Stepping Stones on the Path to a Healthier Future for Patients With Primary Hyperoxaluria Type 1: Expert Perspectives on Ensuring Timely Diagnosis and Appropriate Management

Co-Chairs, Matthew C. Breeggemann, MD, and John C. Lieske, MD, discuss primary hyperoxaluria type 1 in this CME activity titled “Stepping Stones on the Path to a Healthier Future for Patients With Primary Hyperoxaluria Type 1: Expert Perspectives on Ensuring Timely Diagnosis and Appropriate Management.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/4bliaDW. CME credit will be available until October 9, 2025.

1. Stepping Stones on the Path to a Healthier Future

for Patients With Primary Hyperoxaluria Type 1
Expert Perspectives on Ensuring Timely Diagnosis
and Appropriate Management

Matthew C. Breeggemann, MD 2 John C. Lieske, MD
© Assistant Clinical Professor Professor of Medicine
be Division of Nephrology Division of Nephrology and

University of California San Francisco Hypertension
San Francisco, California Mayo Clinic
Rochester, Minnesota

Chris Thompson
Patient

Go online to access full CME information, including faculty disclosures.

Copyright © 2000-2024, PeerView

2. Our Goals for Today

Improve your understanding of the prevalence, pathophysiology,
clinical features, symptomatology, consequences, and disease
burden associated with PH1

Enhance your ability to apply the latest guideline recommendations
to diagnose PH1 early, and refer patients, as appropriate, to
specialized nephrology care for targeted treatment

Provide you with an understanding of the mechanisms of action,
efficacy, safety, and ability of current and emerging strategies to
prevent the decline of kidney function and systemic complications in
patients with PH1

Copyright © 2000-2024, PeerView

3. Understanding the Pathophysiology,
Burdens, and Consequences
of Undiagnosed PH1

Copyright © 2000-2024, PeerView

4. Pati

Aged 11 Years

Chief Complaint _ Medical History
+ Sarah presents with a 2-week history of flank pain, | + Recurrent UTIs over the past
| hematuria, and dysuria. Her parents report thatshe | 4 years

has been unusually fatigued and has had is A N A
decreased appetite over the past month 2 prior episodes of kidney stones

ages 5 and 9, both requiring
+ She has had 3 episodes of UTIs in just the past hospitalization for pain

year, which were treated with antibiotics by her PCP

+ Flank pain has been intermittent but has recently = =
become more severe Family History

+ Upon researching on their own, Sarah's parents + No known history of kidney
decide to bring her to a nephrologist disease or hyperoxaluria

management and stone removal

PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

5. Primary Hyperoxaluria: Epidemiology’?

Estimated prevalence of PH

+ Primary hyperoxaluria type 1 is <
(PH1) is an autosomal is <3 per 1,000,000

recessive disease resulting
from mutations in a liver

enzyme alanine glyoxylate O, .
aminotransferase (AGT) 80% or patients
with PH have PH1

+ Majority of patients with PH1
will reach end-stage kidney

disease (ESKD) by young
adulthood PH1 is the most severe and
common phenotype of PH
1. Fargue Set al. Gin Kenoy J 2022:184:8.2. Hopp Ke al J Am Soc Nepal. 2015: 225692510. PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

6. PH1 Pathophysiology

+ Deficiency of AGT, which
catabolizes glyoxylate to glycine

Glyoxylate is converted to
oxalate in the liver when AGT
activity is deficient

This oxalate cannot be
metabolized and must be
excreted by the kidneys

Oxalate -—— Ascorbic acid

This oxalate forms insoluble

calcium oxalate crystals that Hepatocyte
accumulate within the kidney
and, when GFR is reduced, in Metabolism of oxalate in the hepatocyte and
other organs consequences in PH1
1. Farque Seto Gin Key 3. 2022:160upl M8. PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

7. End-Stage Kidney Disease Is Common in PH1

100 PH3
PH2
xe 80
= 60
2
=
2 40
3
El PHI
Π20 _
HR = 13.2 (95% Cl, 3.2-54.4)
P<.001
o 10 20 30
Time Post Diagnosis, y
No. at Risk (4)
PH1 100 (192) 79 (75) 51 (26) 27 (8)
PH2 100 (5) 100 (12) 20) 92(7)
PH3 100 (88) 95 (8) 95 (4) 95 (1)
1. Zhao Fetal. Cin J Am Soe Nopirol 201611:19-128, PeerView

PeerView.com/EZY827 Copyright © 2000-2024, Peerview

8. How Does PH1 Present?!

Onset of symptoms can appear in
OS infancy through the age of 60 or older

+ Nephrocalcinosis affects 10% of + Adults typically present with

patients who present in early recurrent kidney stones and
childhood/adolescence : mild/moderate CKD
+ Majority will have symptomatic _ + Sometimes are not diagnosed until
kidney stones and eventual CKD they develop ESKD
O ree Seat PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

9. Dia

osis of PH

PH1 should be considered

250% of patients have in children with kidney stones
kidney failure or advanced and in children or adults with
CKD at diagnosis nephrocalcinosis or unexplained

chronic kidney disease

Patients with PH1 typically have

=
7 higher urinary oxalate Definitive diagnosis
O) excretion (>70 mg/d) than is achieved
U Sy those with secondary by genetic testing
hyperoxaluria
1. DemoulnN etal. Am Kidney Dis. 202279717-727, PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

10. PH1 Diagnostic Algorithm! ‘practice Al

Kidney failure or insufficiency
(eGFR <30 mL/min/1/73 m?)

Normal kidney function

+ Childhood stones or nephrocalcinosis + Calcium oxalate stones and increased serum creatinine
+ Nephrocalcinosis or recurrent calcium oxalate stones in adulthood + Calcium oxalate tissue deposits
+ Family history + Nephrocalcinosis
y y
Perform urine oxalate test Perform urine and plasma oxalate testing

y

24-h urine oxalate >0.7 mmol/1.73 m? anc 24-h urine oxalate >0.5 mmol/1.73 m? and/or
urine oxalate:creatinine ratio > normal for patients age

and/or plasma oxalate >20 umol/L

late:creatinine ratio > normal for patient's age

+ Repeat testing to confirm hyperoxaluria
+ Consider hyperoxaluria urine panel (glycolate, glycerate, HOG) to
narrow down PH type

Are any secondary causes present?
+ Malabsorption

+ Gastrointestinal disease

y + Low calcium diet with very high oxalate

+ Premature infant

Hyperoxaluria confirmed?

: Evaluate then treat accordingly

1. Adepled kom hts: mayocnlbs.commedatenmbles/ Speci: Zoistchons ER 1Myperasaie_Diognosie Agorthin. PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

11. gnostic Algorithm, continued! RA
Downlood the
Practice Aid!

laps Hyperoxaluria confirmed? |H™NEB+{ Are any secondary causes present? |

Yes

Evaluate then

Perform genetic testing as indicated for primary hyperoxalurias
treat accordingly

+ AGXT genetic testing; full gene analysis
+ GRHPR genetic testing; full gene analysis
+ HOGAT gene analysis

Homozygosity or compound heterozygosity for known mutations of AGXT, GRHPR, or HOGA1?

AGXT
pathogenic

Consider clinical management
based on presentation OR
research testing for causes related
to novel genetics

1 Adaped hor hos win mayocincabs com/4medialt-mmls'Spece20lnshuctons/E!Myperxahyie_Diegroste_ Ager. PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

12. Case Revisited: Sa

Aged 11 Years

Further Diagnostic Testing
Initial Workup. + Given the significant elevation in urinary
+ Urinalysis: significant hematuria, mild proteinuria, oxalate levels and the presence of
and presence of calcium oxalate monohydrate nephrocalcinosis and kidney stones
crystals in a child, a diagnosis of PH is
Serum creatinine: 1.2 mg/dL (elevated for age) strongly suspected
Serum calcium: normal i

Genetic Testing
Serum bicarbonate: 18 mmolL (low)

+ Sequencing of the AGXT gene reveals a
pathogenic homozygous mutation,
confirming diagnosis

Abdominal ultrasound: bilateral nephrocalcinosis,
multiple kidney stones in the right kidney
24-h urine collection

= Oxalate: 150 mg/24 hours (markedly elevated)
— Calcium: normal
- Citrate: low

PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

13. Expert Perspectives on the Updated
Guidance and Evidence for Managing
Patients With PH1

14. hydra’

+ Hallmark of conservative treatment for + Infants and toddlers may need a

all stone diseases gastrostomy tube
+ High fluid intake: >3 L/1.73 m2 + Even with good fluid compliance,
BSA/day patients with PH1 can still progress to

+ Initiate in any patient with high UOx kidney failure

when PH1 is suspected, and genetic + Even mild dehydration (eg, from
confirmation is pending gastroenteritis) can lead to acute
kidney injury

ERKNet and OxalEurope Guideline Recommendations for
Suspected PH and Preserved Kidney Function

1. Hoppe B, Nartn-Higuras Drugs. 2022:52:1077-1094. 2. Groth JW et al Not Rev Novo! 2023:19-194211.3.Gupta A etai Gin Ktney 20221510418 PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

15. + Citrate is part of the standard of + Citrate inhibits growth and
care along with hyperhydration aggregation of calcium phosphate
and calcium oxalate crystals in the
urinary tract

ERKNet and OxalEurope Guideline Recommendations

1. Hoppe B, artn-Higeras . Drugs. 202282:1077-1094. 2 Grove JW et al. Nat Rev Nephrol. 2023:10:104:211.9. Gupta Act al. Gin aney 20221519413 PeerView

PeerView.com/EZY827 Copyright © 2000-2024, Peerview

16. Pyridoxine (Vitamin B6)!

+ Monitor urine oxalate to determine
responsiveness (or plasma oxalate if ERKNet and OxalEurope
kidney failure) Guideline Recommendations

- Partial responsiveness >30%
decrease in urinary oxalate
excretion after 3 mo on optimal
dose of VB6

— Fully responsive: normalization of
urinary oxalate excretion

+ Initial dose 5 mg/kg; higher doses to
7-10 mg/kg in select patients with
monitoring

1. SODOM JW et Nat Rev Hero 2023:19:194211 PeerView

PeerView.com/EZY827 Copyright © 2000-2024, Peerview

17. Place in PH1 Therapy!

4-Hydroxy-L-proline

Glycine
PH1: LUMASIRAN |
Glycine
AGT j | DAO
+. Glyoxylate Giyoxylate —+ Oxalate
. LDI
“co 1 lor ©
Glycolate ————————— Glycolate
PEROXISOME :
PH1, PH2, and PH3:
NEDOSIRAN
1. Bacchtla J, Leske JC. Cin Key J 202215417422 PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

18. Lumasiran??

Lumasiran

mRNA encoded by the HAOT gene that
(©) encodes glycolate oxidase is silenced by a

small-interfering RNA

« Approved as an orphan drug for the treatment of PH1 in
all age groups
* Dosing is based on body weight

1. Gang X etat Frot Pec 2023:10:1052625 7
2. One (umasran) Presrbing Infomation, ps mn accessdaa (da goVióugsatid, docs/abelZ023/2141006004Ia pa. PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

19. Phase 3 ILLUMINATE-A!

+ Ongoing, phase III trial of subcutaneous lumasiran

Primary efficacy analysis
Lumasiran —
@ à 3 mg/kg QM x 3 UE
Patients with i 3 mg/kg Q3M

Followed by Q3M
PH1 26 years of

age with eGFR 5 3 mg/kg Q3M
230 mL/min/1.73 m? Placebo Lumasiran

Lumasiran

ved by Q3M

1. Garelfs SF et al, NEUM. 2021.984:1216-1226

PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

20. Reduction in Urinary Oxalate Excretion: Results From

ILLUMINATE-A!

Double-blind period Extension period

Percent Change From BL in
24-h UOx Corrected for BSA
5
ë

Placebo/lumasiran

Lumasiran/lumasiran

-80
100 T + + + +
Ble1 23456789 12 15 18 21 24 30
Study Visit, mo
No.of Patients
Piooobofumasian 13 13 12 13 13 13 13 13:13:13 13 1 no ”
Lumastentunasten 25 25 26 25 23 25.25 A A2 24 2 a ». oz 2

+ Baseline is the modi ola val 24-hour urine assossments collected por tothe fst dose ofthe study drug Jumasitan or placebo), > At month 36, the
lumasranfumastan group had received lumasiran treatment lor 36 months, and the place for
1. Saland JM ela. Kidney int Reports. 2024.9:2037-2046.

PeerView.com/EZY827

bolumasiran group had received lumasiran veatmen for 30 months.

‘36°

12
2

PeerView

Copyright © 2000-2024, PeerView

21. Reduction in Kidney Stone Event Rates: Results From

ILLUMINATE-A cont'd?

g M Historical®
E

Eo + 319 Ml Lumasiran

Se (257-396)

GH 30

Pe

SE 20

FÉ 10 0.56 0.63 0.52 0.46

2 (02512) 03013) (024117) (0181.10)
E oo

>M30 to M36

>M18 to M24

>M12toM18 >M24 to M30

12M Prior to >M6 to M12
Consent
36 Months of Lumasiran
No. of pationts with 21 event 5 7 2 5 5 3

Start lumasiran

‘kidney stone events defined as an event hat incudes at least 1 ofthe flowing: Ws toa healthcare provider because of a kidney stone, medication for

renal eae, tone passage, or macroscopichamauira ue 1 a ney sone a
Y Saland et a Kidney In pois 2024:92037-2046 PeerView

PeerView.com/EZY827 Copyright © 2000-2024, Peerview

22. umasiran Safety

(%) (Rate)
Any AE 12 (92) (100/323.3) 24 (92) (255/369.5) 36 (92) (355/355.2)
AE related to study drug 6 (46) (29/93.8) 13 (50) (59/85.5) 19 (49) (88/88.1)
Serious AE 1 (8) (2/6.5) 3 (12) (5/7.2) 4 (10) (7/7)
Severe AE o 2 (8) (2/2.9) 2 (5) (2/2)
a o 1er 1008
AEs occurring in 215% of patients
in the all-lumasiran-treated set
Injection-site reactions 6 (46) (26/84.1) 13 (50) (49/71) 19 (49) (75/75)
Abdominal pain 1 (8) (7/22.6) 7 (27) (14/20.3) 8 (21) (21/21)
Headache 2 (15) (2/6.5) 5 (19) (9/13) 7 (48) (11/11)
COVID-19 3 (23) (4/12.9) 3 (12) (3/4.3) 6 (15) (7/7)
Death 0 0 0
1. Saland JM ea Kidney nt Repo. 2024920872046. PeerView

PeerView.com/EZY827

Copyright © 2000-2024, PeerView

23. ILLUMINATE-B: Lumasiran Demonstrated Rapid, Sustained

Reduction in Spot Urinary Ox:Cr Ratio in Children!

ILLUMINATE-B
Study Design*

Patient Population (N = 18)
+ Infants and children <6 years old
"757 * Confirmed AGXT pathogenic variants
NEW! corr 245 mln. Tan ete mont os
normal serum creatine f<12 months old

ns

0.0.9, 50 Primary Analysis Period

2 Lames
BES) - aux ona oso, on on maintnance
ii bee Sonn

54-mo Extension Period
Lumasiran
+ QM or Q3M maintenance weight-based
dosing

‘Continued woight-based dosing using weight obiained 7 days prior to

sing dosing.
1.838 DJ et a. Gonot Mod 2022 24.664.082. 2. Hayes W et a Podiar Nepirol.2023:38-1075-1086,

PeerView.com/EZY827

Percent Change From BL at Each Vi

Ss 0 '
3 i
ze i
ef 20 1
ss >
É
Se
5 0 to <20 kg n= 12) 220g (n=
59 Pr RN] 220 kg (n= 3)
SS 7
ES
ES + AI limasiran treated
= =
88 (0718)
29 -100
B123 4 5 6 9 12
Study Visit, mo
No.of Patients
“om 3 3 9 2 39 8 a a
wann 2 wR 2 2 0 2 ”
ug 3 3 9 9 3 9 3 3
Altman
fe 1 1 8 1 1 1 10
PeerView

Copyright © 2000-2024, Peerview

24. ILLUMINATE-B: Improv in Nephrocalcinosis and Kidney

Stone Events?

Patients With Nephrocalcinosis at Baseline

Month 6 (N = 14) Month 12 (N = 14) Lumasiran (N = 18)
100 100 30
z
so so 7 5
y Historical
20 M Lumasiran
qe 4» ;
€ € E
2 3 wu
Eso Es 2
é E E
2 ö
20 » >
A
E
o o E
Worsened Stable Improved DataWA Worsened Stable Improved’ Data NIA ERA TO
© Unilateral improvement ”
Tr Pe
12 Bilateral improvement esate Paris
Start lumasiran
Matar! copied hoy of ney stone even; anus ee was no closed or patents € man. .
Vas Wat al Boca nephron 2022 8 1075-080, FER En PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

25. ILLUMINATE-C!

Ongoing Phase lll Single-Arm Trial of Subcutaneous Lumasiran

Stratified by hemodialysis at enrollment
(Yeso) . a B
} 6-mo Primary Analysis 54-mo Extension
+

Cohort A: No hemodialysis

Lumasiran QM x 3 or Q3M

Patients with PH1 with eGFR
45 mL/min/1.73 m? (age 212 mo)
or elevated SCr (age <12 mo)
and POx 220 mmol/L

Cohort B: Hemodialysis (n = 15)
Lumasiran QM x 3
Followed

Cohort B: Hemodialysis
Lumasiran* QM x 3 or Q3M

(N=21)

+ 6-mo preliminary data: significant reductions in POx in both cohorts + 12-mo data: mean % reduction in POx was
= Cohort A: mean reduction in POx of 33.3% from baseline 98.9% (Cohort A) and 94.4% (cohort 6)
— Cohort B: mean reduction in POx of 42.4% from baseline
an dee a bho Sah PARA OM ang dose UMD GM Sie hos Ras dare DOMO CN MITO Sse es aed

ere Am Knoy DS 202381151551 PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

26. Actual Values at Each Vi:

120
ÿ 105
E 90
2 75 Cohort B (n = 15)
x=
03 86 E = =
se 4 E =
ea 45
a 30 = — = +
E 15] Cohort A(n=6)
0 7 7
BL 1 2 3 4 5 6
Assessment Visit, mo
No. at Risk
Cohort A 6 6 6 6 6
Conor 8 15 1 15 5 13 14 1
1.Mhael ot. Am J Key Ds 2029:1:145-155. PeerView

PeerView.com/EZY827

Copyright © 2000-2024, PeerView

27. BONAPH1DE!

+ Prospective observational study

+ Currently recruiting (N = 200 estimated enrollment)

Goal of BONAPH1DE

Describe the natural course of
patients with PH1 and to eS

evaluate the long-term efficacy
and safety of lumasiran

1. ntpsitencatilsgovisudyINCTO49623857condPrimaryk20Hyperoxahats20Type%20 Stemetuasiansrarkes PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

28. Nedosiran

GalNAc-conjugated RNAi treatment that targets
(©) hepatic lactate dehydrogenase, the enzyme that

mediates oxalate production in all subtypes of PH

+ Once-monthly subcutaneous injection; approved 2023 based on results from
PHYOX2 (other trials in PHYOX program ongoing)

+» For adults and children aged 29 y with PH1 and eGFR 230 mL/min/1.73 m?
« Dosing based on body weight

1 God tt toss 2023140 2 Hoppe Beal oy I 200101 28434 3 Baum MA 0 Kine im. 2028108207 217 à
4: Coenen tt ta J Am Soc Nophrl 2020:31(108)15. 5. Haagensen À ei al. Kidney Week 2021. Abstract IN PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

29. Nedosiran: PHYOX2'

+ Multinational, randomized, double blind, placebo controlled

+ AIM: evaluate the efficacy and safety of monthly subcutaneous nedosiran in participants
with PH1 or PH2 over 6 months

+ Primary endpoint: % change from baseline in 24-h UOx excretion from day 90 to day 180

Screening
35 days

Dosing, salty Or, POs, PK ED Dosing, ait UOx Po

1. Baum MA. Kany It 2028:108:207-217.

PeerView
PeerView.com/EZY827

Copyright © 2000-2024, PeerView

30. PHYOX2: Reduction in Urinary Oxalate’

PHYOX2 Met Primary Endpoint Achieving a Significant Reduction in UOx
Mean AUC241, UOx (Day 90 to Day 180)

Overall mITT Population’ (PH1 + PH2)
»

Standardized AUC,,, UOx Nedosiran AUCH
From D90 to D180° (n=22 e. 2

Ss
LS mean (SE) 3,507.4 (788.49) -1,664.4 (1,189.96) À a o

za
95% CI for LS mean 1,961.7 to 5,053.) -3,997.2 to 6,684 E 2

ge
LS mean difference from placebo 40
& 5,171.7 (1,144.07)
95% CI for difference from placebo 2,929.3 to 7,414.2

Day of Treatment

P for difference from placebo <.0001

ATT popular = al parcpans int IT poulain who had a last ono oc assesmant aer ro day 0 doing vai
atole mputaton under the missing random asumpson was used lo hard maang Zah UOx ala, N
1. Baum MA etal Kidney nt. 2028103 207217. PeerView

PeerView.com/EZY827 Copyright © 2000-2024, PeerView

31. Complexities in PH1 Guidelines!

+ Routine follow-up in patients with
PH1 and grade 24 CKD

— Measure plasma oxalate levels every
3 to 12 months

— Patients who have not reached 5D
CKD should have renal imaging at
least yearly to assess stone presence
and nephrocalcinosis

+ RNAi therapy recommended for
patients with suspected PH1 with
CKD5 even while awaiting
genetic confirmation

1. Grootholl JW eta. Not Rev Nephrol. 2028,19:194-211,

PeerView.com/EZY827

+ Kidney transplant alone should be
considered in patients with stage 5
CKD PH1 with pyridoxine-responsive
mutations or who respond well to
RNAi therapy

— Need for combined liver-kidney
transplant is based on plasma oxalate
response to VB6 + RNAi therapy

» Dialysis may be needed for patients
with PH who have progressed to stage
4/5 CKD even before uremia develops,
based on risk of systemic oxalosis
(POx levels >30-40 pmol/L)

PeerView

Copyright © 2000-2024, Peerview