatment with Ocrevus resulted in a majority of patients experiencing no disease progression in a one-year analysis of CONSONANCE, a first-of-its-kind open-label Phase IIIb trial to evaluate the effect of Ocrevus in SPMS and PPMS patients. After one year, 75% of Ocrevus-treated patients with SPMS and PPMS achieved No Evidence of Progression (NEP; no evidence of confirmed disability progression as measured by an increase in Expanded Disability Status Score sustained for at least 24 weeks, and less than 20% worsening of performance on the timed 25-foot walk [T25-FW] and Nine-Hole Peg Test [9-HPT]). NEP is a novel composite endpoint and reflects no evidence of worsening of a person’s physical disability.
Additionally, 59% of Ocrevus-treated patients in the trial achieved No Evidence of Progression or Active Disease (NEPAD; NEP plus no protocol-defined relapses, new and/or enlarging T2 lesions or T1 gadolinium-enhancing lesions) over one year. NEPAD is another novel composite endpoint and reflects no evidence of clinical or MRI disease activity or worsening of a person’s physical disability. Progression was primarily driven by T25-FW (16% of patients) and activity of new and/or enlarging T2 lesions (19% of patients), detected almost exclusively within the first six months of the trial.
The analysis also demonstrated the positive effects of Ocrevus on cognition, with 70% of patients having stable or improved cognition over one year, as measured with the Symbol Digit Modalities Test (SDMT). Clinically meaningful improvement (increase of ≥4 points on the SDMT) was observed in 34% of patients treated with Ocrevus and worsening (decrease of ≥4 points) in 30% of patients treated with Ocrevus. At enrollment, patients had moderate-to-severe dysfunction in information processing speed and visuospatial memory, which was stable or improved in a majority of patients after Ocrevus treatment.
After one year of participating in the trial, 75% of patients had one or more adverse events (AEs) and 7% experienced at least one serious AE. The interim analysis included 629 patients, and longer-term evaluation of Ocrevus will continue for four years with a target of 900 patients with PPMS or SPMS (in a 1:1 ratio) across 26 countries.
Continued research on the treatment patterns of minority populations living with MS
Current treatment guidelines recommend the initiation of high-efficacy disease modifying therapies (DMTs) for patients with highly active disease, as frequently seen with Black and Hispanic populations. However, a recent analysis of a U.S. commercial claims database found that only 30% of non-Hispanic Black, and 20% of Hispanic patients initiated any high-efficacy DMTs, in comparison to 39% of non-Hispanic white patients in the first two years after diagnosis.
These insights further support Genentech’s Phase IV ‘Characterization of ocrelizumab in Minorities with Multiple Sclerosis’ (CHIMES) trial in Black/African-American and Hispanic/Latino patients with relapsing MS (RMS). The results are expected to improve the current understanding of MS disease biology and treatment response to Ocrevus among these populations with MS, to improve standard of care in traditionally underserved communities and improve inclusivity in clinical research.
With rapidly growing real-world experience and more than 225,000 people treated globally, Ocrevus is the first and only therapy approved for relapsing MS (RMS; including relapsing-remitting MS [RRMS] and active SPMS, in addition to clinically isolated syndrome [CIS] in the United States) and PPMS. Genentech are constantly striving to optimise the care for people with MS and a shorter two-hour Ocrevus infusion time, dosed twice yearly (six-monthly), is approved for eligible people with RMS or PPMS in the United States and European Union (EU).
Ocrevus is approved in 100 countries across North America, South America, the Middle East, Eastern Europe, as well as in Australia, Switzerland, the United Kingdom and the EU.
About Genentech in neuroscience
Neuroscience is a major focus of research and development at Genentech and Roche. Our goal is to pursue groundbreaking science to develop new treatments that help improve the lives of people with chronic and potentially devastating diseases.
Genentech and Roche are investigating more than a dozen medicines for neurological disorders, including multiple sclerosis, stroke, Alzheimer’s disease, Parkinson’s disease and autism spectrum disorder. Together with our partners, we are committed to pushing the boundaries of scientific understanding to solve some of the most difficult challenges in neuroscience today.
About Genentech
Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and 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.
Genentech, a member of the Roche Group, announced new Ocrevus® (ocrelizumab) data on 4th April 2022 that show its benefit on disease progression and cognitive outcomes in primary progressive multiple sclerosis (PPMS) and secondary progressive MS (SPMS). Separate analyses on treatment disparities among newly diagnosed patients with MS by race and ethnicity were presented at the 74th American Academy of Neurology (AAN) Annual Meeting April 2-7, 2022 in Seattle. CONSONANCE data will be presented virtually April 24-26, 2022.
We continue to work on closing treatment gaps for all people impacted by MS, as everyone living with this neurodegenerative condition experiences disease progression from the start. For people with progressive forms of MS and in some Black and Hispanic subpopulations, the disease may progress faster. We are encouraged by the low levels of disability progression and cognitive decline in Ocrevus-treated patients seen across the complete spectrum of progressive MS for the first time, since SPMS and PPMS often bring a substantial quality of life burden.
Levi Garraway, M.D., Ph.D. chief medical officer and head of Global Product Development.
CONSONANCE interim analysis: low levels of disease progression in SPMS and PPMS
Treatment with Ocrevus resulted in a majority of patients experiencing no disease progression in a one-year analysis of CONSONANCE, a first-of-its-kind open-label Phase IIIb trial to evaluate the effect of Ocrevus in SPMS and PPMS patients. After one year, 75% of Ocrevus-treated patients with SPMS and PPMS achieved No Evidence of Progression (NEP; no evidence of confirmed disability progression as measured by an increase in Expanded Disability Status Score sustained for at least 24 weeks, and less than 20% worsening of performance on the timed 25-foot walk [T25-FW] and Nine-Hole Peg Test [9-HPT]). NEP is a novel composite endpoint and reflects no evidence of worsening of a person’s physical disability.
Additionally, 59% of Ocrevus-treated patients in the trial achieved No Evidence of Progression or Active Disease (NEPAD; NEP plus no protocol-defined relapses, new and/or enlarging T2 lesions or T1 gadolinium-enhancing lesions) over one year. NEPAD is another novel composite endpoint and reflects no evidence of clinical or MRI disease activity or worsening of a person’s physical disability. Progression was primarily driven by T25-FW (16% of patients) and activity of new and/or enlarging T2 lesions (19% of patients), detected almost exclusively within the first six months of the trial.
The analysis also demonstrated the positive effects of Ocrevus on cognition, with 70% of patients having stable or improved cognition over one year, as measured with the Symbol Digit Modalities Test (SDMT). Clinically meaningful improvement (increase of ≥4 points on the SDMT) was observed in 34% of patients treated with Ocrevus and worsening (decrease of ≥4 points) in 30% of patients treated with Ocrevus. At enrollment, patients had moderate-to-severe dysfunction in information processing speed and visuospatial memory, which was stable or improved in a majority of patients after Ocrevus treatment.
After one year of participating in the trial, 75% of patients had one or more adverse events (AEs) and 7% experienced at least one serious AE. The interim analysis included 629 patients, and longer-term evaluation of Ocrevus will continue for four years with a target of 900 patients with PPMS or SPMS (in a 1:1 ratio) across 26 countries.
Continued research on the treatment patterns of minority populations living with MS
Current treatment guidelines recommend the initiation of high-efficacy disease modifying therapies (DMTs) for patients with highly active disease, as frequently seen with Black and Hispanic populations. However, a recent analysis of a U.S. commercial claims database found that only 30% of non-Hispanic Black, and 20% of Hispanic patients initiated any high-efficacy DMTs, in comparison to 39% of non-Hispanic white patients in the first two years after diagnosis.
These insights further support Genentech’s Phase IV ‘Characterisation of ocrelizumab in Minorities with Multiple Sclerosis’ (CHIMES) trial in Black/African-American and Hispanic/Latino patients with relapsing MS (RMS). The results are expected to improve the current understanding of MS disease biology and treatment response to Ocrevus among these populations with MS, to improve standard of care in traditionally underserved communities and improve inclusivity in clinical research.
With rapidly growing real-world experience and more than 225,000 people treated globally, Ocrevus is the first and only therapy approved for relapsing MS (RMS; including relapsing-remitting MS [RRMS] and active SPMS, in addition to clinically isolated syndrome [CIS] in the United States) and PPMS. A shorter two-hour Ocrevus infusion time, dosed twice yearly (six-monthly), is approved for eligible people with RMS or PPMS in the United States and European Union (EU).
Ocrevus is approved in 100 countries across North America, South America, the Middle East, Eastern Europe, as well as in Australia, Switzerland, the United Kingdom and the EU.
SB623 Demonstrated Sustained Improvement in Motor Impairment up to 48 Weeks and Associated with Improvement in Function and Activities of Daily Living in Patients with Chronic Traumatic Brain Injury
Positive results from the one-year analysis of the Phase 2 STEMTRA trial were presented for the first time at the 2022 American Academy of Neurology (#AAN2022) Annual Meeting, 4-7 April, 2022.
SB623 has the potential to be the first cell treatment for chronic motor deficit from TBI
The SanBio Group (SanBio Co., Ltd. of Tokyo, Japan, SanBio, Inc. of Mountain View, California, US, and SanBio Asia Pte. Ltd. of Singapore) announced on April 5 2022 that SB623 met the primary endpoint and demonstrated a trend toward maintaining the improvement of function and activities of daily living in the final, one-year analysis of the Phase 2 STEMTRA trial, which evaluated the efficacy and safety of SB623 compared to sham surgery in patients with chronic motor deficit from traumatic brain injury (TBI). These results were presented in an oral plenary session at the American Academy of Neurology (AAN) Annual Meeting on April 5, 2022, in Seattle, Washington, USA.
SB623 is an investigational, regenerative cell medicine comprised of bone-marrow-derived, mesenchymal stem cells that are implanted intracranially around the area of the injury.
“The results of this study are promising for the millions of people struggling with long-term disabilities caused by traumatic brain injury, many of whom are often overlooked in the healthcare system,” said Peter McAllister, M.D., board-certified Neurologist and Medical Director and Chief Medical Officer of the New England Center for Neurology and Headache.
These findings reinforce the potential for SB623 to provide clinically meaningful improvements in motor function and ability to resume daily activities.
Peter McAllister
In this clinical study involving a total of 61 patients, 46 were treated with SB623 and 15 underwent sham surgery as a control group. Patients treated with SB623 saw significant improvements in motor function at 24 weeks compared to sham surgery, as measured by the change from baseline in the Fugl-Meyer Motor Scale (FMMS), the study’s primary endpoint (8.3 [1.4] vs. 2.3 [2.5], p=0.04). These improvements in motor impairment were maintained up to 48 weeks in the treatment group. SB623 cell implantation was associated with an improvement of function and activities of daily living at 48 weeks, as measured by scales including Action Research Arm Test (ARAT), Gait Velocity and NeuroQOL upper and lower extremity function T scores.
SB623 was well tolerated, consistent with previous studies, and no new safety signals were identified. No patients withdrew due to adverse events, and there were no significant differences in the rate of adverse events between patients treated with SB623 and sham surgery.
In March 2022, SanBio completed approval filing based on the STEMTRA trial data with Japan’s Ministry of Health, Labour and Welfare (MHLW) for SB623 as a treatment for chronic motor deficit from TBI under the Sakigake Designation System. In addition to receiving the Sakigake designation, SB623 was granted orphan regenerative medicine designation by the MHLW and regenerative medicine advanced therapy (RMAT) designation by the U.S. Food and Drug Administration (FDA).
“These data reaffirm the potential for SB623 to regenerate the brain after injury, an implication that would not only profoundly change the lives of those living with chronic traumatic brain injuries, but help shape the future of regenerative neurologic research,” said Keita Mori, chief executive officer at SanBio. “We have just completed the application for approval of SB623 in Japan based on these results, and will continue our efforts to obtain swift approval by responding promptly to the review by the regulatory authority, so that we can bring a new treatment option as quickly as possible to patients suffering from this underserved condition, which has no underlying cure.”
SanBio is preparing to initiate a Phase 3 trial for SB623 in the United States, where many traumatic brain injury patients currently live.
About Traumatic Brain Injury
Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. The estimated global incidence of acute TBI during 2016 was 27 million cases, and the estimated global prevalence of chronic impairment secondary to TBI was 55.5 million cases.1 Overall, TBI and long-term motor deficits secondary to TBI significantly impair a person’s self-care, employability, and quality of life, and are major burdens on healthcare systems worldwide. In the United States, approximately 43% of surviving hospitalized persons with TBI experience long-term disabilities,2 and it is estimated that 3.17 million people are living with long-term disabilities secondary to TBI.3
About SanBio
SanBio is engaged in the regenerative cell medicine business, spanning research, development, manufacture, and sales of regenerative cell medicines. SanBio targets patients with high unmet medical needs that cannot be addressed by existing medical treatments, mainly in diseases of the central nervous system. SanBio is headquartered in Tokyo, Japan and has subsidiaries based in Mountain View, California, and Singapore. Additional information about SanBio Group is available at https://www.sanbio.com/en/.
About SB623
SB623 (INN: vandefitemcel) is a human (allogeneic) bone marrow-derived modified mesenchymal stem cell that is produced by modifying and culturing mesenchymal stem cells derived from the bone marrow aspirate of healthy adults. Implantation of SB623 cells into injured nerve tissues in the brain is expected to trigger the brain’s natural regenerative ability to restore lost functions. SB623 is currently being investigated for the treatment of several conditions including chronic neurological motor deficit resulting from traumatic brain injury and ischemic stroke.
About the STEMTRA Trial
STEMTRA is a 48-week, Phase 2, randomized, double-blind, surgical sham-controlled, global trial evaluating the efficacy and safety of SB623 compared to sham surgery in 61 patients with stable chronic motor deficits secondary to traumatic brain injury. In this study, SB623 was inserted via stereotactic, intracranial implantation. Patients underwent stratified randomization in a 1:1:1:1 ratio to receive either 2.5×106, 5×106 or 10×106 SB623 cells or sham surgical procedure.
To be eligible for this trial, patients (ages 18-75) must have been at least 12 months post-TBI and had a Glasgow Outcome Scale extended (GOS-E) score of 3-6 (e.g., moderate or severe disability). Patients must also have been able to undergo all planned neurological assessments and had no seizures in prior three months. The primary endpoint was mean change from baseline in Fugl-Meyer Motor Scale (FMMS) score at six-months. The STEMTRA trial enrolled 61 patients from 13 surgical and 18 assessment sites globally, including the U.S. and Japan.
Sources:
1James SL, et al. “Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.” Lancet Neurol 2019;18:56-87.
2Selassie AW, et al. “Incidence of long-term disability following traumatic brain injury hospitalization, U.S.”, 2003. J Head Trauma Rehabil 2008;23:123-31
3Zaloshnja E, Miller T, Langlois JA, Selassie AW. “Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005.” J Head Trauma Rehabil. 2008 Nov-Dec;23(6):394-400.
TG Therapeutics, Inc. announced data from the ULTIMATE I & II Phase 3 trials evaluating ublituximab in patients with relapsing forms of multiple sclerosis (RMS) at the American Academy of Neurology (#AAN2022) annual meeting, 2-7 April 2022 in Washington, USA. Highlights of the presentations are outlined below.
We are pleased to present additional analyses from the ULTIMATE I & II trials, which continue to highlight encouraging data for ublituximab as a potential treatment for patients with relapsing forms of multiple sclerosis. Of note, post hoc/pooled analyses demonstrate approximately 95% of ublituximab treated patients who demonstrated 12-week CDI sustained the improvement through the end of the study at week 96, a consistent NEDA benefit for ublituximab-treated patients was demonstrated across treatment epochs and key patient subpopulations, and 96% of patients completed their ublituximab infusions without interruptions. We believe these data reinforce the potential of ublituximab, if approved, to offer RMS patients a treatment option that can be administered in a one-hour infusion every six months after the first dose.
Michael S. Weiss, Chairman and Chief Executive Officer of TG Therapeutics
Among ublituximab patients who demonstrated 12-week Confirmed Disability Improvement (CDI), 95.4% (62/65) sustained the improvement through the end of the study at week 96.
In patients with a baseline Expanded Disability Status Score (EDSS) score ≥2.0, more patients in the ublituximab group than teriflunomide group had EDSS improvements of 1.0 and 1.5 points at Weeks 60, 72, 84, and 96 (P<0.05 for all)
At 96 weeks, a ≥20% improvement in 9-HPT was observed in 11.4% and 5.5% (dominant hand; P=0.0009) and 11.4% and 5.7% (nondominant hand; P=0.0016) of ublituximab (n=543) and teriflunomide (n=546) treated patients, respectively
ULTIMATE I and II post hoc pooled analyses demonstrated a consistent NEDA benefit for ublituximab treated patients across treatment epochs and key patient subpopulations
In pooled post hoc analyses evaluating NEDA-3 by treatment epoch and patient subtype:
NEDA-3 rates for ublituximab vs teriflunomide cohorts by treatment epoch at 0-96 weeks were 44.6% (232/520) vs 12.4% (65/524), respectively, and at 24-96 weeks (re-baselined) were 82.1% (418/509) vs 22.5% (115/511) (P<0.0001 for both)
NEDA-3 at 24-96 weeks (re-baselined) was achieved in 82.7% (268/324) vs 23.1% (81/350) of treatment-naive, 81.1% (34/161) vs 21.1% (150/185) of previously treated (prior disease-modifying therapy [DMT]), 82.4% (206/250) vs 18.6% (48/258) of early-disease, and 81.9% (212/259) vs 26.5% (67/253) of late-disease patients in ublituximab- vs teriflunomide-treated cohorts, respectively (P<0.0001 for all)
The leading cause of disease activity during Weeks 24-96 (re-baselined) was new/enlarging T2 lesions for teriflunomide (occurring in 71.6% of patients) and relapse for ublituximab (occurring in 11.4% of patients)
In pooled analyses of the ULTIMATE studies, 96.6% of patients (n=545) completed ublituximab infusions without interruption, and 94.6% completed Dose 2-5 maintenance infusions within 1 hour±5 minutes
43% of patients had an IRR at Dose 1, the proportion of patients experiencing an IRR markedly decreased to <10.0% for all subsequent infusions, and 69.5% did not have an IRR recurrence
78.8% of Dose 1 and 69.2% of Dose 2 IRRs with ublituximab occurred during the infusion period or within 1 hour post infusion
The administration route of premedications (oral, intravenous [IV], intramuscular [IM], or mixed) did not impact the frequency of IRRs
IRRs were the prevailing adverse event (AE) with ublituximab in ULTIMATE I and II; the vast majority were mild to moderate in severity
ABOUT THE ULTIMATE I & II PHASE 3 TRIALS ULTIMATE I and ULTIMATE II are two independent Phase 3, randomised, double-blinded, active-controlled, global, multi-center studies evaluating the efficacy and safety/tolerability of ublituximab (450mg dose administered by one-hour intravenous infusion every 6 months, following a Day 1 infusion of 150mg over four hours and a Day 15 infusion of 450mg over one hour) versus teriflunomide (14mg oral tablets taken once daily) in subjects with relapsing forms of Multiple Sclerosis (RMS). The ULTIMATE I & II trials enrolled a total of 1,094 patients with RMS across 10 countries. These trials were led by Lawrence Steinman, MD, Zimmermann Professor of Neurology & Neurological Sciences, and Pediatrics at Stanford University and were conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA). As previously announced, both studies met their primary endpoint with ublituximab treatment demonstrating a statistically significant reduction in annualized relapse rate (ARR) compared to terifunomide over a 96-week period (p<0.005 in each trial). Additional information on these clinical trials can be found at http://www.clinicaltrials.gov (NCT03277261; NCT03277248).
ABOUT UBLITUXIMAB Ublituximab is an investigational glycoengineered monoclonal antibody that targets a unique epitope on CD20-expressing B-cells. When ublituximab binds to the B-cell it triggers a series of immunological reactions, including antibody-dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), leading to destruction of the cell. Additionally, ublituximab is uniquely designed, to lack certain sugar molecules normally expressed on the antibody. Removal of these sugar molecules, a process called glycoengineering, has been shown to enhance the potency of ublituximab, especially the ADCC activity. Targeting CD20 using monoclonal antibodies has proven to be an important therapeutic approach for the management of B-cell malignancies and autoimmune disorders, both diseases driven by the abnormal growth or function of B-cells.
ABOUT TG THERAPEUTICS, INC. TG Therapeutics is a fully-integrated, commercial stage biopharmaceutical company focused on the acquisition, development and commercialisation of novel treatments for B-cell malignancies and autoimmune diseases. In addition to an active research pipeline including five investigational medicines across these therapeutic areas, TG has received accelerated approval from the U.S. FDA for UKONIQ® (umbralisib), for the treatment of adult patients with relapsed/refractory marginal zone lymphoma who have received at least one prior anti-CD20-based regimen and relapsed/refractory follicular lymphoma who have received at least three prior lines of systemic therapies. Currently, the Company has three programmes in Phase 3 development for the treatment of patients with relapsing forms of multiple sclerosis (RMS) and patients with chronic lymphocytic leukemia (CLL) and several investigational medicines in Phase 1 clinical development. For more information, visit http://www.tgtherapeutics.com
UKONIQ® is a registered trademark of TG Therapeutics, Inc.
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