ANX1502 First In Human SAD / MAD Data Overview
December 2023
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Overview of ANX1502 Program
- Potential first oral small molecule inhibitor of the classical pathway in development, targeting the active form of C1s
- Successfully completed single and multidose Phase I study in healthy volunteers with liquid suspension formulation
- Observed desired PK (well above minimum targeted drug levels), consistent with BID dosing
- Obtained supportive PD data in subjects with higher C4d baseline measures
- Data support advancing to tablet bridging study to assess ANX1502 efficacy in CAD patients
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ANX1502: First Oral, Small Molecule Inhibitor of Classical Complement Pathway in Development
Orally administered prodrug ANX1502 which releases the active moiety ANX1502-AM*
Targeting active form of C1s responsible for transmitting classical pathway activation from C1q
Potent and selective inhibitor of C1s (serine protease): selective over related proteases (200 - 50,000-fold)
Highly specific for classical pathway
* ANX1502-AM: ANX1502 Active Moiety
C1s
.
C1q
ANX1502-AM* binds to
C1s catalytic site to inhibit enzymatic activity
.
ANX005 binds to
C1q globular heads to block C1q binding Y
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Following C1q Binding to a Specific Target Surface, ANX1502-AM* Observed to Inhibit Activated C1s to Block the Classical Cascade
C1q binding to a specific surface substrate activates C1s
ANX1502 administration | ||
ANX005 blocks | blocks activated C1s | |
C1 complex | C1q binding | |
Activated C1s cleaves C4 into | ||
C1q | C1s | activated fragments |
C1r | C4 | |
C4a | ||
Specific C1q | C4d cleavage fragment | |
released into serum | ||
surface substate | ||
C4b |
C1 Complex Is comprised of C1r, C1s and C1q
* ANX1502-AM: ANX1502 Active Moiety
Modified from Sharp et al, PNAS, 2019
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Minimum Target Drug Level (100 nM) ANX1502-AM* for Robust Functional Inhibition of Classical Complement Pathway
- ANX1502-AM*demonstrated robust functional inhibition of classical pathway (IC50 = 5 nM)
- Comparable to ANX005 and sutimlimab
- In vitro hemolysis assay w/ high serum (30%)
- Normal sigmoidal dose response vs. antibodies likely due to rate-limiting concentrations of activated C1s
- Minimum target drug levels for IC95, desired at trough, set conservatively at 100 nM
* ANX1502-AM: ANX1502 Active Moiety
Potent for In Vitro Hemolysis in 30% Human Serum
ANX1502- | ANX005 |
AM* | 70 nM |
5 nM | |
Sutimlimab |
0.01 0.1 1.0 10 100 1000 10,000
IC95=100 nM
Target Trough Concentration
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Achieved Objectives for ANX1502 Ph 1 Program (Healthy Volunteers)
Demonstrate favorable tolerability of ANX1502 in initial liquid suspension formulation
Achieve target levels of active drug consistent with BID dosing
Upside: demonstrate initial in vivo pharmacodynamic (PD) signal with biomarkers of complement activation in healthy volunteers
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ANX1502 Phase 1 Study Design (Healthy Volunteers)
Initial suspension formulation, dosed up to 1050 mg in SAD and 525 mg BID in MAD
- Single Ascending Dose (SAD):
- 6 ANX1502 + 2 placebo subjects per dose cohort
- Doses from 25 mg to 1050 mg evaluated
- Multiple Ascending Dose (MAD):
- 9 ANX1502 + 3 placebo subjects per dose cohort
- Twice daily dosing for 2 weeks (BID)
- Doses from 200 mg BID to 525 mg BID evaluated
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ANX1502 Suspension Formulation Generally Well-Tolerated Across SAD & MAD Cohorts in Healthy Volunteers
Manageable GI tolerability issues
Safety Results from Phase 1
- ANX1502 generally safe and well tolerated through the highest dose level tested
- All treatment-emergent adverse events (TEAEs) mild or moderate
- Most frequent TEAEs are gastro-intestinal and include nausea, emesis, and diarrhea
- No serious adverse events (SAEs) observed
- No significant clinical/lab findings (e.g., liver function enzymes, serum chemistry, hematology) observed
SAD | MAD | |||||||||||
Subjects | (Single Dose) | (BID Dose) | ||||||||||
with TEAEs | 25mg | 150mg | 450mg | 525mg | 1050mg | Placebo | 200mg | 325mg | 525mg Placebo | |||
(N=6) | (N=6) | (N=6) | (n=6) | (N=6) | (N=10) | BID | BID | BID | BID | |||
(N=9) | (N=9) | (N=9) | (N=9) | |||||||||
Subjects with | 4 | 2 | 4 | 5 | 6 | 6 | 7 | 8 | 6 | 7 | ||
any TEAE | ||||||||||||
(66.6) | (33.3) | (66.6) | (83.3) | (100.0) | (60.0) | (77.7) | (88.9) | (66.6) | (77.7.) | |||
(%) | ||||||||||||
Subjects with TEAE | 3 | 2 | 4 | 4 | 6 | 4 | 6 | 8 | 5 | 6 | ||
reported as related | ||||||||||||
(%) | (50.0) | (33.3) | (66.6) | (66.6) | (100.0) | (40.0) | (66.6) | (88.9) | (55.5) | (66.6) | ||
Subjects with any ≥ | 2 | 1 | 1 | |||||||||
Grade 2 TEAE* | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |||||
(22.2) | (11.1) | (12.5) | ||||||||||
(%) | ||||||||||||
Subjects with any | ||||||||||||
Serious TEAE | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
(%) |
*No AEs higher than Grade 2
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SAD Data: Target Concentration Achieved at Single Doses of ANX1502 of 525-1050 mg
PK Results from SAD
- Dose-proportionalPK (AUC) in SAD cohorts across 25 mg - 525 mg cohorts
- Mean target drug level of 100 nM at 12h observed at single doses >525 mg
- Enabled BID dosing regimen in MAD study as planned
800 | 25 mg (n=5) | ||||||
150 mg (n=6) | |||||||
450 mg (n=6) | |||||||
(nM) | 600 | 525 mg (n=6) | |||||
1050 mg (n=5) | |||||||
Concentration | 400 | ||||||
200 | Minimum Target Drug Level | ||||||
(100 nM) | |||||||
0 | |||||||
0 | 12 | 24 | 36 | 48 | 60 | 72 |
Time (h)
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Serum C4d as a Biomarker of C1s Activation In Vivo
In vivo activation of C1s leads to cleavage of C4 and release of C4d into the serum
- Proximal biomarker of C1s activation
- C4d serum levels are low in healthy individuals, but elevated in LN and CAD patients
Circulating C4d levels decrease with C1q inhibition in CAD patients (ANX005 Ph2)
C4d used as a biomarker reflects drug's in vivo impact on C1s activation
- CH50 ex vivo measures not relevant because involves 100-fold serum dilution / dilution of drug prior to ex vivo C1s activation
C1q binding to specific surface substrate activates C1s
C1 complex
C1q | C1s | Activated C1s cleaves C4 to |
into several fragments | ||
C1r | C4 | |
C4a | ||
Specific C1q | C4d cleavage fragment | |
measurable in serum | ||
surface substate | ||
C4b |
Modified from Sharp et al, PNAS, 2019
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Annexon Inc. published this content on 20 December 2023 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 21 December 2023 15:18:16 UTC.