Advancements in IgA Nephropathy: Discovering the Potential of Complement Pathway Therapies

Co-Chairs and Presenters, Gerald Appel, MD, and Dana V. Rizk, MD, discuss kidney disease in this CME activity titled “Advancements in IgA Nephropathy: Discovering the Potential of Complement Pathway Therapies.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/48UHvVM. CME credit will be available until February 25, 2026.

1. Advancements in IgA Nephropathy

Discovering the Potential of Complement Pathway Therapies

Gerald Appel, MD Dana V. Rizk, MD
Center for Glomerular » Division of Nephrology
Diseases University of Alabama at
Columbia University Irving Birmingham

Medical Center A N Birmingham, Alabama
New York, New York

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

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2. Our Goals for Today

Augment your knowledge of IgAN pathophysiology

Equip you with strategies for managing patients
with IgAN using the latest guidelines and trial data

Provide guidance on how to implement emerging
therapies that target the complement system

Copyrigh

3. Pathophysiology and Identification of IgAN

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4. Glomerular Diseases and Their Uncommon Occurrences

Estimated Annual Global Incidence

New Cases per Million

aHUS? IgAN®

5.4-45

Of these rare glomerular diseases,
IgAN is one of the more common types

1: Caravaca Fontán Fetal Kltny060. 20294650672 2. Yan Ketal in Epdomil 2020122853059. Schen FP, ir Som Nepal 201830435442. Dear View
Hocaogiu Mela. this Fhoumaal 2023.75:567-573,

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5. “Four Hit” Hypo

IgAN Pathogenesis sí L

Elevated levels of galactose-deficient IgA1 A gg ee

(Hit 1)

Formation of autoantibodies specific à ee
for the galactose-deficient IgA1 (Hit 2) a ste eus position
uta

Formation of circulating pathogenic op br
immune complexes (Hit 3) AA re
Mesangial
Deposition of immune complexes e NS mmunodeposits
in the mesangium, leading to activation )
of mesangial cells, complement,

inflammation, and glomerular injury (Hit 4)

Glomerular injury

1. Poppelars F, Thurman JM. Mo Immunol. 2020:128:175-187. 2. MagiswoniR et al. kidney nt. 2015:88:974-989, 3. PatrapompisutP et al. Am J Kidney Dis PeerView
2021.79:429-441. 4. Gleeson PJ el al. Nephrol Dial Transplant. 2023:38-246,

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6. Screening for a

+ Urine tests showing + IgAN can only be diagnosed
— Gross hematuria or with'aikidney blopsy
- Persistent microscopic hematuria + — Biopsy should be performed in all
proteinuria or adults with proteinuria 20.5 gid
(or equivalent) in whom IgAN is
| + Blood testing showing suspected and who do not have a
- Slowly progressive renal contraindication for kidney biopsy?
| function decline + Once diagnosed, assess for
+ Early onset HTN secondary causes
+ If primary IgAN, determine the
MEST-C score
2 hip sige crip contenu 20308KDIGO 2028 AN IA dino Pub Revew Dap. PeerView

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7. Biopsy Findings for IgAN!

Light Microscopy (A), Immunofluorescence (B),

1. Merit LC et a On J Am Soe Nepal. 20149:1039-1039 PeerView

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8. C Criteria in Updated Oxford Classification of IgAN*

istologic Variable Score

MO: <50% of glomeruli showing mesangial hypercellularity

CESE Cat) M1: >50% of glomeruli showing mesangial hypercellularity

E0: no endocapillary hypercellularity
E1: any glomeruli showing endocapillary hypercellularity

SO: absent
$1: present in any glomeruli

TO: 0%-25% of cortical area
T1: 26%-50% of cortical area

Endocapillary hypercellularity

Segmental glomerulosclerosis

Tubular atrophy/interstitial

proces T2: >50% of cortical area
CO: absent
aa 2 C1: 0%-25% of glomeruli
C2: 225% of glomeruli
1. Marko ©. Not Rev Nephrol. 2017.13:385388. 2 Catvan DC etal. Kidney Int 2000.7 534-545. PeerView

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9. Elements of the International IgAN Prediction Tool”?

Estimated eGFR mL/min/1.73 m2

Systolic BP mmHg

Diastolic BP mmHg

Proteinuria g/day

Age Years

Race Caucasian Japanese
Chinese Other

Use of ACEI or ARB? Yes or No

MEST M-score (at biopsy) Dor1

MEST E-score (at biopsy) ODor1

MEST S-score (at biopsy) Dor1

MEST T-score (at biopsy) 0,1,0r2

Immunosuppression use Yes or No

1. KOIGO Glomerular Diseases Work Group. Kidney Int 2021:100.51-5276.
2. Mos ko orp wp-contentuploads/2024/08/KDIGO-2024-gAN-IQAV-Guldene-Publi-ReviewOraft pd.

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Populate the
International IgAN Prediction Tool
with patient data to calculate prognosis

Calculates the risk of a 50% decline
in eGFR or kidney failure up to 7 years
from kidney biopsy in adults and children

Can be used at the time of biopsy, 1 year
after biopsy, or 2 years after biopsy

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10. Current Management and Guidelines

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11. IgAN Draft Treatment Algorithm’

In al patients, these should be (TAPIE

Divas terrenos | addressed simultaneously

Reduce pathogenic Re eruar

forms of IgA and lg ce glomerula hyperfitration and the

immune complex impact of proteinuria
mi o nth

Treatment goals

Interventions with efficacy
reported in clinical tials,
‘across populations

Geographic
practice variation

1. htpsthcigoorgvp-contentuponds/2024/08KDIGO 2024 IgANIgAV.Guielne-Puble-Review-Oraf pd. PeerView

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12. Supportive care to manage the consequence
of IgAN-induced nephron loss SHOULD include

+ Lifestyle modifications: dietary sodium restriction,
smoking cessation, weight control, and exercise,
as appropriate

« Blood pressure control with a target of 120/70 mmHg
+ Use of RAAS inhibitors, DEARA, and/or SGLT2i

+ Assess and address cardiovascular risk

1. hesugeorivp-contentuploada/2024081KDIGO-2024gANIGAV. Guidetne Publ Review Draft pd. PeerView

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13. SGLT2 Inhibitor Data in Patients With IgA Nephropathy’

Dapagliflozin Empagliflozin
Subgroup of DAPA-CKD ‘Subgroup of EMPA-KIDNEY

+ n= 254 participants with biopsy-confirmed IgAN + n= 817 participants with IgAN
+ Primary endpoint: composite of sustained eGFR decline 250%, + Primary endpoint: composite of sustained eGFR decline 240% or
ESKD, or death from kidney disease-related or CV cause below 10 mL/min/1.73 m2, ESKD, or death from kidney failure
Primary Endpoint (IgA FAS) EvontalPartcipants
(05% cn
won HR = 029 Empagiiozin Placebo no)
2
Pa) TEL
Es DiabetKióney disease AS 102 —#— 064 (0520.80)
g Hypeensive orrenovesclar disease TAB ern Pe] ae (050-108)
En mai tas visas a | orramamı
2% ther isesse or unknown CORRE 067 (040-082)
3: Types ot gomenar diseases H
Es n—— ISA nephropathy Se ero —#— 067 (048-097)
LE DS Focal sogmenagomenonsens WM 1a “+ 1360665281)
5 tner gemenonephriis ame u — 078 (053-116)
o 4.5 a % 0 à à» à participants <= 0.74 (082.081)
Time Since Randomization, mo

o4 06 08 112
Favors empagiiiozn ¢——— Favors placebo

+ Dapaglíflozin + ACEI or ARB therapy significantly reduced + Empagiiflozin reduced progression of kidney disease in participants
the risk of CKD progression with IgAN and other CKD
4. Wer DO et al Kidney Int. 202:100:215 224. 2. EMPA KIDNEY Colaborative Group. Lancet Diabetes Endocrine 2024.12.51-60, PeerView

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14. New Drugs FDA Approved for IgAN'®

TR budesonide dus re
Drug Mechanism of Action in IgAN == sí EP

Dual antagonist of endothelin and Galactose-defecient gat Antgiycan antibodies
angiotensin II (DEARA) to reduce O | ee
glomerular hyperfiltration and the effects
of proteinuria on the tubulointerstitium

Sparsentan

Immune complex formation disposition

Exerts antiinflammatory and
immunosuppressive effects Sparsentan PA

TR at the glucocorticoid receptors on =) nm Iptacopan

budesonide mucosal B cells in the ileum to reduce
the production of pathogenic forms
of IgA and IgA immune complexes

‘Complement
‘activation

Mesangial

immunodeposits

Binds factor B to inhibit the actions
ofthe alternate complement pathway
Iptacopan to suppress inflammation, prevent
‘complement deposition,
and decrease proteinuria

‘Glomeruiar injury

eyo (budesonide) Prescribing Infrmaton, psn ecessdata fa. goWerupsatida_doesabeV2024/2 15835200501 pat
2 Füsgan (sparsentan) Preserbng Inermaton, its ww acessdata a govdrugsata_ docslabel2024/21403S003Bpa. 3. Fabhalta(ptacopan) Prescribing

lomo. Rips ccessdala a govdrgsatisa_catabel202421627ex00%8\ pel À po ago cpp conierduposesTPNOBKOIGO22GANGAY- Do aj ew
Guideline Publi Review Dra pal. 5. Magiston Ret a Kinoy It. 2015,88 974-089.

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15. ROTECT Trial: Sparsentan for IgAN!

Change From Baseline
= in UPCR at 36 Weeks, %

+ Phase 3 trial of sparsentan (n = 203) vs
| irbesartan 300 mg/day (n = 203) in adults with
biopsy-confirmed IgAN and proteinuria 21 g/day
who were receiving a stable dose of ACEi or
ARB therapy for 212 weeks before screening
| + Sparsentan decreased proteinuria compared
with irbesartan at the 36-week interim analysis

— Reduction first observed at week 4

Geometric Least Squares Mean
Change in UPCR, %

Sparsentan Irbesartan
(n = 202) (n= 202)

1. Heerpink HL eta, Lancet, 2023401:1504-1504 PeerView

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16. PROTEC ar Proteinuria and Adverse Effects!

+ Adverse effects were similar between the two study groups

Geometric Least Squares
Mean Change in UPCR, %

"Irbesartan

-10:

-20

-30:

#0 H H Sissi

0 46 12 24 36 48 58 70 82 9 106 110
Weeks After First Dose of Study Drug

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1. Rovin BH et al. Lancet, 2023,402 2077-2090.

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17. PROTEC ar Estimated Glomerular Filtration Rate!

+ REMS programs exist to prevent hepatotoxicity and embryofetal toxicity

2

End of double-blind period:
End of treatment 1

“| Sparsentan

sof oesatan

Least Squares Change From Baseline
in eGFR, mL/min per 1.73 m?
&

0246 12 24 36 48 58 70 82 9 106110114
Weeks Since First Dose of Study Drug

1. Rain BH etal. Lancet 2029402 2077-2050) PeerView

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18. PROTECT: Post Hoc Assessment of Complete o

Partial Proteinuria Remis:

n

Proportion of Patients Achieving Complete or Partial Proteinuria Remission

RR (95% Cl) = 1.5
460 mSparsentan — s Irbesartan (1119)
90 1
80 RR (95% CI) = 2.1 78
(1529)
10
2 w RR (95% Cl) = 25
$ (1.64) st 53
g 5
3
3 4
& 3
30 2
20
11
10
of
‘Complete Response UPE <0.5 g/d Partial Response
UPE <0.3 g/d UPE <1.0 gid

1. Rovin BH etal, Lancet. 2023,402 2077-2080.

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19. NeflgArd Efficacy and Safety: Proteinuria and Adverse Effects!

+ Phase 3 trial of TR budesonide (n = 182) vs placebo (n = 182) in patients with IgAN

(126 to 124)

TR budesonide
16 mg/day
30.7
(-38.9 to -21.5)

‘Treatment period
r 7 r
0 3 6 9 12 18 24

Time, month

‘Observational follow-up period

TR budesonide was well tolerated, with a safety profile consistent with what is expected of a locally acting
corticosteroid (peripheral edema, hypertension, acne, headache)

1. Lafayette Rot al. Lance. 2029402 860-870. PeerView

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20. acy: Estimated Glomerular Filtration Rate (eGFR)!

z
a
=
[2]
>
=
2
m

EE
0»
ah 5
SE
82
0
83 |
SE TR budesonide
Bs 5 16 mplday
3£ 611
3 (-8.04 to -4.11;
E 3 10 € )
Te Treatment period Observational follow-up period Placebo
ES 5 E
= (~" 1
si 0 3 6 9 12 18 24 (13.76 0-10.15)
Time, month
A. Lafayette Fetal Lance. 2029402 860-870. PeerView

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21. NeflgArd Trial: Composite Renal Endpoint!

+ TR budesonide positively affected risk of achieving the composite endpoint of kidney failure
event or an eGFR decrease of 30% consistently, regardless of baseline UPCR

TR pe LES HR (95% CI)
Allpatients oa 82) ca == 026079
UPCR <1.5 g/g aan te —— 027112
1
UPCR 21.5 g/g ey en —e—! 021089)

1. Lafayette R el al. Lancet 2023,402.850-870.

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0.125 0.25 0.5
a

Favors TR budesonide Favors placebo

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22. Complement System Targeting and
Clinical Trial Insights

23. The Role of the Complement System in IgAN!

Lectin Pathway Classical Pathway Alternative Pathway

0. Ao
ee = onl ce ad
ere
ea a
ESG] —{ 03 convertases
«a
Opsonization
and phagocytosis Converter
©
©
a : MAC formation
“OF and cell lysis, fs
1. S0BYF etal Front mano! 202213:1009664 PeerView

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24. The Alternative Pathway’

C3 convertases
a E
. ©
C5 convertases
Opsonization
and phagocytosis So
= = MAC formation
© ® and cell lysis
1.50 BVF etal. Front Immuno. 2022.13:1000064. PeerView

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25. New Drugs FDA Approved for IgAN'®

TR budesonide
Drug Mechanism of Action in IgAN u) Sul, poz
Galaclose-deficient ght Anghcan antocies

OS a ae

Immune complex formation disposition

ress Sparsentan wa
; mn) Sch nz ote preu Iptacopan

Binds factor B to inhibit the actions
ofthe alternate complement pathway

to suppress inflammation, prevent
‘complement deposition,
and decrease proteinuria

‘Glomeruiar injury

1. Tarpeyo (budesonide) Prescbing Information. ps: accessdatafda.gov/erugsatida_doesiabe/2024/215835s005b pat 2. Fispa (sparsentan)
Presering Information. ps vw accessdata 132 govidrugsatida_docsabel2024/2 1640330031 pd. 3. Fabhaa (tacopan) Prescebing Information.
tpshewaccesscata (da govidrugsatida_docsabel2024/218276300 bl pl. 4. Nips: orp'wp-cortentuploads/2024/08IKDIGO-2024-IgAN-IgAV- PeerView

Guideline Public Review-Draf pal, 5 Magisvon Reta. Kidnoy In. 2015:88.074.080

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26. Alternative Complement Pathway Drug Targets’

Guen wc Alternative
par pay pathway
A ma
bli y
score
Targeting th ww
fargeting the <
Alternative Pathway (53 converting a — + E
in Complement-Associated = Aita

Kidney Diseases? (C3 mmbtoe

ome aa:
Ravulizumab
Eculizumab

5 bo

A an
. A Legend
ES A |
© Trapt ga

1. Bomback AS et al Kidney In Rep. 2022.72150-2159.2. Soir (eculzumas) Prescring Information ps. accesscata fa. govidrugsatida_docaabal/2024/12516594471 pal,
3. Utomits (ravslzumab-cwez) Presenbing Informaton, ps vw accessdata da gov/änugsauda_d0os1abeV2024/781 108603718 pa.

4. Tawmeos (avacopan) Preserbin information. ps: hrww.accessdata 3 govidnigeatida docslabel2024/21440701 150041 pa.

5. Fabhata(ptacopan) Prescbing Information, hips: accessdata fda govidrugsatida_docs/abel/2024/21827680011BIpat PeerView
8. Empaveñ [Pegcetacoplan) Preserbing Information. ps ww accessdata da govidrugstfda_ dces/abe/2024/2150 1450081 pal

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27. ‘geting the Complement System in Glomeruloneph

Currently Approved Indications

ANCA-Associated
Vasculitis

Drug Route of Administration aHUS PNH IgAN

IV infusion

Eculizumab

Ravulizumab IV infusion x x
Avacopan Oral x
Iptacopan Oral x

Pegcetacoplan Infusion via SC pump

+ REMS programs exist to prevent serious infections (eg, meningitis)
+ Patients must be up to date on vaccinations against encapsulated organisms before starting drug therapy
(eg, pneumococcal, meningococcal)

1. Bomback AS et al Kidney It Rep. 2022721802150. 2. Soir (eculzumas) Prescring Information ps Au aczessdata fd. govidrugsatida_docaabal/2024/12516594471 pat
3. Utomins (avuizumab-owe) Presenbing Informaton, tps accessdata da gov/änugsauda_d0os1abeV2024/781 10850371 pa

44 Tawmeos (avacopan) Preserbin Information. tos. hrww.accessdata 3 govidnigeattda docsllabell2024/2 1448709130041 pa

5. Fabhata(ptacopan) Presenbing Information Iutps vw accessdat fda govirugsatisa_docsabel/2024/2 1827650011. pa PeerView
8. Empavell(Pegeetacoplan) Prescribing Information. hiipsworw accessdata da gov/drugsatida_ doeslabel/2024/2150 4s 0060 pal

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28. Iptacopan for IgAN!

+ Phase 3, double-blind, randomized, placebo-controlled trial

+ Primary outcome of interim analysis: assess change from baseline in 24-hour UPCR
at month 9

Oral iptacopan
200 mg twice daily
n= 222

24 months

Adults with
biopsy-confirmed
IgAN and proteinuria,
despite supportive therapy

Interim analysis at 9 months
N = 250 (n = 125 from each group)

N= 443 Placebo
twice daily

n=221

24 months

1. Pee Y al. N Engl Mod. 2024 October 25 Epub e o it). PeerView

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29. APPLAUSE: Baseline Characteristics!

= Iptacopan Placebo 2 = Iptacopan Placebo
Characteristic Gee ice MEST-C Score, % an a
Age, yr 39.34 12.4 39.64 12.6 no
Female, n (%) 54 (43.2) 65 (62.0) Eo
El
From Asia, n (9%) 64 (61.2) 64 (51.2) so
si
Time since kidney PER eS
biopsy, mean yr To
Ti orT2
eGFR, mLimin/
FE 62.7 £260 6551267 es
a
24-hour UPCR, gg 18(1427) 1.9(1.5-28) c2
ACEI or ARB use >98% >98%
. + Baseline characteristics were balanced between groups
SGLT2i use, n (%) 18 (14.4) 14 (11.2)
+ Representative of patients with IgAN at risk for progression
Prior GC use, n (%) 37 (29.6) 36 (28.8)
|. Peso Veal ME Mod. 2024 Octobe Es abs fin PeerView

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30. APPLAUSE: Efficacy Results!

+ Inthe interim analysis, iptacopan significantly reduced proteinuria compared with placebo

Change in 24-Hour Urinary Protein-to-Creatine Ratio

2

E

2

ge Placebo

os ‘Adjusted geometric mean

ss between-group difference

2 3 ‘at 9 months = 38.3%

ea (95% CI, 26.0486)

FE

és Ipieoopen

ge Adjusted geometric mean

3 0.562 iptacopan
0.910 placebo

Geometric mean ratio = 0.617
Baseline 6 9 (95% CI, 0.514-0.740)

Time, month P<.001

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1. Perkove V eL al. N Eng J Mod, 2024 October 25 [Epub ahead of pit

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31. Conclusions

+ IgA nephropathy is a common form of glomerular disease worldwide
+ Mechanism of IgA nephropathy includes the Four Hit Hypothesis
+ Therapeutic options are rapidly evolving for IgA nephropathy
- Guidelines will likely be updated more frequently to reflect the new agents
+ The complement system is important in glomerular diseases

+ Iptacopan is the first complement blocker approved for IgA nephropathy

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