Amplio’s Phase 1b data hint at better first-line arthritis treatment

Methotrexate is an established drug that reduces inflammation and helps slow joint damage in rheumatoid arthritis, an autoimmune disease in which the immune system attacks the joints. Its effectiveness, long clinical track record and low cost make it the standard first-line treatment.

Why it matters: According to Amplio, only about 40% of patients reach remission on methotrexate alone. Its hypothesis is that insufficient retention of the drug inside immune cells contributes to that shortfall. The company is trying to make methotrexate work for more patients, potentially reducing the need for expensive biologics and other targeted therapies.

How it works: NovoBioJect combines methotrexate with low-dose novobiocin, a former antibiotic that blocks ABCG2, a transporter that pumps methotrexate out of cells.

• Keeping more methotrexate inside gives cells more opportunity to convert it into polyglutamates, metabolites associated with its therapeutic activity. Amplio’s intended product is a once-weekly subcutaneous autoinjector.

Zoom in: In an open-label Phase 1b study at the Centre for Human Drug Research in Leiden, 12 rheumatoid arthritis patients received single subcutaneous doses of 80, 150 or 200 mg novobiocin alongside their regular weekly methotrexate.

• The company reported a 38% increase in two long-chain methotrexate polyglutamates in blood immune cells compared with methotrexate alone, a statistically significant result. The only reported treatment-related adverse events were mild, dose-dependent injection-site reactions.
• The study assessed drug exposure, safety and biomarkers. It did not establish whether patients experienced better disease control.

What they’re saying: “The question we now need to answer is whether more active methotrexate inside the cell translates into more patients reaching remission faster on first-line therapy,” said CEO and co-founder Marguérite Mensonides-Harsema.

Backstory: The idea grew out of Mensonides-Harsema’s experience at methotrexate manufacturer medac, where she led its autoimmune disease portfolio and gained insight into the drug’s limitations.

• A pharmacist with a research background at AstraZeneca, she brought the concept to two former colleagues, pharmacologist Charlott Brunmark and immunologist Karin von Wachenfeldt, in 2016. Following preclinical studies and a granted patent, the three women founded Amplio in Lund, Sweden, in 2020.
• Mensonides-Harsema established the Dutch company in 2023, building relationships with Amsterdam UMC, Leiden University Medical Center and CHDR. Amplio reached its first clinical study with a €1.4 million seed round backed by Libertatis Ergo Holding, Amsterdam UMC Ventures Holding, ROM InWest and Innovatiefonds Noord-Holland.

Yes, but: Novobiocin brings a complicated history. In 2011, the FDA determined that the former oral product Albamycin (a brand name for novobiocin) had been withdrawn for safety or effectiveness reasons, citing skin reactions, liver problems and blood disorders.

• Amplio uses substantially lower, less frequent doses than historical oral regimens. However, the different administration route and planned chronic use mean that long-term safety will need to be established in further trials.
• There is also a question inherent in the mechanism: increasing methotrexate retention could increase toxicity as well as benefit. Preclinical research has linked reduced ABCG2 activity to increased systemic methotrexate exposure, pointing out that variations in ABCG2 activity may “affect the therapeutic efficacy and toxicity in patients”.

What’s next: Subject to financing and regulatory approval, Amplio plans a 100-patient Phase 2a trial in the Netherlands starting in 2027. The 12-week study will compare NovoBioJect with methotrexate alone, with safety as its primary endpoint and clinical response among its secondary endpoints.