Inflection Point: Abivax Challenges Pharma Giants in Ulcerative Colitis

Nearly seven years after raising the largest initial public offering (IPO) of any French biotech company, Abivax says 2022 marks another inflection point for the developer of therapies designed to treat chronic inflammatory diseases, cancer, and viral infections.

Abivax’s lead candidate, ABX464, is gearing up to launch a Phase III program this year in about 1,400 patients with moderate-to-severe ulcerative colitis (UC). The company has held an end-of-Phase II meeting with the FDA and received scientific feedback from the European Medicines Agency. Both agencies supported ABX464 advancing into Phase III.

“This program is going to start towards the end of the second quarter with patient enrollment,” Abivax CEO Hartmut J. Ehrlich, MD, told GEN Edge.

“Based on dialogue with our Clinical Steering Committee and also based on feedback from our regulatory advisors, we strongly believe that we will be able to embark on the Phase III program taking into account [regulators’] suggestions,” Ehrlich added. “Both induction studies will then feed the single maintenance study that we are planning.”

Abivax’s treatments are designed to modulate the body’s inflammation and immunological pathways.

ABX464 is an oral, first-in-class, small molecule designed to upregulate miR-124, an anti-inflammatory microRNA. ABX464 enhances the selective splicing of a single long non-coding RNA to generate miR-124, which downregulates cytokines and chemokines shown to promote inflammation, including tumor necrosis factor (TNF) alpha, IL-6, monocyte chemoattractant protein-1 (MCP-1) and IL-17, as well as Th17+ cells.

ABX464 was initially developed against HIV but was repurposed to fight inflammatory conditions based on its anti-inflammatory effect. More recently, ABX464 has shown safety and effective anti-inflammatory activity in Phase IIa and Phase IIb induction and long-term maintenance trials as well as in preclinical studies.

As a result, Abivax reasons, ABX464 has broad potential as an anti-inflammatory therapeutic agent in numerous indications.

Positive induction data

Abivax released positive results in May 2021 from a Phase IIb induction study (NCT03760003) showing ABX464 met its primary endpoint of achieving statistically significant reduction of the modified Mayo Score from baseline after eight weeks of treatment with ABX464 in 254 patients with UC.

Depending on the dose (25/50/100 mg) and whether patients were previously treated with biologics or JAK inhibitors, the mean change from baseline ranged from -2.8 to -3.2—compared with a -1.0 to -1.9 range for placebo patients. Also at week 8, 35%, 40%, and 44% of all patients treated with 25, 50, and 100 mg, respectively, achieved endoscopic improvement compared to 14% in the placebo group.

Four months later, last September, Abivax announced additional data from patients who had a second endoscopy performed at week 16 after showing no improvement at week 8. Those patients showed higher percentages of clinical remission in the (25/50100 mg ABX464 treatment groups (15%, 20% and 23% respectively) vs. 13% in the placebo group.

And in October, Abivax said ABX464 achieved clinical remission in 59 patients—58.4% of the first 101 patients who completed an ongoing Phase IIb open-label maintenance study (NCT04023396) following the Phase IIb induction study.

“These are the highest clinical remission rates ever reported for any late-stage or licensed product after one year of maintenance,” Ehrlich said.

He contrasted ABX464’s clinical remission rate to the 33% of patients achieving clinical remission reported by Arena Pharmaceuticals for its lead candidate etrasimod, an oral selective sphingosine 1-phosphate (S1P) receptor modulator also being developed to treat UC and other immune-mediated and inflammatory diseases.

Abivax also released further results showing that 15 of 22 patients initially enrolled in the maintenance study completed the third year of treatment. Among 13 patients with centrally read endoscopies after year three, 11 were still in clinical remission, of which seven patients (54%) achieved endoscopic remission and the other four showed endoscopic improvement.

“By and large, we are seeing in both [Abivax] studies, two thirds of the patients achieving clinical remission after the first year. And that stays during the second and third year of maintenance with daily administration of ABX464,” Ehrlich said. “We are actually providing a chronic treatment that is effective in the long run for this chronic inflammatory disease that actually needs to be treated in a chronic manner.”

Market opportunity

Abivax estimates a total market opportunity for ABX464 of $6 billion annually, based on 2020 pharmaceutical sales estimates for UC in G7 countries (US, France, Germany, Italy, Spain, UK and Japan). Several big pharma companies are looking to tap into that market—starting with Pfizer, which last month agreed to acquire Arena Pharmaceuticals for approximately $6.7 billion.

“At the heart of this deal is etrasimod,” declared Mike Gladstone, Pfizer’s Global President, Inflammation & Immunology, addressing analysts on December 13. “The driver is etrasimod’s potential in IBD [inflammatory bowel disease] and its near-term launch in ulcerative colitis.”

In conducting due diligence on the deal, Gladstone added, Pfizer found etrasimod showed “potential superiority to the standard of care.”

In acquiring Arena, Pfizer hopes to go head-to-head with Bristol-Myers Squibb’s Zeposia^® (ozanimod), first approved in 2020 for relapsing forms of multiple sclerosis. On May 27, Zeposia won FDA approval as the first and to-date only S1P receptor modulator approved for treating moderately to severely active UC. Zeposia generated $40 million in product revenue during the third quarter (up from $2 million in Q3 2020) and $86 million during the first three quarters of 2021 (up from $3 million a year earlier).

“We believe ARNA’s lead asset, etrasimod, is partially de-risked given the positive read through from Bristol-Myers Squibb’s ozanimod (Zeposia), combined with the positive Phase II OASIS data in ulcerative colitis,” Joseph P. Schwartz, managing director, rare diseases, and a senior research analyst with SVB Leerink, wrote December 13 in a research note.

Eli Lilly plans to submit a Biologics License Application (BLA) to the FDA for mirikizumab in UC in the first half of 2022, following positive results for its Phase III LUCENT-2 maintenance study (NCT03524092). That study showed that mirikizumab met the primary endpoint of clinical remission after one year in patients with moderately-to-severely active UC who were treated in the earlier LUCENT-1 12-week induction study (NCT03518086).

Mirikizumab is a humanized IgG4 monoclonal antibody that binds to the p19 subunit of interleukin 23. A statistically higher proportion of mirikizumab patients met the primary endpoint compared to patients who were re-randomized to placebo, Lilly said, without giving details. Last year the FDA approved Bristol Myers Squibb’s Zeposia^® (ozanimod) as the first and only sphingosine 1-phosphate (S1P) receptor modulator approved for moderately to severely active UC.

Three potential indications

UC is the first of three indications for which Abivax is developing ABX464. The others are rheumatoid arthritis (RA) and Crohn’s disease. In RA, Abivax says it’s planning to launch a Phase IIb dose-ranging study this year, after reporting positive results in June from the 12-week induction phase of a 60-patient Phase IIa trial (NCT03813199).

The study—which evaluated ABX464 with methotrexate in patients with active moderate to severe RA—met its primary endpoint, with a once-daily 50 mg oral dose of ABX464 showing a favorable safety and tolerability profile. The study also showed 60% patients dosed with ABX464 achieved at least a 20% improvement in RA symptoms as measured through the American College of Rheumatology’s ACR20 scale, compared with 22% of patients randomized to placebo.

As for Crohn’s, Abivax is planning a Phase IIb trial after being encouraged by its Clinical Steering Committee that the drug will show sufficient benefit in patients to justify the study. The committee has cited the clinical similarities between the disease and UC, as well as the predictability of the DSS model for both diseases, Ehrlich said.

The timing of that Phase IIb trial in Crohn’s will depend on how soon Abivax attracts either additional financing or a collaboration partner, said Philippe Pouletty, MD, Chairman of Abivax’s board.

“If we do a partnering, we will move forward with the three indications—UC, Crohn’s and RA—in 2022,” Pouletty said. If we decide not to do yet a big partnering, then we’ll prioritize and UC will be the priority indication, so that we maximize shareholder value.

“We will not embark into highly diluted financing to conduct three indications at once,” added Pouletty, founder and CEO of Truffle Capital, a Paris-based venture capital firm that has raised more than $1.1 billion to support over 75 companies in the life sciences and digital technologies added.

Pouletty and Truffle founded Abivax in 2013 to commercialize ABX464 and ABX196, the company’s second clinical candidate and a synthetic glycolipid agonist of invariant Natural Killer T cells (iNKT) in a liposomal formulation administered intramuscularly. Two years later, the company went public through an IPO that raised €57.7 million ($65.5 million)—still the largest IPO for a French biotech.

Headquartered in Paris, with a research center 465 miles south in Montpellier, Abivax saw its shares close last week at €25.90 ($29.38), between the 52-week high close of €35.85 ($40.67) on September 9, 2021, and 52-week low close of €17.74 ($20.13).

Extending the runway

In July, Abivax completed €85 million ($96.4 million) in new financing, consisting of an oversubscribed capital increase of €60 million and convertible bonds of €25 million. The financing extended the company’s runway through the second quarter. That runway could stretch into Q3 if Abivax prioritizes ABX464 development in UC.

ABX464 is part of the company’s proprietary library of more than 2,200 compounds, while ABX196 was in-licensed from Scripps Research, the University of Chicago, and Brigham Young University.

At the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, held in San Francisco and online January 20–22, Abivax reported positive results from the 10-patient dose escalation phase of a Phase I/II trial (NCT03897543), assessing treatment with ABX196 in combination with Bristol Myers Squibb’s marketed checkpoint inhibitor Opdivo^® (nivolumab) in patients with hepatocellular cancer (HCC).

Of the 10 heavily pre-treated HCC patients, five experienced clinical benefit: One patient showed a partial response, while the other four showed stable disease. Median progression-free survival for all patients was 113.5 days, which more than doubled to 276 days in those who showed a clinical benefit.

Abivax said the results supported further clinical development of ABX196. The company is assessing the design of follow-on study of ABX196 in HCC and at the same time assessing potential partnering options.

Because ABX196 is in earlier clinical development, Abivax says its attention this year will center on ABX464. “For us it is clear that the absolute priority is ABX464, because if you look at the valuation of Abivax, ABX464 by itself carries more than 90% of the value of the company,” Pouletty said.

Abivax estimates that ABX464’s three indications account for a combined market of $50 billion—while overall chronic inflammatory disease commands roughly $100 billion. “If you have good data and a good drug, it’s the type of field where you can take 10%, 20%, 30% market share in the second- and third-line therapies,” Pouletty said.

Abivax’s pipeline also includes three preclinical candidates: An antiviral drug targeting respiratory syncytial virus, and candidates for Dengue and influenza, both in research phases.

Abivax’s Clinical Steering Committee includes Séverine Vermeire, MD, PhD, head of the department of chronic diseases & metabolism (CHROMETA) at KU Leuven; William Sandborn, MD, a gastroenterologist and professor of Medicine at University of California (UC) San Diego Health; and Bruce Sands, MD, the Professor of Medicine at Icahn School of Medicine at Mount Sinai in New York City.

The company’s regulatory advisors include two former directors of the FDA’s Division of Gastroenterology Products: Donna Griebel, MD, now a consultant with Griebel and Rosebraugh Consulting; and Brian E. Harvey, MD, PhD, now Senior Regulatory Lead with Thetis Pharmaceuticals.