aldumastat (GLPG1972) / Galapagos, Servier, Gilead - LARVOL DELTA

Advances and Challenges in the Pursuit of Disease-Modifying Osteoarthritis Drugs: A Review of 2010-2024 Clinical Trials. (PubMed, Biomedicines) - " Eleven DMOAD candidates are reviewed and critically analyzed for their potential benefit in OA treatment-Lorecivivint (SM04690), TissueGene-C, Cindunistat (SD-6010), Sprifermin, UBX0101, TPX-100, GLPG1972/S201086, Lutikizumab (ABT-981), SAR113945, MIV-711, and LNA043-and relevant challenges to their development are discussed. Six DMOADs have demonstrated statistically significant evidence of a structural or symptomatic benefit without major safety concerns in phase II and III randomized controlled trials post-2010."

Journal • Review • Developmental Disorders • Immunology • Osteoarthritis • Pain • Rheumatology

Serum ARGS-aggrecan in a phase 2 clinical trial targeting osteoarthritis. (PubMed, Osteoarthritis Cartilage) - P2 | "Systemic inhibition of ADAMTS-5 resulted in markedly reduced serum ARGS, but change in serum ARGS concentrations showed no association with the progression of cartilage thinning, or patient reported pain and function."

Journal • P2 data • Immunology • Osteoarthritis • Pain • Rheumatology • ACAN • ADAMTS5

THE AGGRECAN ARGS NEOEPITOPE IN A PHASE 2 CLINICAL TRIAL TARGETING OSTEOARTHRITIS (OARSI 2024) - "Purpose (the aim of the study): In the quest for finding the first disease-modifying OA drug (DMOAD) the ADAMTS-5 inhibitor S201086 (in previous publications also called GLPG1972) was tested in a human phase 2 clinical trial. We here report the temporal evolution of circulating levels of the ADAMTS-5 generated aggrecan ARGS neoepitope and investigate the relationship between reduction in ARGS and change in cartilage thickness, and knee related pain and function."

Clinical • P2 data • Immunology • Osteoarthritis • Pain • Rheumatology • ACAN • ADAMTS5

Evaluation of S201086/GLPG1972, an ADAMTS-5 inhibitor, for the treatment of knee osteoarthritis in ROCCELLA: a phase 2 randomized clinical trial. (PubMed, Osteoarthritis Cartilage) - P2 | "Despite enrolment of participants who experienced substantial cartilage loss over 52 weeks, during the same time period, S201086/GLPG1972 did not significantly reduce rates of cartilage loss or modify symptoms in adults with symptomatic knee osteoarthritis."

Clinical • Journal • P2 data • Immunology • Osteoarthritis • Pain • Rheumatology

Discovery of Isoindoline Amide Derivatives as Potent and Orally Bioavailable ADAMTS-4/5 Inhibitors for the Treatment of Osteoarthritis. (PubMed, ACS Pharmacol Transl Sci) - "In addition, compound 18 exhibited excellent druglike properties and showed better pharmacokinetic (PK) profiles than GLPG1972 cross-species. Compound 18 demonstrated dose-dependent efficacy in two in vivo rat osteoarthritis models."

Journal • Developmental Disorders • Immunology • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology

How to Successfully Generate an Alternative Approach to a Thorough QT Study: GLPG1972 as an Example. (PubMed, Clin Pharmacol Ther) - "How is an alternative approach generated, what information is available, and which instructions are considered missing today to generate such an approach? This tutorial describes the considerations and path followed to create an early and feasible alternative to a TQT study using experience-based insights from a successful application to the U.S. Food and Drug Administration for GLPG1972, an ADAMTS-5 inhibitor, and discusses the approach used in light of the current guidelines and literature."

Journal

Galapagos 2021 results set stage for future growth (GlobeNewswire) - "Galapagos NV...presents financial results 2021, reviews key events for the company, and provides outlook for 2022....Outlook 2022...Our R&D expenditure in 2021 amounted to €491.7 million, compared to €523.7 million in 2020. This decrease was primarily due to the winding down of the programs with...and GLPG1972 (OA), and reduced spend on our other programs....Within our broader inflammation portfolio, we expect the read out from a Phase 1b trial with JAK1 inhibitor GLPG0555 in osteoarthritis and from multiple Phase 1 trials in healthy volunteers."

Discontinued • P1 data • Immunology • Inflammation • Osteoarthritis

Safety, Pharmacokinetics, and Pharmacodynamics of the ADAMTS-5 Inhibitor GLPG1972/S201086 in Healthy Volunteers and Participants With Osteoarthritis of the Knee or Hip. (PubMed, Clin Pharmacol Drug Dev) - P1 | "Multiple dosing significantly reduced ARGS levels vs baseline at all time points for all doses vs placebo. GLPG1972 was generally well tolerated at all doses."

Clinical • Journal • PK/PD data • Immunology • Osteoarthritis • Pain • Rheumatology

Pharmacological characterization of GLPG1972/S201086, a potent and selective small molecule inhibitor of ADAMTS5. (PubMed, Osteoarthritis Cartilage) - "GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • IL1B

[VIRTUAL] Efficacy and safety of s201086/GLPG1972, an ADAMTS-5 inhibitor, in patients with knee osteoarthritis: roccella, a 52-week, randomized, double-blind, dose-ranging phase 2 study (OARSI 2021) - "S201086/GLPG1972 has been shown to reduce cartilage degradation in preclinical models of OA. Therefore, we aimed to evaluate the efficacy and safety of S201086/GLPG1972 in patients with knee OA."

Clinical • P2 data • Immunology • Osteoarthritis • Pain • Rheumatology

[VIRTUAL] Test-retest reliability and smallest detectable change (SDC) of MRI-based cartilage thickness analysis in a large multicenter randomized controlled clinical trial of knee osteoarthritis (OARSI 2021) - P2 | "It was designed to test the safety and efficacy of a disease modifying osteoarthritis drug (DMOAD) candidate that inhibits ADAMTS-5 (GLPG1972/S201086)...As this was a clinical study that involved a large number of centers, it was deemed important to evaluate the test-retest reliability of the primary endpoint and other structural measures, as well as the smallest detectable change (SDC) threshold at which progression can be assumed to have occurred with 95% confidence in single cases. The objective of this analysis is thus to assess the test-retest reliability with repositioning of the knee at baseline as well as at 12-month follow-up, a prerequisite for computing the SDC."

Clinical • Immunology • Osteoarthritis • Pain • Rheumatology • MRI

Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis. (PubMed, J Med Chem) - P2 | "The cocrystal structure of GLPG1972/S201086 with human recombinant ADAMTS-5 is discussed. GLPG1972/S201086 has been investigated in a phase 2 clinical study in patients with knee OA (NCT03595618)."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology

Galapagos reports Q3 2020 results (GlobeNewswire) - "Revenues and other income for the first nine months of 2020 decreased to €368.6 million…due to one-time recognition in revenue in the first nine months of 2019 of the upfront payment received from Gilead related to ziritaxestat for €667.0 million; No signal observed with GLPG1972 in osteoarthritis"

Clinical • Commercial • Immunology • Osteoarthritis • Pain • Systemic Sclerosis

Galapagos mid-stage trial failure raises concerns for Gilead deal (PMLive) - "Last year, Gilead announced a $5.1bn deal for access to Galapagos’ late-stage pipeline, and gained rights to GLPG1972 in the process. At that time, Gilead agreed to an option fee for GLPG1927 worth $250m if the drug proved promising in the targeted osteoarthritis indication, as well as a further $200m related to endpoints in the phase 2b study and $550m in related milestones. Following the disappointing results, Galapagos has lost out on the funds, with more pressure piled onto the other focal drug of the Gilead alliance – filgotinib."

Financing • Licensing / partnership • CNS Disorders • Osteoarthritis • Pain

Galapagos and Servier report topline results for ROCCELLA Phase 2 clinical trial with GLPG1972/S201086 in knee osteoarthritis patients (GlobeNewswire) - P2, N=932; ROCELLA (NCT03595618); Sponsor: Galapagos; "The trial failed to meet the primary objective. The change from baseline to week 52 in cartilage thickness, in mm (SD) was -0.116 (0.27) for the placebo group and -0.068 (0.20), -0.097 (0.27) and -0.085 (0.22), for the low, medium and high dose, respectively. Statistically significant difference versus placebo was not reached in any of the treated groups."

P2 data • CNS Disorders • Immunology • Osteoarthritis • Pain

"$GLPG off 9% in Amsterdam this am, even though GLPG1972 had virtually no sellside numbers attached." (@JacobPlieth)

Galapagos reports solid H1 2020 progress (GlobeNewswire) - "...In the second half of 2020, we and Servier expect to report topline results from the ROCCELLA Phase 2b trial of GLPG1972 in knee osteoarthritis (OA), and upon successful completion of this trial, Gilead has the option to license development and commercialization rights in the U.S. for GLPG1972."

P2b data • Osteoarthritis • Pain

Roccella: A Study to Assess Efficacy and Safety of GLPG1972/S201086 in Patients With Knee Osteoarthritis (clinicaltrials.gov) - P2; N=938; Completed; Sponsor: Galapagos NV; Active, not recruiting ➔ Completed; Trial completion date: Dec 2020 ➔ Jul 2020; Trial primary completion date: Dec 2020 ➔ Jul 2020

Clinical • Trial completion • Trial completion date • Trial primary completion date • Immunology • Osteoarthritis • Pain • Rheumatology • MRI

[VIRTUAL] STUDY DESIGN OF ROCCELLA: A PHASE 2 CLINICAL TRIAL WITH A DISEASE-MODIFYING OSTEOARTHRITIS DRUG CANDIDATE GLPG1972/S201086 (EULAR 2020) - P2 | "This is the first large Phase 2 study where patients with primary KOA are treated for 52 weeks with GLPG1972/S201086, an orally administered DMOAD candidate. This clinical trial was designed with a combination of two radiological selection criteria to ensure sufficient structural progression (cartilage loss) in the study population."

Clinical • P2 data • Immunology • Osteoarthritis • Pain • Rheumatology • MRI

[VIRTUAL] BASELINE CHARACTERISTICS OF THE STUDY POPULATION IN ROCCELLA, A PHASE 2 CLINICAL TRIAL EVALUATING THE EFFICACY AND THE SAFETY OF S201086/GLPG1972 IN PATIENTS WITH KNEE OSTEOARTHRITIS (EULAR 2020) - P2 | "For this clinical trial, patients were selected to present radiological criteria ( i.e. OARSI JSN 1 and 2) to ensure sufficient structural progression (cartilage loss) over 12 months, as well as clinical symptoms. These stringent selection criteria were the main cause for the high screen failure rate. These baseline characteristics should warrant the ability to evaluate the efficacy of S201086/GLPG1972 as a DMOAD candidate."

Clinical • P2 data • Back Pain • Immunology • Musculoskeletal Diseases • Orthopedics • Osteoarthritis • Pain • Rheumatology • MRI

[VIRTUAL] SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS IN HEALTHY MALE JAPANESE SUBJECTS OF THE ADAMTS-5 INHIBITOR S201086/GLPG1972, A POTENTIAL NEW TREATMENT IN OA (EULAR 2020) - P2 | "S201086 was shown to be safe and well-tolerated in Japanese and Caucasian healthy male subjects with a suitable PK profile and a significant decrease of the ARGS neoepitope, indicating target engagement. A global Phase 2 study to evaluate the efficacy of S201086 in patients with knee OA is ongoing (NCT03595618)."

Clinical • PK/PD data • Immunology • Osteoarthritis • Pain • Rheumatology

"When can we expected new analyses of GLPG1972 ? Thanks" (@pejsdubrava)

On track for clinical read-outs and commercial readiness in 2020 (GlobeNewswire, Galapagos NV) - As a consequence of COVID-19 measures...we see an impact on recruitment rates of the ISABELA Phase 3 program with ziritaxestat (GLPG1690) in IPF....Within our fibrosis portfolio, in the second half of the year, we anticipate reporting topline results from the PINTA Phase 2 trial with GLPG1205 in IPF...Also in the second half of 2020, we and Servier expect to report topline results from the ROCCELLA Phase 2b trial of GLPG1972 in knee osteoarthritis. Upon successful completion of this trial, Gilead has the option to license development and commercialization rights in the U.S. for GLPG1972."

Enrollment status • P2 data • P2b data • CNS Disorders • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Interstitial Lung Disease • Osteoarthritis • Pain • Pulmonary Disease • Respiratory Diseases • Rheumatology

Transformational year for Galapagos (GlobeNewswire, Galapagos NV) - "Recruitment completed in ROCCELLA Phase 2b trial with GLPG1972 in osteoarthritis...We also plan to report topline data from the ROCCELLA Phase 2b study of GLPG1972 in OA, together with our collaboration partner Servier. Following the results, Gilead will have the option to inlicense GLPG1972 for the U.S. market."

Enrollment status • P2b data

Inhibition of MMPs and ADAM/ADAMTS. (PubMed, Biochem Pharmacol) - "Of note, a monoclonal antibody, GLPG1972, developed as an ADAMTS-5 inhibitor, entered a Phase I OA clinical trial. However, the failure of many of these previously developed inhibitors to move beyond the preclinical testing phase has required that novel strategies be developed that are designed to suppress both MMP, ADAM and ADAMTS production and activity."

Journal • Review