Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial

Jonathan Barratt; Adrian Liew; See Cheng Yeo; Anders Fernström; Sean J. Barbour; C. John Sperati; Russell Villanueva; Ming Ju Wu; Dazhe Wang; Anna Borodovsky; Prajakta Badri; Elena Yureneva; Ishir Bhan; Daniel Cattran; Anand Achanti; Milos Budisavljevic; Linda Walker; Naresh Aggarwal; Stephanie Andres; Marie Stella Navarro; Haydee Gabuay; Peter Barany; Olof Heimbürger; Ulrika Jensen Durgé; Sean Barbour; Zainab Sheriff; Paula Macleod; Jonathan Barratt; Chee Kay Cheung; Haresh Selvaskandan; Justyna Sklarzewicz; Daniel Cattran; Heather N. Reich; Paul Ling; Arenn Jauhal; Francois Chantrel; Jimmy Grellier; Camille Alzina; Jin Bor Chen; Kuan Hsing Chen; Hsiang Hao Hsu; Huang Yu Yang; Kun Hua Tu; Montserrat Diaz Encarnacion; Helena Marco Rusiñol; Luz San Miguel Amigo; Beatriz Bardaju De Quixano; Irene Silva Torres; Mario Espinosa; Isabel López-López; Rocío Regalado; Anders Fernström; Micael Gylling; Fredrik Uhlin; Fernando Fervenza; Bak Leong Goh; Fairol H. Ibrahim; Aida Azlin Alias; Tay Li Lian; Billy Hour; Tyrone Rosales; Veronica Macias; Marwan Kaskas; Antoine Lanot; Victor Gueutin; Sylvie Brucato; Eric Legrand; Julie Cabantous; Nadia Martin; Xoana Barros; Cristina Martínez; Montserrat Capdevila; Irene Rovira; Fariz Safhan Mohamad Nor; Mohd Kamil Ahmad; Wan Ahmad Syahril Rozli Wan Ali; Tze Jian Ng; Izzah Atira Hisham; Nur Liyana Kamaronzaman; Nadia Shahirah Mohamed Asri; Mohamad Haziq Abu Othman; Mohd Shahril Mohd; Olivier Moranne; Kok Peng Ng; Shok Hoon Ooi; Joan Torras Ambros; Ana Coloma; Juliana Draibe; Claudia Galofre; Stephan Troyanov; Guylaine Marcotte; Russell Villanueva; Donnah Franceska De Leon; Ming Ju Wu; Shan Lee; Rosnawati Yahya; Seow Yeing Yee; Wan Hazlina Wan Mohamad; Nurul Zaynah Nordin; Muhamad Zaimi Abdul Wahab; Zurina Che Rohani; Mohd Alfaisal Mod Baharuddin; Muhamad Nur Asswad Md Kassim; Siti Nur Zuhafifah Mohd Zaki; See Cheng Yeo; Ru Sin Lim; Siew Hwa Soh; Felicia Lee; Hongli Jiao; Rosa Lim; Kai Yan Lin; Philippe Zaoui; Pierre Louis Carron; David Tartry; Mathilde Bugnazet; Farida Imerzoukene; Florence Theo; Séverine Dhion; Meryll Argoud; Gaëlle Vial; Audrey Lehman; Thierry Romanet

doi:10.2215/CJN.0000000000000384

Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial

Jonathan Barratt, Adrian Liew, See Cheng Yeo, Anders Fernström, Sean J. Barbour, C. John Sperati, Russell Villanueva, Ming Ju Wu, Dazhe Wang, Anna Borodovsky, Prajakta Badri, Elena Yureneva, Ishir Bhan, Daniel Cattran, Anand Achanti, Milos Budisavljevic, Linda Walker, Naresh Aggarwal, Stephanie Andres, Marie Stella NavarroHaydee Gabuay, Peter Barany, Olof Heimbürger, Ulrika Jensen Durgé, Sean Barbour, Zainab Sheriff, Paula Macleod, Jonathan Barratt, Chee Kay Cheung, Haresh Selvaskandan, Justyna Sklarzewicz, Daniel Cattran, Heather N. Reich, Paul Ling, Arenn Jauhal, Francois Chantrel, Jimmy Grellier, Camille Alzina, Jin Bor Chen, Kuan Hsing Chen, Hsiang Hao Hsu, Huang Yu Yang, Kun Hua Tu, Montserrat Diaz Encarnacion, Helena Marco Rusiñol, Luz San Miguel Amigo, Beatriz Bardaju De Quixano, Irene Silva Torres, Mario Espinosa, Isabel López-López, Rocío Regalado, Anders Fernström, Micael Gylling, Fredrik Uhlin, Fernando Fervenza, Bak Leong Goh, Fairol H. Ibrahim, Aida Azlin Alias, Tay Li Lian, Billy Hour, Tyrone Rosales, Veronica Macias, Marwan Kaskas, Antoine Lanot, Victor Gueutin, Sylvie Brucato, Eric Legrand, Julie Cabantous, Nadia Martin, Xoana Barros, Cristina Martínez, Montserrat Capdevila, Irene Rovira, Fariz Safhan Mohamad Nor, Mohd Kamil Ahmad, Wan Ahmad Syahril Rozli Wan Ali, Tze Jian Ng, Izzah Atira Hisham, Nur Liyana Kamaronzaman, Nadia Shahirah Mohamed Asri, Mohamad Haziq Abu Othman, Mohd Shahril Mohd, Olivier Moranne, Kok Peng Ng, Shok Hoon Ooi, Joan Torras Ambros, Ana Coloma, Juliana Draibe, Claudia Galofre, Stephan Troyanov, Guylaine Marcotte, Russell Villanueva, Donnah Franceska De Leon, Ming Ju Wu, Shan Lee, Rosnawati Yahya, Seow Yeing Yee, Wan Hazlina Wan Mohamad, Nurul Zaynah Nordin, Muhamad Zaimi Abdul Wahab, Zurina Che Rohani, Mohd Alfaisal Mod Baharuddin, Muhamad Nur Asswad Md Kassim, Siti Nur Zuhafifah Mohd Zaki, See Cheng Yeo, Ru Sin Lim, Siew Hwa Soh, Felicia Lee, Hongli Jiao, Rosa Lim, Kai Yan Lin, Philippe Zaoui, Pierre Louis Carron, David Tartry, Mathilde Bugnazet, Farida Imerzoukene, Florence Theo, Séverine Dhion, Meryll Argoud, Gaëlle Vial, Audrey Lehman, Thierry Romanet

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

BackgroundIgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression.MethodsIn this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments.ResultsThirty-one patients were randomized (cemdisiran, N=22; placebo, N=9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%).ConclusionsThese findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.

Original language	English (US)
Pages (from-to)	452-462
Number of pages	11
Journal	Clinical Journal of the American Society of Nephrology
Volume	19
Issue number	4
DOIs	https://doi.org/10.2215/CJN.0000000000000384
State	Published - Apr 2024

Keywords

GN
IgA nephropathy

ASJC Scopus subject areas

Epidemiology
Critical Care and Intensive Care Medicine
Nephrology
Transplantation

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10.2215/CJN.0000000000000384

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Barratt, J., Liew, A., Yeo, S. C., Fernström, A., Barbour, S. J., Sperati, C. J., Villanueva, R., Wu, M. J., Wang, D., Borodovsky, A., Badri, P., Yureneva, E., Bhan, I., Cattran, D., Achanti, A., Budisavljevic, M., Walker, L., Aggarwal, N., Andres, S., ... Romanet, T. (2024). Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial. Clinical Journal of the American Society of Nephrology, 19(4), 452-462. https://doi.org/10.2215/CJN.0000000000000384

Barratt, J, Liew, A, Yeo, SC, Fernström, A, Barbour, SJ, Sperati, CJ, Villanueva, R, Wu, MJ, Wang, D, Borodovsky, A, Badri, P, Yureneva, E, Bhan, I, Cattran, D, Achanti, A, Budisavljevic, M, Walker, L, Aggarwal, N, Andres, S, Navarro, MS, Gabuay, H, Barany, P, Heimbürger, O, Durgé, UJ, Barbour, S, Sheriff, Z, Macleod, P, Barratt, J, Cheung, CK, Selvaskandan, H, Sklarzewicz, J, Cattran, D, Reich, HN, Ling, P, Jauhal, A, Chantrel, F, Grellier, J, Alzina, C, Chen, JB, Chen, KH, Hsu, HH, Yang, HY, Tu, KH, Encarnacion, MD, Rusiñol, HM, San Miguel Amigo, L, Bardaju De Quixano, B, Torres, IS, Espinosa, M, López-López, I, Regalado, R, Fernström, A, Gylling, M, Uhlin, F, Fervenza, F, Goh, BL, Ibrahim, FH, Alias, AA, Lian, TL, Hour, B, Rosales, T, Macias, V, Kaskas, M, Lanot, A, Gueutin, V, Brucato, S, Legrand, E, Cabantous, J, Martin, N, Barros, X, Martínez, C, Capdevila, M, Rovira, I, Mohamad Nor, FS, Ahmad, MK, Syahril Rozli Wan Ali, WA, Ng, TJ, Atira Hisham, I, Kamaronzaman, NL, Mohamed Asri, NS, Abu Othman, MH, Mohd, MS, Moranne, O, Ng, KP, Ooi, SH, Ambros, JT, Coloma, A, Draibe, J, Galofre, C, Troyanov, S, Marcotte, G, Villanueva, R, De Leon, DF, Wu, MJ, Lee, S, Yahya, R, Yee, SY, Wan Mohamad, WH, Nordin, NZ, Abdul Wahab, MZ, Rohani, ZC, Mod Baharuddin, MA, Asswad Md Kassim, MN, Zuhafifah Mohd Zaki, SN, Yeo, SC, Lim, RS, Soh, SH, Lee, F, Jiao, H, Lim, R, Lin, KY, Zaoui, P, Carron, PL, Tartry, D, Bugnazet, M, Imerzoukene, F, Theo, F, Dhion, S, Argoud, M, Vial, G, Lehman, A & Romanet, T 2024, 'Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial', Clinical Journal of the American Society of Nephrology, vol. 19, no. 4, pp. 452-462. https://doi.org/10.2215/CJN.0000000000000384

@article{f5d9c77fc4c44e0eb3f5a5999a79422e,

title = "Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial",

abstract = "BackgroundIgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression.MethodsIn this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments.ResultsThirty-one patients were randomized (cemdisiran, N=22; placebo, N=9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%).ConclusionsThese findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.",

keywords = "GN, IgA nephropathy",

author = "Jonathan Barratt and Adrian Liew and Yeo, {See Cheng} and Anders Fernstr{\"o}m and Barbour, {Sean J.} and Sperati, {C. John} and Russell Villanueva and Wu, {Ming Ju} and Dazhe Wang and Anna Borodovsky and Prajakta Badri and Elena Yureneva and Ishir Bhan and Daniel Cattran and Anand Achanti and Milos Budisavljevic and Linda Walker and Naresh Aggarwal and Stephanie Andres and Navarro, {Marie Stella} and Haydee Gabuay and Peter Barany and Olof Heimb{\"u}rger and Durg{\'e}, {Ulrika Jensen} and Sean Barbour and Zainab Sheriff and Paula Macleod and Jonathan Barratt and Cheung, {Chee Kay} and Haresh Selvaskandan and Justyna Sklarzewicz and Daniel Cattran and Reich, {Heather N.} and Paul Ling and Arenn Jauhal and Francois Chantrel and Jimmy Grellier and Camille Alzina and Chen, {Jin Bor} and Chen, {Kuan Hsing} and Hsu, {Hsiang Hao} and Yang, {Huang Yu} and Tu, {Kun Hua} and Encarnacion, {Montserrat Diaz} and Rusi{\~n}ol, {Helena Marco} and {San Miguel Amigo}, Luz and {Bardaju De Quixano}, Beatriz and Torres, {Irene Silva} and Mario Espinosa and Isabel L{\'o}pez-L{\'o}pez and Roc{\'i}o Regalado and Anders Fernstr{\"o}m and Micael Gylling and Fredrik Uhlin and Fernando Fervenza and Goh, {Bak Leong} and Ibrahim, {Fairol H.} and Alias, {Aida Azlin} and Lian, {Tay Li} and Billy Hour and Tyrone Rosales and Veronica Macias and Marwan Kaskas and Antoine Lanot and Victor Gueutin and Sylvie Brucato and Eric Legrand and Julie Cabantous and Nadia Martin and Xoana Barros and Cristina Mart{\'i}nez and Montserrat Capdevila and Irene Rovira and {Mohamad Nor}, {Fariz Safhan} and Ahmad, {Mohd Kamil} and {Syahril Rozli Wan Ali}, {Wan Ahmad} and Ng, {Tze Jian} and {Atira Hisham}, Izzah and Kamaronzaman, {Nur Liyana} and {Mohamed Asri}, {Nadia Shahirah} and {Abu Othman}, {Mohamad Haziq} and Mohd, {Mohd Shahril} and Olivier Moranne and Ng, {Kok Peng} and Ooi, {Shok Hoon} and Ambros, {Joan Torras} and Ana Coloma and Juliana Draibe and Claudia Galofre and Stephan Troyanov and Guylaine Marcotte and Russell Villanueva and {De Leon}, {Donnah Franceska} and Wu, {Ming Ju} and Shan Lee and Rosnawati Yahya and Yee, {Seow Yeing} and {Wan Mohamad}, {Wan Hazlina} and Nordin, {Nurul Zaynah} and {Abdul Wahab}, {Muhamad Zaimi} and Rohani, {Zurina Che} and {Mod Baharuddin}, {Mohd Alfaisal} and {Asswad Md Kassim}, {Muhamad Nur} and {Zuhafifah Mohd Zaki}, {Siti Nur} and Yeo, {See Cheng} and Lim, {Ru Sin} and Soh, {Siew Hwa} and Felicia Lee and Hongli Jiao and Rosa Lim and Lin, {Kai Yan} and Philippe Zaoui and Carron, {Pierre Louis} and David Tartry and Mathilde Bugnazet and Farida Imerzoukene and Florence Theo and S{\'e}verine Dhion and Meryll Argoud and Ga{\"e}lle Vial and Audrey Lehman and Thierry Romanet",

year = "2024",

month = apr,

doi = "10.2215/CJN.0000000000000384",

language = "English (US)",

volume = "19",

pages = "452--462",

journal = "Clinical Journal of the American Society of Nephrology",

issn = "1555-9041",

publisher = "American Society of Nephrology",

number = "4",

}

TY - JOUR

T1 - Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy

T2 - A Randomized Controlled Trial

AU - Barratt, Jonathan

AU - Liew, Adrian

AU - Yeo, See Cheng

AU - Fernström, Anders

AU - Barbour, Sean J.

AU - Sperati, C. John

AU - Villanueva, Russell

AU - Wu, Ming Ju

AU - Wang, Dazhe

AU - Borodovsky, Anna

AU - Badri, Prajakta

AU - Yureneva, Elena

AU - Bhan, Ishir

AU - Cattran, Daniel

AU - Achanti, Anand

AU - Budisavljevic, Milos

AU - Walker, Linda

AU - Aggarwal, Naresh

AU - Andres, Stephanie

AU - Navarro, Marie Stella

AU - Gabuay, Haydee

AU - Barany, Peter

AU - Heimbürger, Olof

AU - Durgé, Ulrika Jensen

AU - Barbour, Sean

AU - Sheriff, Zainab

AU - Macleod, Paula

AU - Barratt, Jonathan

AU - Cheung, Chee Kay

AU - Selvaskandan, Haresh

AU - Sklarzewicz, Justyna

AU - Cattran, Daniel

AU - Reich, Heather N.

AU - Ling, Paul

AU - Jauhal, Arenn

AU - Chantrel, Francois

AU - Grellier, Jimmy

AU - Alzina, Camille

AU - Chen, Jin Bor

AU - Chen, Kuan Hsing

AU - Hsu, Hsiang Hao

AU - Yang, Huang Yu

AU - Tu, Kun Hua

AU - Encarnacion, Montserrat Diaz

AU - Rusiñol, Helena Marco

AU - San Miguel Amigo, Luz

AU - Bardaju De Quixano, Beatriz

AU - Torres, Irene Silva

AU - Espinosa, Mario

AU - López-López, Isabel

AU - Regalado, Rocío

AU - Fernström, Anders

AU - Gylling, Micael

AU - Uhlin, Fredrik

AU - Fervenza, Fernando

AU - Goh, Bak Leong

AU - Ibrahim, Fairol H.

AU - Alias, Aida Azlin

AU - Lian, Tay Li

AU - Hour, Billy

AU - Rosales, Tyrone

AU - Macias, Veronica

AU - Kaskas, Marwan

AU - Lanot, Antoine

AU - Gueutin, Victor

AU - Brucato, Sylvie

AU - Legrand, Eric

AU - Cabantous, Julie

AU - Martin, Nadia

AU - Barros, Xoana

AU - Martínez, Cristina

AU - Capdevila, Montserrat

AU - Rovira, Irene

AU - Mohamad Nor, Fariz Safhan

AU - Ahmad, Mohd Kamil

AU - Syahril Rozli Wan Ali, Wan Ahmad

AU - Ng, Tze Jian

AU - Atira Hisham, Izzah

AU - Kamaronzaman, Nur Liyana

AU - Mohamed Asri, Nadia Shahirah

AU - Abu Othman, Mohamad Haziq

AU - Mohd, Mohd Shahril

AU - Moranne, Olivier

AU - Ng, Kok Peng

AU - Ooi, Shok Hoon

AU - Ambros, Joan Torras

AU - Coloma, Ana

AU - Draibe, Juliana

AU - Galofre, Claudia

AU - Troyanov, Stephan

AU - Marcotte, Guylaine

AU - Villanueva, Russell

AU - De Leon, Donnah Franceska

AU - Wu, Ming Ju

AU - Lee, Shan

AU - Yahya, Rosnawati

AU - Yee, Seow Yeing

AU - Wan Mohamad, Wan Hazlina

AU - Nordin, Nurul Zaynah

AU - Abdul Wahab, Muhamad Zaimi

AU - Rohani, Zurina Che

AU - Mod Baharuddin, Mohd Alfaisal

AU - Asswad Md Kassim, Muhamad Nur

AU - Zuhafifah Mohd Zaki, Siti Nur

AU - Yeo, See Cheng

AU - Lim, Ru Sin

AU - Soh, Siew Hwa

AU - Lee, Felicia

AU - Jiao, Hongli

AU - Lim, Rosa

AU - Lin, Kai Yan

AU - Zaoui, Philippe

AU - Carron, Pierre Louis

AU - Tartry, David

AU - Bugnazet, Mathilde

AU - Imerzoukene, Farida

AU - Theo, Florence

AU - Dhion, Séverine

AU - Argoud, Meryll

AU - Vial, Gaëlle

AU - Lehman, Audrey

AU - Romanet, Thierry

PY - 2024/4

Y1 - 2024/4

N2 - BackgroundIgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression.MethodsIn this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments.ResultsThirty-one patients were randomized (cemdisiran, N=22; placebo, N=9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%).ConclusionsThese findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.

AB - BackgroundIgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression.MethodsIn this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments.ResultsThirty-one patients were randomized (cemdisiran, N=22; placebo, N=9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%).ConclusionsThese findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.

KW - GN

KW - IgA nephropathy

UR - http://www.scopus.com/inward/record.url?scp=85186886444&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85186886444&partnerID=8YFLogxK

U2 - 10.2215/CJN.0000000000000384

DO - 10.2215/CJN.0000000000000384

M3 - Article

C2 - 38214599

AN - SCOPUS:85186886444

SN - 1555-9041

VL - 19

SP - 452

EP - 462

JO - Clinical Journal of the American Society of Nephrology

JF - Clinical Journal of the American Society of Nephrology

IS - 4

ER -

Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial

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