Tapeworm medication may ease ear, nose, throat symptoms in AAV
Niclosamide reduced nasal symptoms in COVID-19-related trial: Analysis
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Nasal administration of niclosamide, a medication used in certain regions for intestinal tapeworm infections, may help reduce ear, nose, and throat (ENT) symptoms in people with ANCA-associated vasculitis (AAV).
In particular, benefits were seen among individuals with self-reactive antibodies against the proteinase 3 (PR3) protein — one of the two most common AAV-driving antibodies — in a COVID-19-related clinical trial.
That’s according to a subsequent subanalysis of data from that now-completed Phase 2/3 trial, called PROTECT-V (NCT04870333). Conducted entirely in the U.K., it tested several medications as potential preventive measures against COVID-19 in vulnerable patient populations — which included AAV patients on immunosuppressive treatments.
“This study provides a signal of potential beneficial clinical effect of niclosamide on nasal symptoms in AAV,” the researchers wrote, noting that treatment benefits on ear, nose, and throat symptoms were linked directly to the medication’s use.
“Not only did the niclosamide treatment group experience fewer AAV-associated nasal symptoms than the placebo group, but this beneficial effect was temporally associated with treatment and ceased upon treatment cessation,” the team wrote.
The study, “The Effect of Intranasal Niclosamide on Nasal Symptoms in Patients with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis,” was published in Arthritis & Rheumatology, a journal of the American College of Ryeumatology.
Characterized by inflammation and damage to small blood vessels, AAV is typically caused by self-reactive antibodies called ANCAs. ANCAs typically target one of two proteins: PR3 or myeloperoxidase.
Ear, nose, throat symptoms reported by over 60% of GPA patients
ENT symptoms are common in people with AAV. Indeed, they are reported by 60%-85% of those with granulomatosis with polyangiitis (GPA), a common AAV type, and are associated with anti-PR3 antibodies.
Despite the prevalence of such symptoms, however, “there is [an] unmet need for drugs to target these manifestations,” the researchers wrote.
Niclosamide, one of a family of medicines called anthelmintics, is used to treat a variety of tapeworm infections. But research has shown that the drug may have other uses beyond treating parasites.
It works by suppressing the IL-6-STAT3 signaling pathway, which has previously been shown to be involved in AAV, particularly in disease types with granulomas (immune cell clumps), such as GPA, and anti-PR3 antibodies.
Sold under the brand name Niclocide and with generics available, it is approved in many regions outside the U.S. for the treatment of intestinal infections caused by tapeworms. It had been used for the same indication in the U.S., but was voluntarily withdrawn from the market by its developer Bayer in 1996 due to commercial reasons.
Niclosamide was one of the tested medications in the PROTECT-V study, which aimed to identify a potential preventive treatment for COVID-19 in vulnerable patient populations.
Participants, including those with AAV on standard immunosuppressive treatment, were randomly assigned to receive either niclosamide or a placebo, via a nasal spray pump, twice daily for nine months or until they developed COVID-19. Niclosamide’s total daily dose was 5.6 mg.
“Anecdotally, some patients with AAV receiving treatment during the trial reported an improvement in their longstanding nasal symptoms,” the researchers wrote.
As such, according to the team, “we took this opportunity to test the hypothesis that, in patients with AAV and ENT manifestations, intranasal niclosamide would reduce ENT symptoms.”
Nasal symptoms were reduced while patients took niclosamide
To find out, the team retrospectively analyzed data from 32 AAV participants with a history of ENT manifestations. A total of 14 had received at least two weeks of niclosamide treatment, while 18 had been on the placebo. None had eosinophilic granulomatosis with polyangiitis, the rarest AAV type.
These participants were mainly men (66%), had a median age of 69, and had lived with an AAV diagnosis for a median of 5.4 years. More than half had anti-PR3 ANCAs (59%) and active disease in the year before trial enrollment (59%).
Disease duration was significantly longer in people treated with niclosamide (11.9 vs. 3.9 years). Median treatment duration was 200 days, or about 6.5 months.
The main goal of the subanalysis was to assess how many participants experienced ENT symptoms in the nine months before, during, and after treatment was stopped. The results showed that 57% people in the niclosamide group and 61% of those in the placebo group had at least one episode of ENT symptoms during that entire period.
While there were no significant group differences before treatment and long after treatment was stopped, during the treatment period, a significantly lower proportion of niclosamide-treated patients experienced ENT symptoms (7% vs. 39%), the data showed.
In the niclosamide group, the rate of participants experiencing ENT manifestations dropped from before treatment to during treatment (29% vs. 7%), and increased after treatment discontinuation (36%). In contrast, rates in the placebo group “remained relatively constant” between periods, the researchers wrote.
Among patients with anti-PR3 ANCAs, none in the niclosamide group experienced ENT symptoms, compared with 56% of those on the placebo, suggesting that “the effect of niclosamide treatment was more pronounced in PR3-ANCA patients,” the researchers wrote.
These data do not support routine clinical use of intranasal niclosamide. … [But] they do suggest that the investigation of niclosamide or other [similar medications] as a therapy is indicated.
Intranasal niclosamide had a favorable safety profile, with similar rates of serious adverse events compared with the placebo. Additionally, blood niclosamide levels following intranasal delivery were low, showing it acts locally with minimal systemic, or bodywide, effects.
“In the PROTECT-V trial, the niclosamide group experienced significantly higher rates of early drop-out than the placebo group, predominantly due to local nasal irritation — sneezing, itching, burning sensation and nasal pain,” the researchers wrote. Still, these issues appeared to occur soon after starting treatment and did not worsen over time, the team noted.
Data support future studies of tapeworm medication in AAV
While “these data do not support routine clinical use of intranasal niclosamide,” the researchers wrote, “they do suggest that the investigation of niclosamide or other IL-6-STAT3 pathway [blockers] as a therapy is indicated.”
For instance, tocilizumab, an anti-IL6 antibody, “has been successfully used in severe or resistant cases of PR3-positive and ANCA-negative AAV,” although [body-wide] administration presents “significant risks,” the team concluded.
