MP0317

Table of contents

• What is MP0317?
• How does MP0317 work?
• Which conditions is MP0317 studied for?
• How is MP0317 given?
• What do the clinical trials show?
• What side effects are known?

What is MP0317?

MP0317 is a protein-based substance described as a FAP x CD40 DARPin (designed ankyrin repeat protein). It is an investigational medicine with no marketing authorisation in the product records, supplied by Molecular Partners AG.^[1] DARPins are small engineered proteins built to bind very specifically to chosen targets. MP0317 is designed to bind two targets at once: fibroblast activation protein (FAP), which is found on cancer-associated fibroblasts in the tumour microenvironment, and CD40, a receptor on immune cells.^[3]

How does MP0317 work?

MP0317 is a CD40 agonist, meaning it activates the CD40 pathway. CD40 activation normally stimulates immune cells, but activating it throughout the body can cause serious side effects. MP0317 is built to be active only where FAP is present, which is mainly in the tumour microenvironment. This is intended to localise the immune activation to the tumour while reducing systemic toxicity.^[2] In a phase 1 study, paired tumour biopsies confirmed that MP0317 colocalised with FAP and CD40, and that CD40 pathway activation in the tumour microenvironment led to increased infiltration of antigen-presenting cells, plasma cells, follicular helper T cells, dendritic cell maturation and interferon-γ signalling.^[3]

Which conditions is MP0317 studied for?

• Advanced biliary tract carcinoma — a cancer of the bile ducts or gallbladder that has spread and cannot be removed by surgery. This is the condition in the current EU phase 2 trial.
• Advanced solid tumours — a broad group of cancers. An earlier phase 1 study tested MP0317 in adults with selected advanced solid tumours, most often colorectal cancer.^[2]

How is MP0317 given?

MP0317 is given as a solution for infusion into a vein (intravenous use). In the phase 2 trial in biliary tract carcinoma, the dose is 3 mg/kg.^[1] In the earlier phase 1 study, MP0317 was given intravenously at doses ranging from 0.03 to 10 mg/kg, either weekly or every 3 weeks.^[3]

What do the clinical trials show?

One EU clinical trial is registered for MP0317 as the test substance.^[1] It is a randomised, non-comparative proof-of-concept phase 2 study called TACTIC. The trial tests MP0317 in combination with durvalumab, cisplatin and gemcitabine as a first-line treatment for people with advanced biliary tract carcinoma. The planned enrolment is 75 participants.

The primary endpoint is progression-free survival (PFS) at 12 months from the date of randomisation, evaluated using RECIST criteria version 1.1. Progression-free survival means the length of time a person lives without their cancer getting worse. The trial is currently authorised.^[1]

An earlier phase 1 study in 46 patients with advanced solid tumours found that most treatment-related adverse events were grades 1 and 2 (95%), a maximum tolerated dose was not reached, one patient had an unconfirmed partial response and 14 patients had stable disease. The terminal half-life of MP0317 in the blood ranged from 21.8 to 120 hours.^[3]

What side effects are known?

In the phase 1 study, most treatment-related adverse events were mild to moderate (grades 1 and 2), and a maximum tolerated dose was not reached. One patient experienced a dose-limiting toxicity: an asymptomatic grade 3 elevation of alanine and aspartate aminotransferases, which are liver enzymes, at the highest planned dose.^[2] The phase 1 publication reported a favourable safety profile overall.^[3]