Gilead's Promising Anti-inflammatory Drug Filgotinib Fails in Two Phase 2 Clinical Trials for Cutaneous Lupus and Sjögren’s Syndrome

Compiled by Keke

In Phase 2 clinical trials for cutaneous lupus and Sjögren's syndrome, Gilead’s most promising drug, filgotinib, along with two other investigational compounds, all ended in “resounding failure.”

In 2017, Gilead Sciences initiated two studies (NCT03134222 and NCT03100942) targeting moderate-to-severe systemic lupus erythematosus and Sjögren’s syndrome in women, with results expected in the second half of 2019. Recently, during its third-quarter earnings conference call, John Sundy, Senior Vice President at Gilead Sciences, revealed thatDespite earlier studies showing "positive evidence," neither of the two trials ultimately met their primary endpoints.。

Study NCT03134222(Source: https://clinicaltrials.gov)

Study NCT03100942(Source: https://clinicaltrials.gov)

Sundy acknowledged that there was indeed evidence demonstrating the therapeutic potential of filgotinib, particularly showing greater activity in patients with specific biomarkers or signs of disease. Therefore, this unsuccessful outcome represents only the initial analysis of these data; the company is currently reviewing the full trial dataset to determine the next steps for patients with lupus and Sjögren's syndrome.

In the fields of lupus erythematosus or Sjögren's syndrome, success in either indication could open up an untapped market for Gilead Sciences. Currently, many companies, including Biogen and Novartis, are also developing candidate drugs to combat these diseases, as clinically available treatment options have not yielded satisfactory outcomes for patients.

Filgotinib is a Janus kinase (JAK) inhibitor. JAKs belong to the cytoplasmic tyrosine kinase family and comprise four subtypes that mediate signaling pathways activated by cytokines, such as interferons. The signaling of numerous pro-inflammatory cytokines relies heavily on JAK1. Currently, less selective JAK inhibitors (e.g., tofacitinib) are commercially available and have demonstrated long-term efficacy in treating various inflammatory and autoimmune diseases; however, their lack of selectivity leads to dose-limiting side effects, with the adverse effects of pan-JAK inhibition potentially outweighing their benefits. As filgotinib exhibits 30-fold greater selectivity for JAK1, this highly selective JAK1 inhibitor is considered a promising therapeutic agent. Developed jointly by Gilead Sciences and Galapagos, the drug is primarily being investigated for rheumatoid arthritis (RA) and Crohn’s disease. Additionally, clinical trials are underway for several other inflammatory conditions.

In early October, Gilead Sciences announced that filgotinib demonstrated efficacy, safety, and tolerability in the Phase 3 FINCH 1 and FINCH 3 clinical trials involving patients with moderately to severely active rheumatoid arthritis (RA). Previously, Gilead had stated that it would submit a New Drug Application (NDA) to the U.S. FDA for filgotinib in the treatment of RA by the end of this year, and was actively discussing the study results and application process for filgotinib in the treatment of moderately to severely active ulcerative colitis or Crohn’s disease. Currently, the positive results from the FINCH 1 and FINCH 3 trials are expected to directly pave the way for filgotinib to receive approval for its first indication.

In addition to filgotinib, two trials in lupus and Sjögren’s syndrome also involved Gilead’s lanraplenib (also known as GS-9876), a Syk kinase inhibitor. The Sjögren’s syndrome trial NCT03100942 also tested tirabrutinib (also known as GS-4059), a BTK inhibitor developed by Gilead in collaboration with Ono Pharmaceutical.

Ongoing Clinical Trials and Phases of Filgotinib(Source: Galapagos NV official website)

Ongoing Clinical Trials of Filgotinib and GS-9876

Last week, Gilead Sciences released its third-quarter financial report, with sales reaching $5.516 billion, which analysts considered in line with expectations. Currently, Gilead’s primary revenue source is its anti-HIV products, which generated $4.2 billion in sales in the third quarter of this year (compared to $3.7 billion in the same period last year). This change was mainly driven by the continued growth in sales volume of Biktarvy®.

During the conference call for Gilead’s third-quarter financial report, the company not only disclosed the failure of filgotinib but also explained its strategic shift in HIV treatment. Previously, Gilead was developing GS-9131, a nucleotide reverse transcriptase inhibitor for HIV therapy, but this asset has recently disappeared quietly from its R&D pipeline.

“The discontinuation of GS-9131 was driven by the emergence of another investigational drug, GS-6207, a viral capsid inhibitor that initiated Phase 1b clinical trials earlier this year; its positive data ultimately led the company to abandon GS-9131,” noted Diana Brainard, Senior Vice President of HIV and Emerging Viral Infections at Gilead Sciences. “Given the potent efficacy of this novel mechanism of action and the absence of pre-existing resistance, we believe capsid inhibitors represent the most effective therapeutic agents for patients who have undergone multiple prior treatment regimens.”

References:

[1] Gilead’s filgotinib fails midphase tests in lupus, Sjogren's

[2] Gilead and Galapagos Announce Efficacy and Safety Results of Filgotinib Through 52 Weeks in FINCH 1 and FINCH 3 Studies in Rheumatoid Arthritis