Galapagos presents GLPG1972 data at OARSI meeting

Compound is a potent, selective, orally available ADAMTS-5 inhibitor for osteoarthritis

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MECHELEN, Belgium—Galapagos NV has announced presentation of preclinical pharmacology data for GLPG1972 at the recent Osteoarthritis Research Society International (OARSI) annual meeting in Las Vegas. Galapagos and its collaboration partner Servier are developing a potential disease-modifying oral therapy for osteoarthritis with GLPG1972.
According to Galapagos, GLPG1972 is a potent and highly selective inhibitor of ADAMTS-5, a key enzyme involved in cartilage breakdown. At the OARSI 2017 World Congress, the company presented GLPG1972 data showing cartilage protection in both rodent and human explant assays, as well as disease-modifying activity with GLPG1972 in the gold-standard, destabilization of the medial meniscus (DMM) rodent model.
Galapagos had previously announced that a Phase 1 study in healthy human volunteers demonstrated favorable safety and pharmacokinetic profiles of GLPG1972, and up to a 60-percent reduction in a cartilage breakdown biomarker within two weeks of treatment. This biomarker is serum ARGS-neoepitope, which is formed from cartilage through ADAMTS-5 and thus serves as a biomarker for target engagement.
“Osteoarthritis is a disease with very limited treatment options, and none which actually address the cause of the disease. By inhibiting ADAMTS-5, for which the literature evidence is growing, GLPG1972 could play a central role in osteoarthritis,” said Dr. Piet Wigerinck, chief scientific officer of Galapagos. “We are eager to see if we can repeat in patients the same impact on cartilage breakdown biomarker ARGS-neoepitope as we saw in healthy volunteers.”
According to the article published in Osteoarthritis and Cartilage on the GLPG1972 data, “Increased aggrecanase activity is a well-known trigger factor for osteoarthritis (OA), initiating loss of cartilage aggrecan that precedes more severe cartilage degradation. A disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) is a key enzyme in that process and as such, is a relevant target for the development of disease-modifying OA drugs.”
“GLPG1972 inhibited human and rat ADAMTS-5 with IC50 values of 20 nM and 23 nM, respectively. Selectivity towards ADAMTS-4 was moderate (8-fold), and >100-fold against a large panel of zinc metalloproteinases. In the mouse explant assay, GLPG1972 dose-dependently and significantly inhibited the GAG release induced by IL1α with an IC50 of 2 µM,” the article continues. “In human cartilage explants, GLPG1972 dose-dependently and significantly inhibited the production of aggrecanase-derived aggrecan fragments induced by IL1β with a mean IC50 estimated to be <1 µM. In the DMM mouse model, GLPG1972 significantly reduced femorotibial cartilage proteoglycan loss and cartilage damage at all doses (39 percent at 120 mg/kg b.i.d.) and subchondral bone sclerosis at all doses (36 percent at 120 mg/kg b.i.d.).”
In July 2010, Servier and Galapagos announced their alliance to develop innovative oral medicines for the treatment of osteoarthritis. Galapagos is responsible for the discovery and development of new candidate drugs against novel targets, and Servier has an exclusive option to license these candidates after the completion of the Phase 1 trial and Phase 2a enabling activities. Upon exercise of each option, Servier will be responsible for the further clinical development, registration and commercialization.
For any marketed products, Galapagos retains exclusive U.S. commercialization rights. Under the terms of the agreement, Galapagos will receive research access payments of €7 million from Servier. Galapagos is also eligible to receive discovery, development, regulatory and other milestone payments that could reach €290 million, plus royalties upon commercialization of products outside the U.S. covered under the agreement.
According to the Galapagos website, “The mechanism of action of GLPG1972 remains undisclosed. Galapagos and partner Servier are considering next steps for further development of GLPG1972 in osteoarthritis. Galapagos has the full U.S. commercial rights in the osteoarthritis collaboration with Servier.” Galapagos reportedly plans to initiate a Phase 1b study in osteoarthritis patients in the United States this quarter.

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