The Aggrecanase OA Research Transitioning into Clinical Data Where Are We and What May We Expect?
Ellen van der Aar, PhD Project Leader Early Development Galapagos NV, Mechelen, Belgium
Clinical Trial Symposium, OARSI meeting, Toronto, Canada 1 May 2019 Disclosure information
I am a Galapagos employee
AND
My presentation does not include discussion of off-label or investigational use
Ellen van der Aar, PhD Project Leader Early Development Galapagos NV, Mechelen, Belgium
2 Cartilage breakdown
• Aggrecan provides cartilage with compressibility and elasticity • Loss of aggrecan from the cartilage results in serious impairment of joint function • Cleavage of aggrecan in the interglobular domain via Matrix metalloproteinases (MMPs) at the Asn341–Phe342 bond Metalloproteinases called 'aggrecanases' at the Glu373–Ala374 bond ADAMTS4 and ADAMTS5
Fosang, A. J. Bioch. et Biophys. Acta 2011, 1812, 1616
3 ADAMTS-5 A promising therapeutic target in OA
• ADAMTS-5 plays a key role in aggrecan degradation in OA • Strong literature evidence for ADAMTS-5: validated in human OA cartilage explants1 adamts-5-/- mice were protected from cartilage degradation and mechanical allodynia in DMM model2 mice treated with ADAMTS-5 mAb had attenuated joint damage and were protected from mechanical allodynia3 ARGS levels increased in human knee synovial fluid in OA4
Source: ¹ Song, 2007; ² Glasson, 2005 & Malfait, 2010; ³ Miller, 2016; 4 Larsson, 2009
4 Anti-catabolic DMOAD development with GSK2394002 • MMP inhibitors: unacceptable adverse events, lack of bioavailability, lack of efficacy • Aggrecanase inhibitors AGG-523 (Pfizer): ADAMTS-4/5 small molecule inhibitor with poor pharmacokinetics, terminated after Ph1 GSK2394002 (GSK): ADAMTS-5 monoclonal antibody, terminated in preclinical phase (increase in arterial pressure and elevated ST segment in safety pharmacology study in cynomolgus monkey (potentially irreversible))
Larkin et al, OARSI 2014 5 GLPG1972 in vitro profiling High potency and selectivity
Target Selectivity (fold) ADAMTS-5 - ADAMTS-4 > 5
ADAMTS-1 >150 GLPG1972 ADAMTS-13 IC50 range (nM) > 5,000 h-ADAMTS-5 potency <25 ADAM17 (TACE) > 1,000 r-ADAMTS-5 potency <25 MMP-1 > 1,500 h-ADAMTS-5 (Aggrecan-ELISA) <70 MMP-2 > 50 MMP-7 > 1,500 MMP-9 > 500 MMP-13 > 1,000 MMP-14 > 150
Amantini et al, OARSI 2017
6 GLPG1972 in vitro profiling
Human cartilage explants: IC50< 1 µM
700 GLPG1972 0.1 µM Human articular cartilage from IL-1b trigger GLPG1972 1 µM OA patient 600 GLPG1972 10 µM
) 500
mL / 12-19 days triggering with 400 ng *** IL1β +/- GLPG1972 *** 300
AGNx1 AGNx1 ( 200 Quantification of AGNx1 in the *** supernatant 100 *** *** *** *** 0 DayDay12 12 DayDay19 19
GLPG1972 features high potency on ADAMTS-5 resulting in strong anti-catabolic activity
Amantini et al, OARSI 2017
7 In vivo mouse DMM Reduction in structural cartilage damage
ArticularCartilage Cartilage Cumulative PG Cumulative Structure Score Score 2030
15 - 23% - 21% ¤¤ 20 - 33%
10 Score 10 5
00 Scoring system modified from Shu et al., Arthritis Rheum. 2016 vehiclevehicle
G504572 30mg/kgG504572 bid 60mg/kg bid G504572 120mg/kg bid GLPG1972 30mg/kgGLPG1972 bid 60mg/kg bid GLPG1972 120mg/kg bid Amantini et al, OARSI 2017
8 In vivo rat MNX Reduction in OARSI score
-6% -24% -23%
*** ** OARSI SCORE OARSI
Vehicle GLPG1972 GLPG1972 GLPG1972 10 mg/kg 25 mg/kg 50 mg/kg BID BID BID
Data expressed as median±IQR Statistics using a stratified Kruskal-Wallis test & Dunnett multiple comparisons post hoc test ***p<0.001; **p<0.01 vs MNX-vehicle Amantini et al, OARSI 2018
9 Conclusions pharmacology GLPG1972
• Potent and selective chondroprotective ADAMTS-5 inhibitor • Orally bioavailable • Significant DMOAD effects in the mouse DMM and rat MNX models: acting on both cartilage and bone pathology (data not shown) • Robust preclinical pharmacology package with good drugability characteristics
GLPG1972 was progressed to First-in-Human studies
10 Reduction of blood ARGS GLPG1972 Phase 1 study in healthy subjects (CL-101)
-20 -10 0 10 placebo 20 300mg 30 600mg 40 1050mg
50 ARGS % reduction vs vs ARGS baseline reduction %
ARGS % reduction vs baseline vs reduction % ARGS 60 blood blood 70 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Daysday post-dosing • Daily administration for 14 days was well-tolerated in healthy subjects, half life ~10h • Progressive reduction of ARGS over time until last dose at Day 14, with no significant differences between the dose levels • Maximal reduction was about 60%, with no plateau being reached Van der Aar et al, ACR 2017 11 Reduction of blood ARGS
GLPG1972 Phase 1b study in OA patients (CL-104)
ARGS % reduction vs vs ARGS baseline reduction % blood blood
day • Well-tolerated in OA patients, similar PK as in healthy subjects • Dose-dependent reduction of ARGS, reaching a plateau from Day 15 onwards • After stop of treatment, ARGS return to baseline reversible effect Deckx et al, EULAR 2018
12 GLPG1972 Ready for Phase 2
1. GLPG1972 is generally safe and well-tolerated in healthy subjects and in OA patients 2. GLPG1972 shows effective target engagement by consistently reducing blood ARGS-aggrecan levels in healthy subjects and in OA patients 3. There is sufficient confidence of potential efficacy to start Ph2 development
13 Phase 2: stratification for ARGS or not?
• Comparison of serum ARGS levels in OA patients and healthy subjects
Literature Inhouse data: CL-101/CL-104
Baseline serum ARGS (mean ± sem)
0.250 )
0.200 nM
0.150 ARGS ARGS (
0.100 serum 0.050
Baseline Baseline 0.000 CL-104 CL-101 OA patients Healthy subjects Germaschewski, O&C 2014
14 Phase 2: stratification for ARGS or not?
• No correlation observed between % reduction of ARGS at D15, 22 or 29 and absolute ARGS levels at baseline (in study CL-104)
ARGS baseline (nM) • No ARGS stratification applied in Phase 2 study • Determination of serum ARGS is planned in Phase 2 study for retrospective analyses
15 ROCCELLA Phase 2 trial (NCT03595618)
52 weeks
‘1972 dose A
‘1972 dose B screening follow-up Topline Part 1 expected‘1972 dose Q3 C ‘18
placebo
• 852 patients with knee osteoarthritis, recruited globally • 3 dose levels of GLPG1972 + placebo • 213 subjects/cohort Recruitment complete in 4Q19, topline results 1Q21
16 Key inclusion criteria ROCCELLA
• Male or female of NCBP (40-75y) • Diagnosed for knee OA based on clinical and radiological criteria of the American College of Rheumatology • History of knee pain for at least 6 months and on the majority of days (>50%) during the preceding month • Symptom severity defined by a pain ≥ 40 mm and ≤ 90 mm on VAS (100 mm) • Documented need for symptomatic as needed-treatment for OA in the target knee with systemic non-steroidal anti-inflammatory drugs (NSAIDs) and/or other analgesics
17 Key objectives ROCCELLA
• Primary Efficacy Objective: to demonstrate for at least one dose, a significant reduction of cartilage loss in the medial compartment of the target knee, compared to placebo (qMRI) • Key Secondary objectives: Safety and tolerability Efficacy based on structural changes (qMRI, X-ray) Efficacy based on clinical changes (WOMAC pain, stiffness and function, pain VAS) PK • Exploratory objectives: PD (ARGS) and other soluble biomarkers
18 GLPG1972 obtained fast track from FDA
Fast Track Program • serious or life-threatening diseases or conditions and that demonstrate the potential to address unmet medical needs • get important new drugs to patients earlier
19 GLPG1972 Summary
Mouse explants
Anti-catabolic activity
Human explants
DMOAD Clinical Rat MNX activity Mouse DMM
biomarker dataset Structural Cartilage Damage Cartilage Structural
serum serum ARGS baseline %reduction vs day
20 GLPG1972 Next steps • Topline results ROCCELLA Ph2 trial in 1Q21 If negative: no need to think “what if…” It is really negative . Post-hoc analyses could help identifying subgroup(s) with treatment effects If positive: good chance for positive Ph3 study . Post-hoc analyses could help identifying subgroup(s) with stronger treatment effects • Considerations towards Ph3 Duration treatment (1-2 year); extension Structural endpoints (X-ray and/or MRI) Clinical endpoints, PROs Subgroups and potential stratification Need to meet structural AND clinical endpoints for registration? 21 Acknowledgement
Department of Clinical Sciences Staffan Larsson, André Struglics, Stefan Lohmander
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