Annexon : ANX1502 First in Human SAD / MAD Data Overview

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):

• 1. 6 ANX1502 + 2 placebo subjects per dose cohort
  1. Doses from 25 mg to 1050 mg evaluated
• Multiple Ascending Dose (MAD):
• 1. 9 ANX1502 + 3 placebo subjects per dose cohort
  1. Twice daily dosing for 2 weeks (BID)
  1. 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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