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.

Safety experience with continued exposure to ofatumumab in patients with relapsing forms of multiple sclerosis for up to 3.5 years.

BACKGROUND: Ofatumumab is approved for the treatment of relapsing multiple sclerosis (RMS). Ongoing safety reporting is crucial to understand its long-term benefit-risk profile. OBJECTIVE: Report the safety and tolerability of ofatumumab in RMS after extended treatment up to 3.5 years. METHODS: Patients completing ASCLEPIOS I/II (phase 3), APLIOS, or APOLITOS (phase 2) trials could enter ALITHIOS, a phase 3b, open-label, long-term safety study. We analyzed cumulative data of continuous ofatumumab treatment and of patients newly switched from teriflunomide. RESULTS: The safety population had 1969 patients: 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched (median time-at-risk 18.3 months, 986 patient-years). A total of 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events. No opportunistic infections or progressive multifocal leukoencephalopathy events were identified; the risk of malignancies was low. Mean serum immunoglobulin (Ig) G levels remained stable. Mean IgM levels decreased but remained above the lower limit of normal in most. Serious infection incidence was low; decreased Ig levels were not associated with serious infections. CONCLUSION: In patients with up to 3.5 years' exposure, ofatumumab was well tolerated, with no new safety risks identified. These findings, with its established effectiveness, support a favorable benefit-risk profile of ofatumumab in RMS.

Incidence rates of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis treated with secukinumab: a retrospective analysis of pooled data from 21 clinical trials.

OBJECTIVES: Here, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a pooled analysis of 21 clinical trials. METHODS: Data from all patients who had received at least one dose of secukinumab were included. Safety analyses were conducted to evaluate cumulative IBD rates as well as per-year rates, by indication. Crohn's disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) events were analysed using exposure-adjusted incidence rates (patient incidence rates per 100 patient-years (PY)). RESULTS: A total of 7355 patients with a cumulative exposure of 16 226.9 PY were included in the pooled analysis. Among 5181 patients with PsO, there were 14 cases of UC, 5 cases of CD and 1 case of IBDU, with exposure adjusted incidence rates (EAIRs) of 0.13, 0.05 and 0.01, respectively. Of these 20 cases, 14 were new-onset. In 1380 patients with PsA, there were 3 cases of UC, 3 cases of CD and 2 cases of IBDU (EAIRs 0.08, 0.08 and 0.05); 7 of these represented new-onset cases. Among 794 patients with AS, there were 4 cases of UC, 8 cases of CD and 1 case of IBDU (EAIRs 0.2, 0.4 and 0.1); 9 were new-onset cases. In the per year analysis, the EAIRs for each indication did not increase over time with secukinumab treatment. CONCLUSIONS: In this pooled secukinumab safety analysis of 7355 patients across 21 clinical trials, cases of IBD events (including CD, UC and IBDU) were uncommon.

Sustained Benefits from Ranibizumab for Central Retinal Vein Occlusion with Macular Edema: 24-Month Results of the CRYSTAL Study.

PURPOSE: To assess the efficacy and safety profile of an individualized, stabilization criteria-driven regimen of ranibizumab 0.5 mg in patients with visual impairment due to macular edema secondary to central retinal vein occlusion (CRVO). DESIGN: A 24-month, prospective, open-label, single-arm, multicenter study. PARTICIPANTS: A total of 357 patients. METHODS: Patients received monthly ranibizumab 0.5 mg injections (minimum, 3 injections) until stable visual acuity (VA) was maintained for 3 consecutive months. Thereafter, ranibizumab 0.5 mg injections were administered if monitoring indicated a loss of VA due to disease activity. The primary outcome results have been published previously. MAIN SECONDARY OUTCOME MEASURES: Mean change from baseline at months 1 through 24 in best-corrected VA (BCVA) in the overall population and in subgroups categorized according to baseline BCVA, CRVO duration, or presence of macular ischemia. RESULTS: The baseline mean BCVA was 53.0 letters and baseline mean CRVO duration was 8.9 months (median, 2.4 months). The mean (standard deviation) gain in BCVA from baseline with ranibizumab 0.5 mg at month 24 was 12.1 (18.60) letters (P < 0.0001). Best-corrected VA gains at month 24 were similar in patients with or without baseline macular ischemia (mean change, 11.1 and 12.9 letters, respectively). The mean BCVA gain at month 24 was higher in patients with CRVO duration <3 months (13.2 letters) compared with that in those with CRVO duration >9 months (10.5 letters). Patients with lower baseline BCVA had larger mean BCVA gains at month 24 (≤39 letters; 18.5 letters) than those with higher baseline BCVA (40-59/≥60 letters; 13.9/7.2 letters), although the absolute BCVA values at month 24 were higher in patients with higher baseline BCVA. The mean (standard deviation) and median number of ranibizumab injections up to month 23 were 13.1 (6.39) and 15.0 injections, respectively. No new ocular or nonocular safety events were reported. CONCLUSION: An individualized, stabilization criteria-driven dosing regimen of ranibizumab 0.5 mg led to sustained BCVA gains for up to 24 months in patients with CRVO. The presence of macular ischemia at baseline did not influence VA gains. Shorter duration of CRVO at baseline was associated with better VA gains. Safety findings were consistent with those reported in previous ranibizumab studies in patients with CRVO.

Sustained Benefits of Ranibizumab with or without Laser in Branch Retinal Vein Occlusion: 24-Month Results of the BRIGHTER Study.

PURPOSE: To evaluate the long-term (24-month) efficacy and safety of ranibizumab 0.5 mg administered pro re nata (PRN) with or without laser using an individualized visual acuity (VA) stabilization criteria in patients with visual impairment due to macular edema secondary to branch retinal vein occlusion (BRVO). DESIGN: Phase IIIb, open-label, randomized, active-controlled, 3-arm, multicenter study. PARTICIPANTS: A total of 455 patients. METHODS: Patients were randomized (2:2:1) to ranibizumab 0.5 mg (n = 183), ranibizumab 0.5 mg with laser (n = 180), or laser (with optional ranibizumab 0.5 mg after month 6; n = 92). After initial 3 monthly injections, patients in the ranibizumab with or without laser arms received VA stabilization criteria-driven PRN treatment. Patients assigned to the laser arm received laser at the investigator's discretion. MAIN OUTCOME MEASURES: Mean (and mean average) change in best-corrected visual acuity (BCVA) and central subfield thickness (CSFT) from baseline to month 24, and safety over 24 months. RESULTS: A total of 380 patients (83.5%) completed the study. Ranibizumab with or without laser led to superior BCVA outcomes versus laser (monotherapy and combined with ranibizumab from month 6; 17.3/15.5 vs. 11.6 letters; P < 0.0001). Ranibizumab with laser was noninferior to ranibizumab monotherapy (mean average BCVA change: 15.4 vs. 15.0 letters; P < 0.0001). However, addition of laser did not reduce the number of ranibizumab injections (mean injections: 11.4 vs. 11.3; P = 0.4259). A greater reduction in CSFT was seen with ranibizumab with or without laser versus laser monotherapy over 24 months from baseline (ranibizumab monotherapy -224.7 µm, ranibizumab with laser -248.9 µm, laser [monotherapy and combined with ranibizumab from month 6] -197.5 µm). Presence of macular ischemia did not affect BCVA outcome or treatment frequency. There were no reports of neovascular glaucoma or iris neovascularization. No new safety signals were identified. CONCLUSIONS: The BRIGHTER study results confirmed the long-term efficacy and safety profile of PRN dosing driven by individualized VA stabilization criteria using ranibizumab 0.5 mg in patients with BRVO. Addition of laser did not lead to better functional outcomes or lower treatment need. The safety results were consistent with the well-established safety profile of ranibizumab.