Iscalimab, an investigational antibody therapy from Novartis, showed promise for safety and preliminary efficacy for lessening disease activity in people with primary Sjögren’s syndrome who experience symptoms across the body.
Larger and longer studies are warranted to assess the clinically meaningful benefits of the potential therapy, researchers said.
The trial findings were reported in a study, “Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren’s syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study,” published in the journal The Lancet Rheumatology.
Most of the available treatments for Sjögren’s syndrome, an autoimmune condition characterized by dry eyes and mouth, only relieve symptoms and help manage long-term complications such as infections and dental disease.
Novartis is developing the antibody iscalimab (CFZ533) to target the biological roots of Sjögren’s syndrome — the abnormal immune reactions that attack the glands that make tears and saliva, and may also affect other parts of the body.
Iscalimab is a fully human antibody that blocks CD40, a co-stimulatory protein involved in the activation of immune B-cells, which are crucial to the development of Sjögren’s syndrome. Immune interactions mediated by CD40 coupling to another protein called CD154 are thought to contribute to inflammation, salivary gland infection, and other kinds of tissue injury linked to the disease.
Novartis led a small, proof-of-concept Phase 2 trial (NCT02291029) to determine if treatment with iscalimab is safe and well tolerated, and to collect the first data on its efficacy for treating patients with primary Sjögren’s syndrome who experience systemic (throughout the body) manifestations of the disease.
The early study took place in the U.S., U.K., Germany, Switzerland, and Hungary.
During the trial, two doses of iscalimab and two routes of administration were tested. Those were direct delivery into the vein (intravenous infusion) and injections under the skin (subcutaneous injection).
The study enrolled 44 patients, ages 24 to 72, who were divided in two groups. In one group, 12 patients were randomly given either subcutaneous iscalimab 3 mg/kg (8 patients) or a placebo (4 patients) at weeks 0, 2, 4, and 8; in the other group, 32 patients were given either intravenous iscalimab 10 mg/kg (21 patients) or a placebo (11 patients) on the same dosing schedule.
Researchers found no changes in disease activity in patients treated with subcutaneous iscalimab, compared to those on subcutaneous placebo.
However, those who received intravenous iscalimab experienced a mean reduction in overall disease activity of 5.2 points on the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) score at week 12, as compared to those on placebo.
Disease activity scores in the intravenous iscalimab group decreased from 10.6 points at the study start to approximately 5.0 points at week 12, and from 11.0 to approximately 10.0 points in the placebo group.
Among all body parts assessed, joints were the regions benefiting the most from iscalimab treatment. They were also the body parts most affected by the disease at study entry.
Result from an open-label part, in which all participants were given iscalimab from week 12 to 32, showed that the treatment sustains its benefits. Patients who were under iscalimab across the whole trial continued to experience lessening in disease activity, while those who switched from placebo began to experience similar effects.
Patients taking iscalimab reported improvements in other, secondary measures. Those included lower scores on the Eular Sjogren’s Syndrome Patient Reported Index (ESSPRI), a patient-reported score of symptoms of dryness, limb pain, and fatigue. Patients also said feeling less fatigue and better physical and mental health. Saliva and tear production increased, and serum levels of a disease biomarker, CXCL13, were lowered.
“To our knowledge, this is the first randomized, placebo-controlled, proof-of-concept study of a new investigational drug for primary Sjögren’s syndrome that indicates preliminary efficacy,” noted the team.
This was also the first agent to result in a clinically meaningful change in systemic complications of the disease, as measured by the recently developed ESSDAI score, they said.
Iscalimab was well tolerated, with similar adverse events in both iscalimab and placebo groups. Throughout the trial, all patients given subcutaneous iscalimab or placebo experienced side effects, as did 52% and 64% of those given the intravenous form, respectively.
The most common adverse event was upper respiratory tract infection. Two serious adverse events were reported, one case of bacterial conjunctivitis (bacterial eye infection) and one case of atrial fibrillation (irregular heartbeat), which were unrelated to iscalimab.
Cytopenias (low blood cell counts), injection site reactions, thromboembolic events (blood clots that block arteries), or increased risk for infections were not observed.
The preliminary findings warrant further investigation of iscalimab to determine if it can deliver “clinically meaningful benefit in patients with primary Sjögren’s syndrome in longer trials with more patients,” the researchers said.
Iscalimab is also in clinical development by Novartis for other autoimmune conditions, and to prevent graft rejection after an organ transplant.
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