QUC398 / EMD Serono, Sanofi, Novartis - LARVOL DELTA

A Proof-of-concept Study to Examine QUC398 in Participants With Knee OA (clinicaltrials.gov) - P2 | N=101 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Sponsor Decision

Trial termination • Immunology • Osteoarthritis • Pain • Rheumatology

Translational pharmacokinetic and pharmacodynamic modelling of the anti-ADAMTS-5 NANOBODY® (M6495) using the neo-epitope ARGS as a biomarker. (PubMed, J Pharmacokinet Pharmacodyn) - "In addition to having enabled a Phase 1 trial with M6495, this is the first PK/PD model describing the pharmacodynamics of the neo-epitope ARGS after ADAMTS5 inhibition. It is expected that in the future, this model can be used or adapted to explore the PK/PD relationship between M6495 serum concentrations and the ARGS serum biomarker."

Biomarker • Journal • PK/PD data • Immunology • Osteoarthritis • Pain • Rheumatology • ACAN • ADAMTS5

A Proof-of-concept Study to Examine QUC398 in Participants With Knee OA (clinicaltrials.gov) - P2 | N=101 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2025 ➔ Jul 2025 | Trial primary completion date: Nov 2024 ➔ Aug 2024

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

A Proof-of-concept Study to Examine QUC398 in Participants With Knee OA (clinicaltrials.gov) - P2 | N=101 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Immunology • Osteoarthritis • Pain • Rheumatology

Safety, Tolerability, and Pharmacodynamics of the ADAMTS-5 Nanobody M6495: Two Phase 1, Single-Center, Double-Blind, Randomized, Placebo-Controlled Studies in Healthy Subjects and Patients With Osteoarthritis. (PubMed, ACR Open Rheumatol) - "Treatment with M6495 in single and multiple doses up to and including 300 mg s.c. was found to be well tolerated and adequately safe for further clinical evaluation of potential disease-modifying effects."

Journal • P1 data • PK/PD data • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology • ACAN

A Proof-of-concept Study to Examine QUC398 in Participants With Knee OA (clinicaltrials.gov) - P2 | N=98 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2025 ➔ Oct 2025 | Trial primary completion date: Jun 2024 ➔ Nov 2024

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

The Current Role of Disease-modifying Osteoarthritis Drugs. (PubMed, Arch Bone Jt Surg) - "It was encountered that many publications have analyzed the impact of several DMOAD methods, including anti-cytokine therapy (tanezumab, AMG 108, adalimumab, etanercept, anakinra), enzyme inhibitors (M6495, doxycycline, cindunistat, PG-116800), growth factors (bone morphogenetic protein-7, sprifermin), gene therapy (micro ribonucleic acids, antisense oligonucleotides), peptides (calcitonin) and others (SM04690, senolitic, transient receptor potential vanilloid 4, neural EGFL-like 1, TPCA-1, tofacitinib, lorecivivint and quercitrin). In conclusion, even though DMOADs seem promising, their clinical effectiveness has not yet been demonstrated for managing OA. Until forthcoming studies can proved the medications' capacity to repair and regenerate tissues affected by OA, physicians should keep using treatments that only intend to alleviate pain."

Journal • Review • Gene Therapies • Immunology • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology • NELL1

A Proof-of-concept Study to Examine QUC398 in Participants With Knee OA (clinicaltrials.gov) - P2 | N=98 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Immunology • Osteoarthritis • Pain • Rheumatology

A proof of concept study to examine QUC398 in participants with knee OA. Estudio de prueba de concepto para investigar QUC398 en participantes con OA de rodilla. (clinicaltrialsregister.eu) - P2 | N=98 | Ongoing | Sponsor: Novartis Farmacéutica S.A.

New P2 trial • Immunology • Musculoskeletal Diseases • Osteoarthritis • Pain • Rheumatology

A Proof-of-concept Study to Examine QUC398 in Participants With Knee OA (clinicaltrials.gov) - P2 | N=98 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Sep 2024 ➔ May 2025 | Trial primary completion date: Oct 2023 ➔ Jun 2024

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

Merck Announces Out-Licensing Agreement for Phase II-ready Anti-ADAMTS5 Nanobody for Osteoarthritis (PRNewswire) - "Merck...today announced that it has entered into an out-licensing agreement with Novartis, for the development of M6495, an anti-ADAMTS5 Nanobody® for the potential treatment of osteoarthritis (OA). The Phase II-ready program represents potential for a disease modifying osteoarthritis drug (DMOAD)....As part of the agreement, Merck will out-license to Novartis the Phase II-ready asset M6495 for further evaluation in OA patients...Novartis will assume full responsibility for the development and commercialization of the M6495 program."

Licensing / partnership • CNS Disorders • Osteoarthritis • Pain

The Anti-ADAMTS-5 Nanobody M6495 Protects Cartilage Degradation Ex Vivo. (PubMed, Int J Mol Sci) - "M6495 showed no effect on PRO-C2. M6495 showed cartilage protective effects by dose-dependently inhibiting ADAMTS-5 mediated cartilage degradation and inhibiting overall cartilage deterioration in ex vivo cartilage cultures."

Journal • Preclinical • Immunology • Osteoarthritis • Pain • Rheumatology

Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors. (PubMed, Osteoarthritis Cartilage) - "TLR2 is expressed in synovium of OA patients and their activation by synthetic ligands causes increased tissue turnover. ADAMTS-5-mediated cartilage degradation leads to release of aggrecan fragments which activates the TLR2 receptor in vitro. M6495 suppressed cartilage degradation by ADAMTS-5, limiting the activation of TLR2. In conclusion, pain and joint destruction may be linked to generation of ADAMTS-5 cartilage metabolites."

IO Biomarker • Journal • IL6

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Doses of the Anti-ADAMTS-5 Nanobody®, M6495, in Healthy Male Subjects: A Phase I, Placebo-Controlled, First-in-Human Study (ACR-ARHP 2019) - P1; "The observed safety profile of M6495 at single doses up to 300 mg appeared to be acceptable for further clinical development. M6495 dose-dependently inhibited release of the ARGS aggrecan fragment family. Table 1."

Clinical • P1 data • PK/PD data

Multiple Ascending Doses (MAD) of Anti-A Disintegrin and Metalloproteinase With Thrombospondin Motifs-5 (Anti-ADAMTS-5) Nanobody in Participants With Knee Osteoarthritis (OA) (clinicaltrials.gov) - P1; N=32; Completed; Sponsor: Merck KGaA, Darmstadt, Germany; Active, not recruiting ➔ Completed

Clinical • Trial completion

Multiple Ascending Doses (MAD) of Anti-A Disintegrin and Metalloproteinase With Thrombospondin Motifs-5 (Anti-ADAMTS-5) Nanobody in Participants With Knee Osteoarthritis (OA) (clinicaltrials.gov) - P1; N=32; Active, not recruiting; Sponsor: Merck KGaA, Darmstadt, Germany; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

ACTIVATION OF TLR2 BY ADAMTS-5-MEDIATED DEGRADATION FRAGMENTS OF CARTILAGE EXPLANTS IS INHIBITED BY THE ANTI-ADAMTS-5 NANOBODY®, M6495 (EULAR 2019) - "ADAMTS-5-mediated cartilage degradation leads to release of aggrecan fragments, which activate the TLR2 receptor in vitro in a specialised reporter system. Anti-ADAMTS-5 inhibiting nanobody®, M6495, showed a suppression in release of degradation biomarkers leading to limited activation of TLR2. The data suggest a potential chondro-protective effect by M6495."

IO Biomarker

Multiple Ascending Doses (MAD) of Anti-A Disintegrin and Metalloproteinase With Thrombospondin Motifs-5 (Anti-ADAMTS-5) Nanobody in Participants With Knee Osteoarthritis (OA) (clinicaltrials.gov) - P1; N=32; Recruiting; Sponsor: Merck KGaA, Darmstadt, Germany; N=24 ➔ 32

Clinical • Enrollment change

THE ANTI-ADAMTS-5 NANOBODY®, M6495, INHIBITS THE ACTIVATION OF TLR BY ADAMTS-5-MEDIATED DEGRADATION FRAGMENTS IN CARTILAGE EXPLANTS (OARSI 2019) - "ADAMTS-5 mediated cartilage degradation leads to release of degradation fragments and these fragments can activate the TLR2 receptor in vitro in a specialised reporter system. Anti-ADAMTS-5 inhibiting nanobody- M6495 which has demonstrated cartilage protective effects elsewhere, leads to a suppression of ADAMTS-5 elicited TLR2 activation."