Inozyme Pharma : ASBMR 2023 - ENPP1 Def. Interim Data

A Phase 1/2 Open-Label, Multiple Ascending Dose Clinical Study to Evaluate the Safety, Tolerability,

Pharmacokinetics, and Pharmacodynamics of INZ-701 in Adults with ENPP1 Deficiency: An Interim Analysis

Yves Sabbagh1, Robert Wermers2, Rainard Fuhr3, Dirk Schnabel4, Terra Arnason5, Alix Besancon6, Borut Cizman1, Deborah Wenkert7, Kurt Gunter1

1 Inozyme Pharma, Boston, MA, USA, 2 Mayo Clinic, Division of Medicine, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Rochester, MN, USA, 3 Parexel International GmbH, Early Phase Clinical Unit Berlin, Germany, 4 Charitè, Universitätsmedizin, Center for Chronic Sick Children, Pediatric Endocrinology, Berlin, Germany, 5 University of Saskatchewan, Division of Endocrinology, Department of Medicine, Saskatoon, Canada, 6 Hôpital Universitaire Necker Enfants Malades,

Endocrinodiabetologie pediatrique, Paris, France, 7 Wenkert & Young, LLC (Former employee, Inozyme Pharma), Thousand Oaks, CA, USA.

Introduction

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that generates extracellular pyrophosphate (PPi), an inorganic metabolite with potent anti-calcificationactivity.1-3 Loss-of- function mutations lead to a state of ENPP1 Deficiency and hypopyrophosphatemia, which is associated with extensive calcification of the arteries, organs and joints. Infants with ENPP1 Deficiency present with severe cardiovascular complications and over 50% mortality in the first 6 months of life.5-6 Most patients will develop an FGF-23 mediated hypophosphatemic rickets (Autosomal Recessive Hypophosphatemic Rickets, type 2, ARHR2) by early adolescence, characterized by growth plate abnormalities, bowed legs, short stature, and/or calcification of the joints and ligaments.4-6

INZ-701 is a recombinant human ENPP1-Fc fusion protein that is used as an enzyme replacement therapy for the treatment of ENPP1 deficiency.

INZ-701 Exhibits a Favorable Safety Profile
	INZ-701 dose cohort - No. of patients with at least one event	Total
Event	0.2 mg/kg biweekly	0.6 mg/kg biweekly	1.8 mg/kg biweekly	patients
	(n=9)
	n=3	n=3	n=3
Adverse event	3	3	2	8
Adverse event related to INZ-701	2	1	0	3
Serious adverse event	0	2	0	2

Most adverse events were mild or moderate in severity

No adverse events led to discontinuation of INZ-701

• 3/9 patients experienced mild adverse events related No adverse events led to study withdrawal from Phase 1

Exploratory Endpoints:

Global Impression of Change Scale (GIC) is an exploratory endpoint in ongoing Phase 1/2 Trial

Assesses overall health compared to baseline

6-Minute Walk Test (6-MWT)

		6-MWT
Normal	100
	90
tedPredic		80
SEM±	70
60
of		50
%
	40
Mean

INZ-701

showed a trend for improvement

Cohort 1

Cohort 2

Cohort 3

Phase 1/2 Trial Design and Goals

A Phase 1/2, open-label, multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmaco- dynamics of INZ-701 followed by an open-labellong-term extension period in adults with ENPP1 Deficiency

to INZ-701

• 2 patients withdrew from Phase 2; not related to adverse

•

Injection site reactions (bruising, hemorrhage,

events

pain, pruritus, swelling) occurred in 2 patients

•

7 patients remain on study; all transitioned to self-

•

Other related adverse events included decreased

administration

appetite and fatigue

•

Time on study range: 98-638+ days; total time on

Cohort 1 (0.2mg/kg) (n=3)

Global	3
2

3 2

Cohort 3 (1.8mg/kg) (n=2)

30
0	20	40	60	80
		Weeks

Percent predicted normal adjusts for subject age, gender, height and weight

Data presented as ± SEM; Data cut July 6, 2023

Study Population:

Adults

Primary Goals

Secondary Goals

•

Evaluate potential endpoints for pivotal study

Pharmacokinetic properties

•

Safety and tolerability

•

Ectopic calcification, skeletal, vascular and

•

Immunogenicity

physical function, and patient reported outcomes

•

Pharmacodynamics (PPi)

•

Exploratory biomarkers

2 serious adverse events - not related to INZ-701

treatment across all patients: ~9 years

• Patella fracture (motor vehicle accident)
• cardiac surgery complication

Favorable Immunogenicity Profile Observed

Clinician's Impression	GIC-C	1
0
20	40	60
-1	Weeks
		-2
		-3

GIC-C

1 0 -1-2

10	20		30	40
											Weeks

Subgroup analysis: 6-minute walk test

Patients with <70% predicted of healthy	Patients with >70% predicted of healthy
6-MWT at baseline (n=5)	6-MWT at baseline (n=4)

Eligibility Criteria:

• Age 18-64 years
• Confirmed clinical and genetic diagnosis

9+ patients enrolled

Study Design:
Cohort 1	Phase 1 - 32 Days	Phase 2 - 48+ weeks
0.2 mg/kg, n=3
DSMB ✓	Cohort 2	Phase 1 - 32 Days	Phase 2 - 48+ weeks
0.6 mg/kg, n=3
	DSMB ✓		Cohort 3	Phase 1 - 32 Days	Phase 2 - 48+ weeks
	1.8 mg/kg, n=3
Cohorts 1-3 Dosing: Subcutaneous; Week 1: Single dose, Post week 1: 2x/week

• Low, non-neutralizing ADA titers detected
• ADAs were transient in 2 patients

Anti-Drug Antibody (ADA) Status

											Highest
Weeks	3	4	5	12	24	36	48	60	72	84	ADA titer
Cohort 1
1				40	40	80	40	160	40		160
2						80	40				80
3				80							80
Cohort 2
1					80						80
2											N/A
3					40	40					40
Cohort 3
1	<40		<40		80	160					160

STRENSIQ® ADA titers: 2,0487; patients with

ADA: 89%10

ALDURAZYME® ADA titers: 31,9728; patients

with ADA: 97%10

LUMIZYME® ADA titers: >51,2009; patients

with ADA: 89%10

ADA titers for other drugs were observed in previously conducted trials by other companies

		3
GlobalPatient's Impression	GICP-	2
1
		0
		20	40	60	80
		-1	Weeks
		-2
		-3

GIC-P

-3

3 2 1 0 -1-2-3

10	20	30	40
	Weeks

Normal	100			550		6MWT-	Normal	100			550		6MWT-
80			500		80			500
PredicteMW%T6-				(meters)	AbsoluteDistance	PredicteMWT%6-				(meters)	soluteDistanceAb
60			450	60			450
			400
										400
	40			350				40			350
	20			300				20			300
	0			250				0			250
	0	20	40	60
				0	20	40	60

Weeks	Weeks
Greater improvement observed in patients with	Stable 6-MWT scores observed in patients with

DSMB = Data Safety Monitoring Board. clinicaltrials.gov: NCT04686175

2	40	160	160
3			N/A

ADA Negative

ADA Positive

Colors represent individual patients in respective cohorts

poor baseline 6-MWT	higher baseline values
	Data presented as ± SEM; Data cut July 6, 2023

Patient Demographics & Baseline Medical Conditions

	Cohort 1	Cohort 2	Cohort 3
	0.2 mg/kg, biweekly	0.6 mg/kg, biweekly	1.8 mg/kg, biweekly
	(n=3)	(n=3)	(n=3)
Median	31	43	25
Age (years)

PPi and Other Biomarkers

Rapid, significant and sustained increase in PPi observed at all doses

Pooled Cohorts 1-3: Baseline vs mean Week 2-36 PPi, FGF-23, and Pi levels (± SEM)

										Plasma PPi	Serum intact FGF-23	Serum Pi
2500
150	2.6	Ref range : 2.5-4.5 mg/dL

Conclusions: Primary Goals Met

Safety and immunogenicity

✓	Well-tolerated,no serious adverse events related to study drug
✓	Support for first studies in infants (ongoing) and children (pending)

Range	23-40	30-58	22-29
Male (n=3)	0	1	2
Gender	3	2	1
Female (n=6)
White (n=8)	3	3	2
Race
Not reported (n=1)	0	0	1
		GACI (1)	GACI (1)
Initial clinical presentation	GACI (3)	ARHR2 1st decade (1)
ARHR2 2nd decade (2)
		ARHR2 3rd decade (1)

Cohort 2 skewed toward older patients

	Cohort 1	Cohort 2	Cohort 3	Total
Medical Condition	0.2 mg/kg , biweekly	0.6 mg/kg, biweekly	1.8 mg/kg, biweekly
(n=9)
	(n=3)	(n=3)	(n=3)
Medical History
Rickets/osteomalacia	3	2	3	8
Cardiovascular disease	2	3	2	7
Arterial calcification/stenosis/surgery	2	3	1	6
GACI	3	1	1	5
Soft tissue/joint calcification	1	2	2	5
Arthritis/arthralgia	2	2	0	4
Bone deformity/orthopedic surgery	0	1	3	4
Nephrocalcinosis/nephrolithiasis	0	2	2	4
Hypertension	1	2	1	4
Hearing loss	0	2	2	4
	Selected Baseline Data
Average 6-minute walk test (% predicted)	76.7	52.2	70.7	66.5
Average PROMIS pain intensity T score	58.1	54.4	47.4	53.3
Average PROMIS pain interference T score	57.5	53.4	52.5	54.5

Note: higher PROMIS T scores = greater pain or greater interference, respectively; reference mean=50

Each patient had a unique ENPP1 mutant genotype

Cohort 1

(0.2mg/kg)

Cohort 2

(0.6mg/kg)

Cohort 3

(1.8mg/kg)

	3000
)(nM	2500
2000
PPi
1500
Plasma
1000
	500
	0
		0
	3000
(nM)	2500
2000
PPi
1500
Plasma
1000
	500
	0
	3000	0
(nM)	2500
2000
PPi
1500
Plasma
1000

500

0

0

Phase 1					Phase 2
										• Rapid increase within 6 hours
										observed after the 1st dose
										• PPi levels reached the healthy
10	20	30	40	100	200	300	400	500	600	volunteer range after the 1st dose
					Days
										Baseline PPi (pre-dose) + 1st INZ-701 dose
										PPi measurement (post-dose)
										PPi measurement (pre-dose)
										Healthy subject PPi levels; n=10
10	20	30	40	100	200	300	400	500	600	Data presented as mean ± SEM
					Days
										Cohort 1: n=2 post day 84; Cohort 2: n=2 post day 336;
										Cohort 3: n=2 post day 168

10	20	30	40	100	200	300	400	500	600
					Days

Plasma PPi (nM)	2000		Ref range : 1002-2169 nM						(mg/dL)Pi Serum
					(pg/mL)3 2-FGF					2.4
1500					100				2.2
1000									2.0
					50
500									1.8
									Ref range : <59 pg/mL
	0						0					1.6
						0	10	20	30	40
	0	10	20	30	40		0	10	20	30	40
			Weeks						Weeks					Weeks

Baseline

Serum intact FGF-23

Data expressed as cohort mean ± SEM

C-Terminal Telopeptide (CTX)

Cohort 1	Cohort 2	Cohort 3
(0.2mg/kg, 2x/week)	(0.6mg/kg, 2x/week)	(1.8mg/kg, 2x/week)

Data expressed as cohort mean ± SEM

✓ Low, sometimes transient levels of non-neutralizinganti-drug antibodies

Pharmacokinetics

• 126-hour half-life supports once-weekly dosing
• Informs and validates PK model

Pharmacodynamics

• Significant elevation of plasma pyrophosphate (PPi), maintained for over 18 months
• Changes in key biomarkers (i.e., FGF-23 and phosphate (Pi)) support clinical hypothesis
• Rapid increase in PPi at 1 week correlated with decreases in FGF-23 levels (p= 0.0371)
• Dose ranging data support adult dose of 1.8 mg/kg/week

Identify clinically meaningful outcome measures to inform design of future study in adults

• Functional improvements can be measured by 6-minute walk test and patient-reported outcomes; strongest improvements seen in patients with greatest impairment at baseline
• Identified areas of bone pathology (low BMC/BMD) may represent locations for radiographic scoring for improvements
• Subset analyses reveal patient populations most likely to benefit from INZ-701 treatment in future adult studies

References:

1.	Mackenzie NC et al. Bone. 2012;51(5):961-968.	6.	Rutsch F, et al. Circ Cardiovasc Genet. 2008;1(2):133-
	140.
2.	Johnson K et al. J Bone Miner Res. 2003;18(6):994-
7.	Hofmann CD, et al. J Clin Endorinol Met.
	1004.
		2019;104(7):2735-2747.
3.	Orriss IR et al. Curr Opin Pharmacol. 2016;28:57-68.
8.	Xue Y, et al. Mol Gen Metab. 2016;117(4):419-426.
4.	Ferreira CR et al. Genet Med. 2021;23(2):396-407
9.	Kazi ZB, et al. JCI Insight. 2017;2(16):e94328.
5.	Ferreira CR et al. J Bone Miner Res. 2021;36(11):2193-
10.	Product USPI 23
	2202

Acknowledgements & Disclosures

The authors would like to acknowledge Jennifer Howe, Inozyme Pharma, for designing the poster. Inozyme and former employees are stockholders in Inozyme Pharma.

Thank you to the patient community, physicians and investigators!