Monthly under-the-skin injections of Novartis’ investigational candidate ofatumumab show promise as a convenient, effective, and safe therapeutic option for people with relapsing multiple sclerosis (MS).
Data from the ASCLEPIOS and APLIOS clinical trials showed that ofatumumab — currently under regulatory review for possible approval in the U.S. and Europe — was superior to the approved MS therapy Aubagio (teriflunomide) by Sanofi Genzyme in people with relapsing forms of MS, and that it can be administered at home through a patient-friendly autoinjector pen.
For Amit Bar-Or, MD, of the Perelman School of Medicine at the University of Pennsylvania, an investigator in the APLIOS study, ofatumumab is a “very attractive prospect in terms of the ability for patients to self-administer, with monthly subcutaneous [under-the-skin] injections, a therapy that is otherwise very well tolerated and very effective against relapsing MS disease activity.”
In an interview with Multiple Sclerosis News Today, Bar-Or, who expressed confidence that ofatumumab will be approved soon, discussed the therapy’s latest clinical data and its promising therapeutic profile.
Ofatumumab, co-developed by Genmab and Novartis, is a fully human antibody that specifically targets a protein receptor called CD20 on the surface of B-cells. B-cells are a type of immune cell involved in the abnormal immune reactions against myelin (the protective sheath around nerve cell fibers) that drive MS development.
By blocking CD20’s activity, ofatumumab is expected to promote B-cell death, potentially lowering interactions with other immune cells — key for the initiation of a series of immune reactions against myelin and MS relapses.
Other anti-CD20 B-cell therapies — including approved MS therapy Ocrevus (ocrelizumab) from Roche and rituximab (used off-label in MS) — were shown to be effective in lowering relapse rates in people with relapsing MS. These therapies typically involve intravenous (into the vein) infusions at a hospital or clinic, once every six months.
According to Bar-Or, ofatumumab has the potential to be a more convenient option for patients, as it can be self-administered at home.
Results from the Phase 3 ASCLEPIOS I (NCT02792218) and II (NCT02792231) trials, involving 1,882 adults with relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (SPMS), showed that monthly injections of ofatumumab led to a greater decrease in relapse rates, active brain lesions, and disability progression risk than did daily Aubagio tablets.
Ofatumumab also showed a favorable safety profile — consistent with results from previous Phase 2 trials — which Bar-Or termed “pretty boring,” noting that “boring is good when it comes to safety.”
Bar-Or said the ASCLEPIOS trials provided “compelling” data of ofatumumab’s “remarkable impact” on MS relapse biology, and of its “excellent” safety profile.
To assess whether ofatumumab could be administered through an even more convenient delivery system, Novartis launched the Phase 2 APLIOS trial (NCT03560739), which compared two subcutaneous delivery devices: a prefilled syringe (used in previous clinical trials) and an autoinjector pen called SensoReady.
Bar-Or, who recently presented APLIOS data at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2020, noted that the prefilled syringe requires the patient or someone else to control all steps of the injection process, including the consistent placement of the needle into the skin at the right depth, and pushing the plunger without losing any therapy solution.
In contrast, he said, the autoinjector pen provides “a very standard, very easy-to-use” method with “presumably fewer issues of potential bruising or people forgetting how to do it.”
“You essentially press the device against the skin and just keep it there, and it injects automatically and will always do it the same way and get all the material in,” Bar-Or said. This simplicity is important to MS patients, who may have difficulty coordinating their movements, he added.
APLIOS evaluated ofatumumab’s pharmacokinetics (uptake, distribution, and elimination), effects on B-cell numbers, and safety when delivered with either device and at different injection sites — the abdomen versus the thigh — in 284 adults with RRMS or active SPMS. The abdomen is ofatumumab’s standard injection site.
Abdomen injections were given to a total of 258 participants (130 with a prefilled syringe, and 128 with an autoinjector pen), while thigh injections were given to 26 patients (13 with a prefilled syringe, and 13 with an autoinjector pen).
Therapy regimen involved a loading dose at days one, seven, and 14, followed by a maintenance dose every four weeks from the fourth week onward.
Ofatumumab significantly lowered the number of circulating B-cells from a median of 214 cells/microliter (mcl) to fewer than 10 cells/mcl in 84.6% of all participants by day 14, and in 94% of patients at week four. Low B-cell counts (10 cells/mcl) were maintained through week 12 in 98.1% of the participants.
Bar-Or noted that while researchers have not yet determined the therapeutic threshold of B-cell numbers in relapsing MS patients, data from the previous Phase 2 MIRROR trial (NCT01457924) showed that lowering patients’ B-cell counts to fewer than 30 cells/mcl with ofatumumab resulted in high therapeutic benefits.
He said he is confident that a reduction in circulating B-cells to fewer than 10 cells/mcl likely results in a therapeutic benefit.
All patients receiving thigh injections achieved the 10 B-cells/mcl predefined threshold (regardless of delivery device), while a small percentage of patients who received abdomen injections (3.2% with a prefilled syringe and 0.8% with an autoinjector pen) did not.
As to whether the thigh may be a better injection site than the abdomen, Bar-Or emphasized that the Phase 3 ASCLEPIOS trials already showed that ofatumumab injections into the abdomen are highly effective, and that the small differences between injection sites are “not likely to be meaningful in terms of efficacy.”
Moreover, the overall pattern of B-cell reduction in APLIOS participants suggested that “individuals will continue to decrease their cell counts over 12 weeks, and eventually everybody [will] get below that threshold [10 cells/mcl],” he said.
Bar-Or also noted that ofatumumab was “very well tolerated and very safe in all regards,” and that few patients interrupted (1.1%) or stopped (0.4%) treatment due to adverse events. In addition, no increased injection site reactions or hypersensitivity to treatment with repeated injections were reported.
While the data also support the use of the thigh as an effective injection site, Bar-Or said that since ofatumumab is administered once a month, “it should be very easy to do the abdomen [administration] essentially every time.”
Ofatumumab vs. other therapies
While it may be tempting to compare ofatumumab’s benefits with those of other anti-CD20 therapies, such as Ocrevus and rituximab, only head-to-head studies allow these comparisons and no such studies seem to be on the horizon.
“We believe that we can do other comparisons in terms of patient-friendliness [of a therapy], in terms of the economics of administration … [and] we are planning some of those studies,” Krishnan Ramanathan, PhD, Novartis’ global program head of neuroscience, said in a separate interview with Multiple Sclerosis News Today.
Bar-Or said that while direct comparisons between ofatumumab and Ocrevus are not possible, “there’s no reason to think” that ofatumumab is inferior to Ocrevus, and they are likely “equivalent.”
“There is room for both, and different people will prioritize different aspects [of each therapy] in a way that suits them,” he said. While some patients, and potentially insurers, will favor “home administration, saving costs of infusions, and making it more simple for patients” by not requiring a hospital or clinic visit, others will prefer “to have an infusion once every six months — to go somewhere and let someone do it, as opposed to taking monthly injections.”
According to Ramanathan, in addition to the potentially more convenient method of administration, ofatumumab has two other possible advantages over available anti-CD20 therapies: it binds to two — rather than one — regions of the CD20 receptor, and it is a fully human antibody.
Ofatumumab’s particular binding mechanism provides a “better foothold” on CD20, and a very slow “functional off-rate, or ability to detach from the receptor,” features shown to be superior to those of rituximab in preclinical studies, Ramanathan said.
That’s likely important “when you’re administering small doses subcutaneously and you need to reach the lymphatic system where [disease-causing B-cells] are residing” and warrant sustained binding to CD20 in B-cells so that they do not interact with other immune cells and promote further damage, he said.
“Typically, with the intravenous administration, your antibody concentration is diminished before the next administration — for example, in rituximab or competitor agents,” he said. “With ofatumumab, with a monthly dosing, we’re able to bind on a sustained basis to the B-cell receptors.”
Ofatumumab is thought to promote B-cell death mainly through a process dependent on the complement system — a set of more than 50 blood proteins that contribute to the body’s natural immune defenses — and in a more effective way than rituximab.
The administration of a fully human antibody such as ofatumumab — instead of an antibody with some mouse-derived regions — likely results in fewer immune responses. This may prevent the occurrence of sensitivity reactions to a therapy, and the production of so-called anti-drug antibodies, which can limit a therapy’s effectiveness over time.
Ramanathan said that “the presence of anti-drug antibodies is expected to be low with a fully human antibody,” and that the company has Phase 3 data on that, which will soon be published.
The mode of administration (subcutaneous versus intravenous) may also play a role in the effectiveness of an anti-CD20 B-cell therapy in MS patients, Ramanathan said.
“We believe that the B-cells in the lymphatic system are the target for multiple sclerosis disease dissemination, and a subcutaneous administration allows us to access these cells very directly rather than intravenous administration where you have a high profusion of other organs … before it gets to the lymphatic system,” he said.
“We think that the convenience is very visible, but the real important difference is the ability to target the right cells for the antibody,” he added.
Bar-Or said future studies are needed to compare the biologic impact of subcutaneous versus intravenous administrations of B-cell therapies in MS patients.
Final regulatory decisions on ofatumumab’s approval for the treatment of relapsing MS are expected by June in the U.S. and by 2021 in Europe.
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