Estuary Biotherapeutics, Inc., a biotechnology company developing genetic medicines for patients with serious kidney diseases, today announced its launch with $103 million in total committed financing. The $93 million Series A was led by RA Capital Management and included participation from Deep Track Capital, Biogen New Ventures, UPMC Enterprises, Pivotal bioVenture Partners, the National Kidney Foundation Innovation Fund and a family office connected to an individual living with autosomal dominant polycystic kidney disease (ADPKD). 4BIO Capital and GV, which co-led the company’s $10 million seed financing, also participated in the Series A.

Proceeds from the financing will support advancement of the company’s two lead programs, EST-201 and EST-101, through clinical proof of concept and to further develop its kidney-targeting platform. Estuary’s lead programs are uniquely designed to target the most common genetic subtypes of ADPKD, an inherited, lifelong, progressive disease characterized by the growth of cysts in both kidneys. Over time, these cysts enlarge, displacing functioning tissue until the organs fail, requiring dialysis or transplant.

“ADPKD is one of the world’s most common genetic diseases, yet patients are still awaiting a therapy that can transform the course of their disease,” said Wayne Sackett, co-founder and CEO of Estuary. “We paired our scientific co-founders’ landmark breakthroughs in disease biology with a dedicated and passionate team focused on solving the most crucial remaining barrier to kidney gene therapy: delivery. By pioneering fit-for-purpose local administration and an efficient global development strategy, our team is moving with urgency to bring these important medicines into the clinic.”

“Estuary’s programs have the potential to transform the care of patients with ADPKD,” said Emily Minkow, managing director, RA Capital Management. “The differentiated approach pairs a known gene therapy modality with focal, kidney-directed delivery designed to reach the nephron directly. Combined with compelling science demonstrating the potential to reverse disease, we believe this approach could fundamentally change what is possible for patients, and we are excited to support the team as it advances toward the clinic.”

Genetic Medicines Built on Groundbreaking ADPKD Research

Estuary’s programs build on groundbreaking research from its scientific co-founders, Dr. Stefan Somlo and Dr. Michael Caplan of Yale School of Medicine.

Dr. Somlo established the in vivo reversal biology underlying Estuary’s approach, demonstrating that restoring polycystin expression in kidneys with established cystic disease can reverse both the structural and functional hallmarks of disease in mice.1 Dr. Caplan further demonstrated that a compact functional region of the polycystin-1 (PC1) protein is sufficient to suppress cystic disease in mice, providing the scientific basis for an adeno-associated virus (AAV)-based approach to ADPKD-PKD1.2

Together, these watershed discoveries have redefined what’s possible from a therapeutic standpoint: moving beyond slowing disease progression to potentially halting or reversing it, with distinct therapies that have the potential to treat all patients with a given genetic mutation. Alongside Drs. Somlo and Caplan, Estuary is advancing locally delivered genetic medicines for ADPKD, starting with its two lead programs:

  • EST-201: a full-length PKD2 gene therapy delivered through AAV, which will be evaluated in patients with ADPKD with a PKD2 mutation and is anticipated to enter the clinic in 2027.

  • EST-101: a gene therapy delivering a PC1-derived functional region via the same AAV as EST-201. EST-101 will be evaluated in patients with ADPKD with a PKD1 mutation and is anticipated to enter the clinic in 2028.

While other ADPKD therapies target pathways downstream of the causal biology, EST-201 and EST-101 are designed to address the underlying genetic root cause directly, using a potentially one-time, locally delivered AAV to transduce individual kidney epithelial cells, with the goal of restoring polycystin protein levels across the entire nephron. This kidney-confined approach is designed to avoid many of the challenges that have complicated the overall risk-benefit profile of systemically delivered AAV gene therapies to date. Further, Estuary plans to extend its leadership position by further expanding its pipeline to target both monogenic and common kidney diseases.

Owen Smith, partner at 4BIO Capital, said: “4BIO exists to back companies developing breakthrough therapies that can change the course of disease for patients who lack good options. Having partnered with Estuary early in its lifecycle by co-leading the company’s seed financing and helping shape the initial business plan, we have seen firsthand how effectively the team has translated ambitious science into a focused development strategy. In a short period, Estuary has generated strong data, advanced both programs materially and built the organization needed for the next stage. We are excited to continue supporting the company in the Series A funding as its lead program moves toward the clinic.”

Leaders in Kidney Disease Drug Development and Innovation

Estuary is led by a mission-driven team combining deep genetic medicine, kidney biology and drug development experience in service of patients:

Management Team

  • Wayne Sackett, Chief Executive Officer and Co-founder

  • Jeremy Duffield, M.D., Ph.D., Chief Scientific Officer

  • Uptal Patel, M.D., Chief Medical Officer

  • Christopher Morrison, Ph.D., Senior Vice President, CMC

  • Kiley Keelin, M.S., Head of Regulatory

Co-founders

  • Michael Caplan, M.D., Ph.D., C.N.H. Long Professor and Chair of Cellular and Molecular Physiology, Yale School of Medicine

  • Stefan Somlo, M.D., C.N.H. Long Professor of Medicine and Genetics and Professor of Nephrology, Yale School of Medicine; Member, National Academy of Sciences

  • Xavier Anguela, Ph.D., Vice President, Gene Therapy, Eli Lilly; prior scientific leadership roles at Nava Therapeutics, AskBio (acquired by Bayer) and Spark Therapeutics (acquired by Roche)

  • Wayne Sackett, CEO

Board of Directors

  • Jake Bauer, Independent Director and Chair

  • Emily Minkow, Managing Director, RA Capital Management

  • Owen Smith, Partner, 4BIO Capital

  • Wayne Sackett, Co-founder and CEO

Advisers

  • Jeff Marrazzo, Founding Adviser; Co-founder and former founding CEO of Spark Therapeutics; developed LUXTURNA, the first FDA-approved gene therapy for an inherited disease

  • Karen Kozarsky, Ph.D., Chief Scientific Adviser; AAV gene therapy pioneer with over three decades of experience; previously at SwanBio, REGENXBIO and GSK

  • Vijay Modur, M.D., Ph.D., Senior Medical Adviser; seasoned clinical development professional who led the venglustat program for ADPKD at Sanofi

  • Frank Czerwiec, M.D., Ph.D., Co-director of the PKD Outcomes Consortium; led the clinical development of tolvaptan (JYNARQUE), the only FDA-approved ADPKD therapy

  • Lou Brenner, M.D., MBA, practicing nephrologist at Mass General Brigham; serial renal biotech executive; developed RENVELA and FERAHEME

  • Matthew Breyer, M.D., former distinguished scientist at Janssen, CSO of Lead Generation Biotechnology Discovery Research at Eli Lilly, and Professor of Nephrology at Vanderbilt

About Autosomal Dominant Polycystic Kidney Disease (ADPKD)

ADPKD is the most common inherited kidney disease, affecting more than eight million people worldwide and representing the fourth most common cause of kidney replacement therapy globally. ADPKD is a monogenic disease caused in more than 90% of patients by mutations in one of two genes, PKD1 or PKD2, which result in the formation and progressive growth of fluid-filled cysts that damage surrounding nephrons and can ultimately lead to end-stage kidney disease (ESKD) requiring dialysis and transplantation.3 Current standard of care has been shown to slow kidney growth and function decline,4,5 and has defined the endpoints and patient segmentation for efficient clinical trials, establishing a strong foundation for next-generation therapies designed to potentially treat the underlying cause of ADPKD.

While PKD2 mutations overall have been associated with later disease onset, patients with rapidly progressing ADPKD-PKD2, based on Mayo Imaging Classification score,6 have disease trajectories nearly identical to rapidly progressing patients with ADPKD-PKD1, underscoring the significant unmet need in both populations.7,8 In the U.S., there are approximately 10,000–15,000 patients with rapidly progressing ADPKD-PKD2 and 100,000–140,000 patients with rapidly progressing ADPKD-PKD1, representing the potential initial treatment populations for EST-201 and EST-101, respectively.

References:

  1. Dong K, Zhang C, Tian X, Coman D, Hyder F, Ma M, Somlo S. Renal plasticity revealed through reversal of polycystic kidney disease in mice. Nat Genet. 2021 Dec;53(12):1649-1663.

  2. Onuchic L, Padovano V, Schena G, Rajendran V, Dong K, Shi X, Pandya R, Rai V, Gresko NP, Ahmed O, Lam TT, Wang W, Shen H, Somlo S, Caplan MJ. The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion. Nat Commun. 2023 Mar 30;14(1):1790.

  3. Torres VE, Ahn C, Barten TRM, Brosnahan G, Cadnapaphornchai MA, Chapman AB, Cornec-Le Gall E, Drenth JPH, Gansevoort RT, Harris PC, Harris T, Horie S, Liebau MC, Liew M, Mallett AJ, Mei C, Mekahli D, Odland D, Ong ACM, Onuchic LF, Pei YP, Perrone RD, Rangan GK, Rayner B, Torra R, Balk EM, Gordon CE, Earley A, Mustafa RA, Devuyst O. KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of autosomal dominant polycystic kidney disease (ADPKD): executive summary. Kidney Int. 2025 Feb;107(2):234-254.

  4. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407-18.

  5. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O; REPRISE Trial Investigators. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2017 Nov 16;377(20):1930-1942.

  6. Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, Bae KT, Chapman AB, Grantham JJ, Mrug M, Hogan MC, El-Zoghby ZM, Harris PC, Erickson BJ, King BF, Torres VE; CRISP Investigators. Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol. 2015 Jan;26(1):160-72.

  7. Yu ASL, Shen C, Landsittel DP, Grantham JJ, Cook LT, Torres VE, Chapman AB, Bae KT, Mrug M, Harris PC, Rahbari-Oskoui FF, Shi T, Bennett WM; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). Long-term trajectory of kidney function in autosomal-dominant polycystic kidney disease. Kidney Int. 2019 May;95(5):1253-1261.

  8. Lavu S, Vaughan LE, Senum SR, Kline TL, Chapman AB, Perrone RD, Mrug M, Braun WE, Steinman TI, Rahbari-Oskoui FF, Brosnahan GM, Bae KT, Landsittel D, Chebib FT, Yu AS, Torres VE; HALT PKD and CRISP Study Investigators; Harris PC. The value of genotypic and imaging information to predict functional and structural outcomes in ADPKD. JCI Insight. 2020 Aug 6;5(15):e138724.

 

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