The FDA ( US Food and Drug Administration ) has approved Kesimpta ( Ofatumumab, formerly OMB157 ) as an injection for subcutaneous use for the treatment of relapsing forms of multiple sclerosis ( RMS ), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Kesimpta is a targeted, precisely dosed and delivered B-cell therapy that has shown superior efficacy with a similar safety profile compared with Teriflunomide and is a first-choice treatment option for RMS patients.
Kesimpta is the first B-cell therapy that can be self-administered once monthly at home via the Sensoready autoinjector pen.
Ofatumumab was first approved by the FDA in 2009 for the treatment of chronic lymphocytic leukemia ( CLL ) as an intravenous infusion with a high dose, administered by a healthcare provider.
Ofatumumab was then investigated in an entirely new development program in relapsing multiple sclerosis, as B-cells are known to play a critical role in the development of autoimmune diseases, such as multiple sclerosis.
The clinical development program for Ofatumumab in relapsing multiple sclerosis took 10 years and has involved more than 2,300 patients around the world.
The approval of Kesimpta is based on results from the phase III ASCLEPIOS I and II studies, in which Kesimpta has demonstrated superiority versus Teriflunomide in significantly reducing the annualized relapse rate ( ARR, primary endpoint ), 3-month confirmed disability progression ( CDP ), and the number of Gadolinium-enhancing ( Gd+ ) T1 and new or enlarging T2 lesions.
Results from these two studies were published in The New England Journal of Medicine ( NEJM ).
ASCLEPIOS I and II are twin, identical design, flexible duration ( up to 30 months ), double-blind, randomized, multi-center phase III studies evaluating the safety and efficacy of Kesimpta 20 mg monthly subcutaneous injections versus Teriflunomide 14 mg oral tablets taken once daily in adults with relapsing multiple sclerosis.
The ASCLEPIOS I and II studies enrolled 1,882 patients with multiple sclerosis, between the ages of 18 and 55 years, with an EDSS ( Expanded Disability Status Scale ) score between 0 and 5.5.
The studies were conducted in over 350 sites in 37 countries.
Kesimpta has demonstrated a significant reduction in ARR by 51% ( 0.11 vs 0.22 ) and 59% ( 0.10 vs 0.25 ) compared with Teriflunomide ( P less than 0.001 in both studies ) in ASCLEPIOS I and II, respectively ( primary endpoint ).
Kesimpta has also shown a relative risk reduction of 34.4% ( P=0.002 ) in 3-month CDP compared with Teriflunomide in pre-specified meta-analysis, as defined in ASCLEPIOS.
Kesimpta has significantly reduced the mean number of both Gd+ T1 lesions ( 98% and 94% relative reduction in ASCLEPIOS I and II, respectively, both P less than 0.001 ) and new or enlarging T2 lesions ( 82% and 85% relative reduction in ASCLEPIOS I and II, respectively, both P less than 0.001 ) vs Teriflunomide.
Kesimpta had a similar safety profile to Teriflunomide, with the frequency of serious infections and malignancies also being similar across both treatment groups. Upper respiratory tract infection, headache, injection-related reactions, and local injection site reactions were the most commonly observed adverse reactions with Kesimpta ( incidence greater than 10% ).
A separate post hoc analysis has demonstrated Kesimpta may halt new disease activity in patients with relapsing multiple sclerosis. It showed the odds of achieving no evidence of disease activity ( NEDA-3; no relapses, no MRI lesions, and no disability worsening combined ) with Ofatumumab versus Teriflunomide were more than 3-fold higher at months 0–12 ( 47.0% vs 24.5% of patients; P less than 0.001 ) and more than 8-fold higher at months 12–24 ( 87.8% vs 48.2% of patients; P less than 0.001 ).
The APLIOS study is a 12-week, open-label, phase II bioequivalence study to determine the onset of B-cell depletion with Kesimpta subcutaneous monthly injections and the bioequivalence of subcutaneous administration of Kesimpta via a prefilled syringe ( as used in ASCLEPIOS I and II )and a Sensoready pen in patients with relapsing multiple sclerosis.
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, Kesimpta 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 less than 10 cells/μL was more than 65% after the first injection by day 7, 94% by week 4, and sustained more than 95% at all following injections.
Kesimpta 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.
Kesimpta is a targeted, precisely dosed and delivered B-cell therapy that provides the flexibility of self-administration for adults with relapsing multiple sclerosis.
Ofatumumab is an anti-CD20 monoclonal antibody ( mAb ) self-administered by a once-monthly injection, delivered subcutaneously.
Initial loading doses of Kesimpta are given at weeks 0, 1 and 2, with the first injection performed under the guidance of a healthcare professional.
As shown in preclinical studies, Kesimpta is thought to work by binding to a distinct epitope on the CD20 molecule inducing potent B-cell lysis and depletion.
The selective mechanism of action and subcutaneous administration of Kesimpta allows precise delivery to the lymph nodes, where B-cell depletion in multiple sclerosis is needed, and preclinical studies have shown that it may preserve the B-cells in the spleen.
Once-monthly dosing of Kesimpta also allows faster depletion of B-cells and offers more flexibility.
Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by myelin destruction and axonal damage in the brain, optic nerves and spinal cord.
Multiple sclerosis, which affects approximately 2.3 million people worldwide, can be characterized into four main types: clinically isolated syndrome ( CIS ), relapsing remitting ( RRMS ), secondary progressive ( SPMS ) and primary progressive ( PPMS ). The various forms of multiple sclerosis can be distinguished based on whether a patient experiences relapses ( clearly defined acute inflammatory attacks of worsening neurological function ), and/or whether they experience progression of neurologic damage and disability from the onset of the disease. ( Xagena )
Source: Novartis, 2020