The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice

Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis : APLIOS, a randomized phase-2 study

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed. Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion

Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial

BACKGROUND: No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis. METHODS: In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25-65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2-10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed. FINDINGS: 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87-82·51) of patients in the fingolimod group versus 80·3% (73·31-87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80-1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%). INTERPRETATION: The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis. FUNDING: Novartis Pharma AG

A new clinico-pathological classification system for mesial temporal sclerosis

We propose a histopathological classification system for hippocampal cell loss in patients suffering from mesial temporal lobe epilepsies (MTLE). One hundred and seventy-eight surgically resected specimens were microscopically examined with respect to neuronal cell loss in hippocampal subfields CA1–CA4 and dentate gyrus. Five distinct patterns were recognized within a consecutive cohort of anatomically well-preserved surgical specimens. The first group comprised hippocampi with neuronal cell densities not significantly different from age matched autopsy controls [no mesial temporal sclerosis (no MTS); n = 34, 19%]. A classical pattern with severe cell loss in CA1 and moderate neuronal loss in all other subfields excluding CA2 was observed in 33 cases (19%), whereas the vast majority of cases showed extensive neuronal cell loss in all hippocampal subfields (n = 94, 53%). Due to considerable similarities of neuronal cell loss patterns and clinical histories, we designated these two groups as MTS type 1a and 1b, respectively. We further distinguished two atypical variants characterized either by severe neuronal loss restricted to sector CA1 (MTS type 2; n = 10, 6%) or to the hilar region (MTS type 3, n = 7, 4%). Correlation with clinical data pointed to an early age of initial precipitating injury (IPI < 3 years) as important predictor of hippocampal pathology, i.e. MTS type 1a and 1b. In MTS type 2, IPIs were documented at a later age (mean 6 years), whereas in MTS type 3 and normal appearing hippocampus (no MTS) the first event appeared beyond the age of 13 and 16 years, respectively. In addition, postsurgical outcome was significantly worse in atypical MTS, especially MTS type 3 with only 28% of patients having seizure relief after 1-year follow-up period, compared to successful seizure control in MTS types 1a and 1b (72 and 73%). Our classification system appears suitable for stratifying the clinically heterogeneous group of MTLE patients also with respect to postsurgical outcome studies

a long-term investigation within the ProGERD-study

Hintergrund und Ziele Die gastroösophageale Refluxkrankheit (GERD) ist eine weitverbreitete Krankheit. Sie kann mit verschiedenen extraösophagealen Erkrankungen (EED) assoziiert sein, wie z.B. chronischer Husten, Asthma, Laryngitis oder nicht-kardialer Brustschmerz. Bisher gab es zahlreiche Arbeiten, die sich mit der Prävalenz von EED bei GERD beschäftigen. Das Ziel dieser Studie ist die Langzeitbeobachtung von Patienten mit GERD, die Entwicklung der EED und die Detektion von Risikofaktoren, die zum Auftreten von EED führen können. Außerdem sollen die ökonomischen Folgen der EED dokumentiert werden. Methoden Die bearbeiteten Daten entstammen der ProGERD- Studie. Hierbei handelt es sich um eine prospektive, multizentrische Studie mit offenen Kohorten. Die Studie begann im Jahr 2000 und ist angelegt für eine Dauer von zehn Jahren. Mehr als 6000 Patienten wurden rekrutiert nachdem sie sich einer Gastroskopie unterzogen, einen Fragebogen ausgefüllt und eine individuelle Heilungsphase mit Omeprazol durchlaufen hatten. Die Patienten wurden jährlich kontaktiert um einen Patientenfragebogen auszufüllen. In den Beobachtungsjahren 2, 5, 7 und 10 werden sie zu einer ärztlichen Visite einbestellt [Arztfragebogen und eine Gastroskopie mit Biopsie]. In dieser Arbeit wurden die Daten aus dem 5. Beobachtungsjahr (FUP5) hinsichtlich der Entwicklung der EED im Vergleich zur Baseline-Erhebung, der Detektion möglicher Risikofaktoren und der Aufdeckung kostenverursachender Folgen untersucht. Ergebnisse 6215 Patienten (47% weiblich, mittleres Alter 54 Jahre) wurden zur Baseline-Erhebung (BL) eingeschlossen. Zum Zeitpunkt des Follow- up-5 nahmen noch 2889 Patienten (46% weiblich, mittleres Alter 55 Jahre) an der Studie teil. 31,6% der Patienten wiesen zum Zeitpunkt des FUP5 extraösophageale Symptome auf. Die Prävalenz der EED hatte sich somit kaum verändert (BL: 32,8%). Um eine bessere Vergleichbarkeit zu erzielen, wurde eine neue Kohorte gebildet, die zum Zeitpunkt der Baseline-Erhebung nur Patienten umfasste, die auch zum Zeitpunkt des Follow-up-5 an der Studie teilnahmen. 12,7% der Patienten berichteten von chronischem Husten (BL: 13,3%), 7,8% der Patienten von Luftnot/ Asthma (BL: 4,5%), 8,8% der Patienten von Laryngitis/ Pharyngitis (BL: 10,6%) und 17,5% der Patienten von nicht- kardialem Brustschmerz (BL: 21,3%). Bei den EED handelt es sich nicht um konstante Erkrankungen. Bei jeder einzelnen EED gab es einen Anteil von Patienten, die über den Beobachtungszeitraum geheilt wurden. Bei einem Teil der Patienten persistierte die Erkrankung, auch kam es bei einigen Patienten zu De-Novo-Erkrankungen. Die multivariate Analyse der Risikofaktoren/ Folgen erbrachte folgendes Ergebnis: Es konnten keine gemeinsamen Risikofaktoren für die EED extrapoliert werden. Einzeln betrachtet zeigten sich beim chronischen Husten die Risikofaktoren hohes Alter und Rauchen als signifikant, bei der EED „Luftnot/ Asthma“ kamen noch weibliches Geschlecht und ein hoher BMI hinzu. Es konnten keine gemeinsamen Folgen der EED ermittelt werden. Lediglich die EED „Chronischer Husten“ und die EED „Nicht-kardialer Brustschmerz“ führten zu vermehrten Arbeitsunfähigkeiten zum Zeitpunkt des FUP5. Schlussfolgerung EED sind ein häufiges Problem bei Patienten mit GERD. Die einzelnen EED unterscheiden sich sowohl hinsichtlich der mit ihnen assoziierten Risikofaktoren als auch hinsichtlich der durch die EED verursachten ökonomischen Folgen.Background and targets: Gastroesophageal Reflux Disease (GERD) is a widespread illness. It can be associated with extraesophageal diseases (EED) like “chronic coughing”, “dyspnoe/ asthma”, “laryngitis/ pharyngitis” or “non- cardiac chest pain”. So far many studies concentrated on the prevalence of EED in GERD. The main target of this study is to evaluate the course of EED in patients with GERD in a long-term follow-up of 5 years and to look for risk factors which might facilitate the development of EED. The study also aimed at looking into the socio-economic consequences of the EED. Methods: All the data analysed evolved from the so called ProGERD-study, which is an open-cohort, multi-centre prospective study. The study started in the year 2000 and is planned to endure over 10 years. More than 6000 patients were recruited who underwent a gastroscopy [including a biopsy] which led to the initial diagnosis. They had to fill in a questionnaire and were treated with omeprazole on an individual scheme. During follow-up the patients were contacted by mail yearly and again had to fill in the questionnaire. In year 2, 5, 7 and 10 [pending] of the follow-up they were seen by a doctor and again underwent a gastroscopy [incl. biopsy] and the doctor filled in a surplus questionnaire. The specific data used for this study is of year 5 of the follow-up (FUP5) and analyses the development of EED compared to the baseline, looking for risk factors and checking for the socio-economic costs or burden. Results: 6215 patients (47% female, mean age 54 y.) were included at baseline (BL). At 5-years-follow-up the cohort comprised of remaining 2889 patients (46% female, mean age 55 y.). At this point (FUP5) 31,6% of the patients showed symptoms of EED, which was close to the baseline-prevalence of 32,8%. For further analysis we focussed on the cohort of patients which remained in the study from baseline to follow-up at 5 years (FUP5; 2889 patients, see above). 12,7% of these patients reported “chronic coughing” (BL: 13,3%); 7,8% reported symptoms of “dyspnoe/ asthma” (BL: 4,5%), 8,8% of these patients suffered from “laryngitis/ pharyngitis” (BL: 10,6%) and 17,5% had “non-cardiac chest pain” (BL: 21,3%). However, these patient-groups were not constant throughout the study as within each group part of the patients were healed during the follow-up-period, in some patients the disease persisted and of course there were also some patients with new-onset disease who joined the groups. The multivariate analysis of the risk factors showed no shared risk factors for all EED. Old age and smoking proved to be a significant risk factor for the EED “chronic coughing” and “dyspnoe/ asthma”. In the latter also a female gender and an elevated BMI showed to be a risk factor. The data of this study showed no evidence that there are common socio-economic consequences which are shared in all EED. However in the EED groups “chronic coughing” and “non-cardiac chest pain” we found significantly increased leave from work. Resume: The coexistence of EED is a frequent problem in patients with GERD. The EED-subpopulations differ in terms of their associated risk factors as well as regarding their socio-economic consequences