United Rheumatology National Meeting

United Rheumatology National Meeting

Source:
Disclosures: Furie R. SLE Update: The Interferon Story. Presented at: United Rheumatology Spring Virtual Conference; April 16-17, 2021.Furie reports no relevant financial disclosures.
April 21, 2021
3 min read
Save

TULIP: Anifrolumab exhibits 'many more pluses than minuses' in lupus

Source:
Disclosures: Furie R. SLE Update: The Interferon Story. Presented at: United Rheumatology Spring Virtual Conference; April 16-17, 2021.Furie reports no relevant financial disclosures.
You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

We were unable to process your request. Please try again later. If you continue to have this issue please contact customerservice@slackinc.com.

After decades of research advances and reverses, blocking the interferon receptor in lupus may finally be showing consistent clinical benefit, according to a presentation at the United Rheumatology Spring Virtual conference.

“Interferon has been hot for a couple of decades now in lupus,” Richard Furie, MD, chief of the division of rheumatology at Northwell Health, and professor of medicine at Hofstra/Northwell School of Medicine in New York. “The majority of lupus patients are interferon gene signature positive.”

“Interferon has been hot for a couple of decades now in lupus,” Richard Furie, MD, told attendees. “The majority of lupus patients are interferon gene signature positive.” Source: Adobe Stock

Furie suggested that lupus begins with genetic susceptibility in the host and may develop with sun exposure, causing apoptosis of the skin, at which point DNA and RNA are released.

“Crosstalk” between the innate and adaptive immune systems is also a key feature of lupus pathogenesis. Plasmacytoid dendritic cells are implicated, as are toll-like receptors nine and seven. “The net is the production of a lot of proinflammatory cytokines, the chief of which is the interferon family,” he said.

Richard Furie

With that in mind, a “burning issue” in the lupus community for the last 20 years is whether interferon inhibition could actually reduce clinical activity, according to Furie. While this search has led to many therapeutic ups and downs, recent findings for anifrolumab (AstraZeneca) have given lupus patients and the doctors that treat them considerable hope.

Among those ups and downs, Furie described rontalizumab (Creative Biolabs) as “rock bottom” and findings for sifalimumab (Creative Biolabs) as slightly more positive in phase 2 trials.

But even anifrolumab caused the field to hit rock bottom again, according to Furie. Results from phase 2 showed that 34% of patients who received a 300 mg dose of anifrolumab reached the primary endpoint of SLE Responder Index (SRI) at 6 months. Just 17% of patients on placebo reached this endpoint, while outcomes for patients treated with a 1,000 mg dose of anifrolumab were “not as good as the 300 mg dose.”

“There was a lot of confidence going into the phase 3 program,” Furie added.

However, phase 3 results from TULIP-1 showed that 36.2% of patients in the 300 mg anifrolumab group and 40.4% of those in the placebo group met the primary endpoint.

While experts are still sorting out how this happened, Furie noted one potentially confounding factor. “If a patient used an NSAID for a headache at the beginning of the study, they were classified as non-responder,” he said.

Post-hoc analyses amended for this, bringing the 300 mg anifrolumab group closer to meeting the primary endpoint. That said, Furie stressed that the study did meet the BILAG-Based Composite Lupus Assessment (BICLA) endpoint, even without adjusting in the post-hoc analysis.

Despite these setbacks, the program continued to TULIP-2. The studies were identical in design, except for one key difference: there was no anifrolumab 1,000 mg arm. Results showed that 47.8% of participants in the anifrolumab group and 31.5% of those receiving placebo achieved the primary endpoint of a BICLA response.

Moreover, among individuals with a high interferon gene signature, 48% of patients treated with anifrolumab reached BICLA response, compared with 30.7% for placebo.

Regarding the question of whether SRI also worked in TULIP-2, Furie was clear: “Well, yes, it actually did, quite nicely,” he said. “So, if you put these composite indices together — from phase 2 and phase 3 — we have six possible outcomes. It was just one study, TULIP-1, where the SRI didn’t work.”

“Five out of six in lupus is not bad,” he added.

Despite this hopeful end to the TULIP series, the discordance between SRI and BICLA responses from TULIP-1 may or may not be problematic, according to Furie. “We need to understand this discordance,” he said. “We have a lot of people working on it.”

Overall, when taken in totality, Furie believes that TULIP was positive for the lupus community. He is hopeful for the future. “I like that word, totality, to describe this program.” he said. “You see many more pluses than minuses.”