A Randomized, Double-blind, Placebo-controlled, Crossover Study of Atrasentan in Subjects With IgA Nephropathy on Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i)

The ASSIST study is a phase 2, double-blind, placebo-controlled crossover study to evaluate the safety and efficacy of atrasentan vs. placebo in subjects with IgA nephropathy (IgAN) while on background standard of care therapy and an SGLT2 inhibitor (SGLT2i).

Start Date20 Jul 2023

Sponsor / Collaborator

Chinook Therapeutics, Inc.

CTRI/2022/06/043396 / RecruitingPhase 3

A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Atrasentan in Patients with IgA Nephropathy at Risk of Progressive Loss of Renal Function.(The ALIGN Study)

Start Date15 Jul 2022

Sponsor / Collaborator

Chinook Therapeutics, Inc.

[+1]

CTR20212405 / Active, not recruitingPhase 3

一项将Atrasentan用于治疗存在进行性肾功能丧失风险的IgA肾病患者的III期、随机、双盲、安慰剂对照研究（ALIGN研究）

[Translation] A phase III, randomized, double-blind, placebo-controlled study of atrasentan in patients with IgA nephropathy at risk of progressive renal function loss (ALIGN study)

比较Atrasentan与安慰剂在存在进行性肾功能丧失风险的IgAN受试者中的疗效和安全性；主要评估第24周时Atrasentan与安慰剂对蛋白尿水平的影响；次要评估评估Atrasentan与安慰剂从基线到第136周（随机治疗停止后4周）对估算肾小球滤过率(eGFR)变化的影响；比较Atrasentan与安慰剂之间的eGFR 2年期治疗变化率（从随机治疗第12周到第120周的eGFR斜率）；比较Atrasentan和安慰剂之间的eGFR总研究变化率（从基线到第136周的eGFR斜率）以及确定Atrasentan与安慰剂相比的安全性和耐受性特征。探索性评估与安慰剂相比，接受Atrasentan的受试者的生活质量(QOL)；Atrasentan的稳态药代动力学(PK)，为探索性暴露-反应分析提供支持；评估疾病生物标志物的变化以及其他安全性结局。

[Translation]

Compare the efficacy and safety of Atrasentan versus placebo in IgAN subjects at risk of progressive renal function loss; Primary assessment of the effect of Atrasentan versus placebo on proteinuria levels at Week 24; Secondary assessments to evaluate the effect of Atrasentan versus placebo on the change in estimated glomerular filtration rate (eGFR) from baseline to Week 136 (4 weeks after cessation of randomized treatment); Compare the 2-year treatment change rate of eGFR between Atrasentan and placebo (eGFR slope from Week 12 of randomized treatment to Week 120); Compare the overall study change rate of eGFR between Atrasentan and placebo (eGFR slope from baseline to Week 136) and determine the safety and tolerability profile of Atrasentan compared to placebo. Exploratory assessment of the quality of life (QOL) of subjects receiving Atrasentan compared to placebo; Steady-state pharmacokinetics (PK) of Atrasentan to support exploratory exposure-response analysis; Assess changes in disease biomarkers and other safety outcomes.

Start Date08 Jan 2022

Sponsor / Collaborator

Chinook Therapeutics U.S., Inc.

[+4]

100 Clinical Results associated with Atrasentan

100 Translational Medicine associated with Atrasentan

100 Patents (Medical) associated with Atrasentan

397

Literatures (Medical) associated with Atrasentan

01 Nov 2024·BRITISH JOURNAL OF PHARMACOLOGY

The role of venous capacity in fluid retention with endothelin A antagonism: Mathematical modelling of the RADAR trial

Article

Author: Hallow, K. Melissa ; Ahlstrom, Christine ; Greasley, Peter J. ; Ambery, Philip ; Hamren, Bengt ; Yu, Hongtao ; Boulton, David W. ; Khan, Anis A. ; Lambers Heerspink, Hiddo J.

Abstract:

Background and Purpose:

Endothelin‐1 (ET‐1) receptor A (ETA) antagonists reduce proteinuria and prevent renal outcomes in chronic kidney disease (CKD) patients, but their utility has been limited because of associated fluid retention, resulting in increased heart failure risk. Understanding the mechanisms responsible for fluid retention could result in solutions that preserve renoprotective effects while mitigating fluid retention, but the complexity of the endothelin system has made identification of the underlying mechanisms challenging.

Approach:

We utilized a previously developed mathematical model of ET‐1 kinetics, ETA receptor antagonism, kidney function, haemodynamics, and sodium and water homeostasis to evaluate hypotheses for mechanisms of fluid retention with ETA antagonism. To do this, we simulated the RADAR clinical trial of atrasentan in patients with type 2 diabetes and CKD and evaluated the ability of the model to predict the observed decreases in haematocrit, urine albumin creatinine ratio (UACR), mean arterial pressure (MAP), and estimated glomerular filtration rate (eGFR).

Background and Key Results:

An effect of ETA antagonism on venodilation and increased venous capacitance was found to be the critical mechanism necessary to reproduce the simultaneous decrease in both MAP and haematocrit observed in RADAR.

Conclusions and Impact:

These findings indicate that fluid retention with ETA antagonism may not be caused by a direct antidiuretic effect within the kidney but is instead be an adaptive response to venodilation and increased venous capacity, which acutely tends to reduce cardiac filling pressure and cardiac output, and that fluid retention occurs in an attempt to maintain cardiac filling and cardiac output.

01 Oct 2024·KIDNEY INTERNATIONAL

Clinical trial designs to assess treatment effects on glomerular filtration rate decline

Article

Author: Little, Dustin J ; Postmus, Douwe ; Gasparyan, Samvel B ; Frison, Lars ; Heerspink, Hiddo J L ; Wanner, Christoph ; Jongs, Niels

Glomerular filtration rate (GFR) decline is used as surrogate endpoint for kidney failure. Interventions that reduce chronic kidney disease (CKD) progression often exert acute GFR reductions which differ from their long-term benefits and complicate the estimation of long-term benefit. Here, we assessed the utility of two alternative trial designs (wash-out design and active run-in randomized withdrawal design) that attempt to exclude the impact of acute effects. Post-hoc analyses of two clinical trials that characterized the effect of an intervention with acute reductions in GFR were conducted. The two trials included a wash-out period (EMPA-REG Outcome testing empagliflozin vs placebo) or an active run-in period with a randomized withdrawal (SONAR testing atrasentan vs placebo). We compared the drug effect on GFR decline calculated from the first on-treatment visit to the end of treatment (chronic slope in a standard randomized trial design) with GFR change calculated from randomization to end of wash out, or GFR change from treatment-specific baseline GFR values (GFR at start-of-run-in for placebo and end-of-run-in for atrasentan) until end-of-treatment. The effect of empagliflozin versus placebo on chronic GFR slope was 1.72 (95% confidence interval 1.49-1.94) mL/min/1.73 m²/year, similar to total GFR decline from baseline to the end of wash-out period using a linear mixed model 1.64 (1.44-1.85) mL/min/1.73 m²/year). The effect of atrasentan versus placebo on chronic GFR slope was 0.72 (0.32-1.11) mL/min/1.73 m²/year, similar to total slope from a single slope model when estimated from treatment specific baseline GFR values 0.77 (0.39-1.14) mL/min/1.73 m²/year). Statistical power of the two designs outperformed the standard randomized design. Thus, wash-out and active-run-in randomized-withdrawal trial designs are appropriate models to compute treatment effects on GFR decline.

01 Sep 2024·NEPHROLOGY

The role of endothelin receptor antagonists in IgA nephropathy

Review

Author: Wong, Muh Geot ; Hunter‐Dickson, Mitchell

Abstract:

There is growing evidence of endothelin receptor antagonists (ERAs) in renoprotection in proteinuric kidney disease including IgA nephropathy (IgAN). Here, we review current evidence, including the use of sparsentan, atrasentan and zibotentan in IgAN. Recent trails of combination therapy including SGLT2 inhibitors and ERAs suggest possible benefit in further reduction of proteinuria and reducing ERA fluid‐retention side effects although more evidence is needed for clinical applications.

117

News (Medical) associated with Atrasentan

26 Oct 2024

·www.prnewswire.com

Novartis oral Fabhalta® (iptacopan) sustained clinically meaningful results at one year in Phase III C3 glomerulopathy (C3G) trial

New APPEAR-C3G data show Fabhalta sustained proteinuria reduction at 12 months1 Upon Fabhalta initiation, improvement observed in estimated glomerular filtration rate (eGFR) slope – a key measure of kidney function – vs. patients' historic rapid decline1 Fabhalta also showed a favorable safety profile with no new safety signals1 Fabhalta is the only oral alternative complement pathway inhibitor to selectively target the underlying cause of C3G, an ultra-rare kidney disease with no approved treatments2-5 Novartis continues to advance multi-asset renal portfolio; C3G regulatory submissions completed in EU, China and Japan, and expected in US by year-end EAST HANOVER, N.J., Oct. 26, 2024 /PRNewswire/ -- Novartis today presented 12-month data from the Phase III APPEAR-C3G study at American Society of Nephrology (ASN) Kidney Week 2024 showing that patients with C3 glomerulopathy (C3G) treated with oral Fabhalta® (iptacopan) in addition to supportive care experienced clinically meaningful, sustained results at one year.1 These data confirm treatment with Fabhalta resulted in clinically meaningful proteinuria reduction, which was seen as early as 14 days, and sustained at 12 months. Similarly, in an open-label period of the study, proteinuria reduction was seen in participants who were switched to Fabhalta. In addition, improvement in estimated glomerular filtration rate (eGFR) slope was observed upon Fabhalta initiation compared to patients' historic rapid decline based on results from a prespecified exploratory analysis. Fabhalta showed a favorable safety profile, with no new safety signals.1 APPEAR-C3G evaluated the efficacy and safety of twice-daily oral Fabhalta in adult patients with C3G. The study was comprised of a 6-month randomized, double-blind treatment period with Fabhalta compared to placebo, followed by an additional 6-month open-label treatment period where all participants received Fabhalta.1 Results previously presented at the 2024 European Renal Association (ERA) Congress demonstrated a statistically significant and clinically meaningful 35.1% proteinuria reduction vs. placebo on top of supportive care at 6 months.6 Longer-term data show sustained results with oral Fabhalta "As a clinician treating young people living with C3G, I see firsthand the challenges with therapies used to treat this condition today, underscoring the vital need for dedicated treatment for these patients," said Carla Nester, M.D., M.S.A., F.A.S.N., Professor of Pediatrics-Nephrology at the University of Iowa and APPEAR-C3G Co-Investigator. "I am encouraged to see these data, which reinforce the clinically meaningful impact on kidney health measures we saw at 6 months. As the only oral complement inhibitor intended to treat C3G, Fabhalta could provide new hope for people living with this condition." "These results mark an important milestone for the management of C3G, as the first study to shed light on longer-term treatment targeting the underlying mechanism of this disease via the alternative complement pathway," said Andrew Bomback, M.D., M.P.H., Associate Professor of Medicine at Columbia University Irving Medical Center and APPEAR-C3G Co-Investigator and Steering Committee Member. "I am optimistic that these iptacopan APPEAR-C3G findings bring us a step closer to revolutionizing the treatment paradigm in this ultra-rare disease with no approved therapies." Approximately 50% of C3G patients progress to kidney failure within 10 years of diagnosis, at which point they require lifelong dialysis and/or kidney transplantation.4,7 Fabhalta, the only oral Factor B inhibitor of the alternative complement pathway, has potential to be the first US Food and Drug Administration (FDA) approved treatment for C3G.2,4,5 Regulatory submissions for Fabhalta in C3G are completed in the EU, China and Japan, and expected in US by year-end. Transforming patient care in kidney disease "We are thrilled to share these data, which demonstrate the potential of Fabhalta in C3G, and look forward to working with regulatory authorities with the goal of bringing this innovative medicine to this patient community," said David Soergel, M.D., Global Head, Cardiovascular, Renal and Metabolism Development Unit, Novartis. "Building on the longstanding experience of Novartis in nephrology and our first rare kidney disease approval in IgA nephropathy earlier this year, these results in C3G show continued advancement of our broad, industry-leading portfolio, which aims to transform care for these patients." Fabhalta, discovered at Novartis, received FDA approval in December 2023 for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH) and accelerated approval in August 2024 for the reduction of proteinuria in certain adults with primary IgA nephropathy (IgAN).2 Fabhalta is being studied in a broad range of rare kidney diseases, including C3G, atypical hemolytic uremic syndrome (aHUS), immune complex membranoproliferative glomerulonephritis (IC-MPGN) and lupus nephritis (LN). Studies are ongoing to evaluate the safety and efficacy profiles in these investigational indications and support potential regulatory submissions. In addition to Fabhalta, Novartis is advancing the late-stage development of two additional IgAN therapies with highly differentiated mechanisms of action: atrasentan, an investigational oral endothelin A receptor antagonist that received FDA filing acceptance in Q2 2024, and zigakibart, an investigational subcutaneously administered anti-APRIL monoclonal antibody that is currently in Phase III development. A conference call to update investors on the Novartis renal portfolio will take place on Monday, October 28, 2024, at 8:00 am ET. Details can be found at Event calendar | Novartis. About APPEAR-C3G APPEAR-C3G (NCT04817618) is a Phase III multicenter, randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy and safety of twice-daily oral Fabhalta (200 mg) in C3G patients. The study comprises a 6-month double-blind period in which adult patients were randomized 1:1 to receive Fabhalta or placebo on top of supportive care, followed by a 6-month open-label period in which all patients receive Fabhalta (including those who were previously on placebo). The primary endpoint for the double-blind period was proteinuria reduction from baseline at 6 months for Fabhalta compared to placebo as measured by 24-hour urine protein to creatinine ratio (UPCR).1,8 In addition to the results from adult patients with C3G, enrollment is ongoing in a separate cohort of adolescent patients with C3G.8 The majority of treatment-emergent adverse events (TEAEs) over the 12-month study period were mild to moderate in severity and there were no deaths, no cases of meningitis and/or meningococcal sepsis and no discontinuations due to TEAEs.1 About C3 glomerulopathy (C3G) C3G is an ultra-rare, progressive kidney disease that initially presents mostly in children and young adults.3,4,9 Each year, approximately 1-2 people per million worldwide are newly diagnosed with C3G, a form of membranoproliferative glomerulonephritis (MPGN).3 In C3G, overactivation of the alternative complement pathway – part of the immune system – causes deposits of C3 protein to build up in kidney glomeruli, which are a network of blood vessels that filter waste and remove extra fluids from the blood.9,10 This triggers inflammation and glomerular damage that results in proteinuria (protein in urine), hematuria (blood in urine) and reduced kidney function.9,11 Indication FABHALTA® (iptacopan) is a prescription medicine used to reduce protein in the urine (proteinuria) in adults with primary immunoglobulin A nephropathy (IgAN), who are at risk of their disease progressing quickly. It is not known if FABHALTA is safe and effective in children with IgAN. FABHALTA has been approved based on a reduction of proteinuria. Continued approval may require results from an ongoing study to determine whether FABHALTA slows decline in kidney function. Important Safety Information FABHALTA is a medicine that affects part of the immune system and may lower one's ability to fight infections. FABHALTA increases the chance of getting serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. These serious infections may quickly become life-threatening or fatal if not recognized and treated early. Patients must complete or update vaccinations against Streptococcus pneumoniae and Neisseria meningitidis at least 2 weeks before the first dose of FABHALTA. If patients have not completed vaccinations and FABHALTA therapy must be started right away, they should receive the required vaccinations as soon as possible. If patients have not been vaccinated and FABHALTA must be started right away, they should also receive antibiotics to take for as long as their doctor tells them. If patients have been vaccinated against these bacteria in the past, they might need additional vaccinations before starting FABHALTA. Their doctor will decide if they need additional vaccinations. Vaccines do not prevent all infections caused by encapsulated bacteria. Patients should call their doctor or get emergency medical care right away if they have any of these signs and symptoms of a serious infection: fever with or without shivers or chills, fever with chest pain and cough, fever with high heart rate, headache and fever, confusion, clammy skin, fever and a rash, fever with breathlessness or fast breathing, headache with nausea or vomiting, headache with stiff neck or stiff back, body aches with flu-like symptoms, or eyes sensitive to light. Doctors will give their patients a Patient Safety Card about the risk of serious infections. Patients must carry it with them at all times during treatment and for 2 weeks after their last dose of FABHALTA. The risk of serious infections may continue for a few weeks after their last dose of FABHALTA. It is important for patients to show this card to any doctor who treats them. This will help doctors diagnose and treat patients quickly. FABHALTA is only available through a program called the FABHALTA Risk Evaluation and Mitigation Strategy (REMS). Before patients can take FABHALTA, their doctor must enroll in the FABHALTA REMS program, counsel patients about the risk of serious infections caused by certain bacteria, give patients information about the symptoms of serious infections, make sure that patients are vaccinated against serious infections caused by encapsulated bacteria and that they receive antibiotics if they need to start FABHALTA right away and are not up to date on vaccinations, as well as give patients a Patient Safety Card about the risk of serious infections. Patients should not take FABHALTA if they are allergic to FABHALTA or any of the ingredients in FABHALTA. Patients should not take FABHALTA if they have a serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b when starting FABHALTA. Before taking FABHALTA, patients should tell their doctor about all their medical conditions, including if they have an infection or fever, have liver problems, are pregnant or plan to become pregnant (it is not known if FABHALTA will harm an unborn baby), or are breastfeeding or plan to breastfeed as it is not known if FABHALTA passes into breast milk. Patients should not breastfeed during treatment and for 5 days after the final dose of FABHALTA. Patients should tell their doctor about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking FABHALTA with certain other medicines may affect the way FABHALTA works and may cause side effects. Patients should know the medicines they take and the vaccines they receive. Patients should keep a list of them to show their doctor and pharmacist when they get a new medicine. FABHALTA may cause serious side effects, including those mentioned above as well as increased cholesterol and triglyceride (lipid) levels in the blood. Doctors will do blood tests to check patients' cholesterol and triglycerides during treatment with FABHALTA. Doctors may start patients on medicine to lower cholesterol if needed. The most common side effects of FABHALTA in adults include headache; nasal congestion, runny nose, cough, sneezing, and sore throat (nasopharyngitis); diarrhea; pain in the stomach (abdomen); infections (bacterial and viral); nausea; and rash. Please see full Prescribing Information, including Boxed WARNING and Medication Guide. Novartis in kidney disease At Novartis, our journey in nephrology began more than 40 years ago when the development and introduction of cyclosporine helped reimagine the field of transplantation and immunosuppression. We continue today with a broad renal R&D portfolio targeting the underlying causes of disease to preserve kidney function. We aim to help transform the lives of people living with kidney diseases, enabling them to live longer without the need for dialysis or transplantation. Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "may," "could," "would," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," "progress," "accelerated," "targets," "continued," "contingent," "progressive," "evolving," "enable," "innovation," "ongoing," "evaluating," "evolve," "committed," "advance," "advancing," "commitment," "to developing," "to provide, "development," "to address," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for Fabhalta or the other investigational or approved products described in this press release, or regarding potential future revenues from such product. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Fabhalta or the other investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people's lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide. Reimagine medicine with us: Visit us at and and connect with us on LinkedIn, Facebook, X/Twitter and Instagram. References Smith RJ, Kavanagh D, Vivarelli M, et al. Efficacy and safety of iptacopan in patients with C3 glomerulopathy: 12-Month results from the Phase 3 APPEAR-C3G study. Presented at American Society of Nephrology (ASN) Kidney Week 2024; October 23-27, 2024; San Diego, CA. FABHALTA prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2024. Schena FP, Esposito P, Rossini M. A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease. Int J Mol Sci. 2020;21(2):525. Martín B, Smith RJH. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. C3 Glomerulopathy. GeneReviews® [Internet]. Updated 2018. University of Washington, Seattle; 1993-2024. Available from: . Accessed September 2024. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. Kavanagh D, Bomback A, Vivarelli M, et al. Efficacy and Safety of Iptacopan in Patients with C3 Glomerulopathy: Results from the Phase 3 APPEAR-C3G Trial. Presented at European Renal Association (ERA) Congress; May 25, 2024; Stockholm, Sweden. Smith RJH, Appel GB, Blom AM, et al. C3 Glomerulopathy – understanding a rare complement-driven renal disease. Nat Rev Nephrol. 2019;15(3):129-143. ClinicalTrials.gov. Study of Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy. (APPEAR-C3G). Available from: . Accessed September 2024. Caravaca-Fontán F, Lucientes L, Cavero T, Praga M. Update on C3 Glomerulopathy: A Complement-Mediated Disease. Nephron. 2020;144(6):272-280. Ravindran A, Fervenza FC, Smith RJH, Sethi S. C3 Glomerulopathy Associated with Monoclonal Ig is a Distinct Subtype. Kidney Int. 2018;94(1):178-186. Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, et al. C3 Glomerulopathy: Clinicopathologic Features and Predictors of Outcome. Clin J Am Soc Nephrol. 2014;9(1):46-53. ### SOURCE Novartis Pharmaceuticals Corporation WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Clinical ResultPhase 3Drug Approval

09 Oct 2024

·www.pharmaceutical-technology.com

Purespring secures $105m to start Phase I/II trial of IgAN gene therapy

Purespring will use the $105m funding to advance its lead candidate PS-002 through the clinic. Credit: Pixel-Shot via Shutterstock. Purespring Therapeutics has secured £80m ($105m) to kick start a Phase I/II trial of its experimental adeno-associated viral (AAV) gene therapy in a kidney disease. The London-based biotech’s lead asset PS-002 will be investigated for IgA nephropathy (IgAN), an autoimmune and kidney disease where too much immunoglobulin A (IgA) protein stays in the kidneys. The condition causes inflammation and can lead to end-stage renal disease. PS-002 is an experimental AAV gene therapy designed to target podocytes, specialised cells critical for proper kidney function. In IgAN, immune complexes damage these cells, leading to protein leakage and kidney dysfunction. Purespring’s portfolio also includes a programme targeting nephrotic syndrome, named PS-001, and another focused on an undisclosed glomerular kidney disease programme. Purespring showcased preclinical data of its PS-001 therapy at the European Renal Association (ERA) Congress in May 2024. The data showed that transgenes can be efficiently targeted to podocytes to replace defective genes or to use the podocyte as a protein factory to modulate kidney biology. The Series B funding round was led by Sofinnova Partners in collaboration with Gilde Healthcare, Forbion, British Patient Capital and founding investor Syncona . Purespring launched out of Syncona in 2021 with $45m Series A funding under its belt. The company has a ‘gene search engine’ platform, dubbed FunSel, which selects the most effective treatments for diseases from a large library of AAV vectors, without focusing on specific genes or mechanisms. See Also: South Korean company Dong-A ST wins FDA approval for Stelara biosimilar Roche wins first-line approval for PI3K inhibitor combo in breast cancer The IgAN field has generated a wave of attention in the last few years, with a flurry of M&As to back it up. In August 2023, pharma giant Novartis bought Chinook Therapeutics in a $3.2bn deal where it acquired two drugs, atrasentan and zigakibart. Both candidates are currently being investigated in Phase III clinical trials for IgAN (NCT04573478 and NCT05852938). Vertex Pharmaceuticals and Biogen followed suit, inking deals with Alpine Immune Sciences and Human Immunology Biosciences, respectively. The deals, both worth more than $1bn, saw the companies inherit assets set to treat IgAN. In the announcement accompanying the funding, Purespring’s CEO Julian Hanak said: “Nearly one-tenth of the world’s population, around 840 million people, suffer from chronic kidney disease. For many of them, there are few options beyond dialysis and transplantation. Our novel treatment platform and deep understanding of kidney disease puts us in a position to stop, reverse and even cure kidney disease. The funds raised will allow us to bring our novel treatments to patients in the clinic.” Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva . Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Optimise your cell therapy process: a guide to cell thawing Typically carried out at the point of care, errors in cell therapy thawing could compromise treatment efficacy, leading to significant patient impact as well as high costs and a compromised reputation for the product’s developer. This guide addresses how cell thawing has historically developed into the new techniques used today, along with the physical and biological implications of key metrics and components such as warming rate and ice structure. Also included are reviews of key studies from scientific literature and a consideration of the interactions between cooling and warming rates, as applicable to cell and gene therapies. Thank you. You will receive an email shortly. Please check your inbox to download the Whitepaper. By Cytiva Thematic By downloading this Whitepaper, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy

AcquisitionGene TherapyPhase 3Cell TherapyDrug Approval

06 Sep 2024

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After failed FSGS bid, Travere wins full FDA approval for Filspari in IgAN

The US FDA has added a boxed warning for hepatotoxicity and birth defects to the Filspari label. Image credit: sasirin pamai / Shutterstock. The US Food and Drug Administration (FDA) has converted the accelerated approval for Travere Therapeutics ’ Filspari (sparsentan) to full approval in primary IgA nephropathy (IgAN). The US regulatory agency also removed the specific requirement of a urine protein-to-creatinine ratio (UPCR) of over 1.5g/g for the drug’s use, thereby, broadening the therapy’s label in IgAN. The agency approved Filspari to slow kidney function decline in adults with primary IgAN who are at risk of disease progression. The approval does come with a boxed warning for hepatotoxicity and birth defects. The boxed warning restricts Filspari availability under a Risk Evaluation and Mitigation Strategies (REMS) programme. As part of the warning, the FDA requires kidney function monitoring in patients before starting Filspari, followed by monthly testing for the first year and every three months during treatment. Earlier, Travere had sought the US FDA’s approval for sparsentan as a treatment for focal segmental glomerulosclerosis (FSGS), a rare kidney disease. However, the US agency requested additional data to support the supplemental new drug application (sNDA) in FSGS and said the two-year results from the Phase III DUPLEX study were insufficient to support the sNDA. The US FDA’s additional data request forced Travere to implement cash-saving measures in December 2023. The company fired 20% of its staff and announced its intention to focus its resources Filspari’s launch in IgAN. See Also: Integrated Nanotherapeutics gains funds for new T1D treatment Moderna’s Laval facility gains Health Canada’s drug establishment licence Filspari is a dual endothelin angiotensin receptor antagonist. It received a US FDA accelerated approval to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression with a UPCR of over 1.5g/g in February 2023. The accelerated approval was based on the results from the Phase III PROTECT trial (NCT03762850), which met its primary UPCR-related endpoint. Proteinuria reduction is a key surrogate marker for delaying kidney failure and is often used to support accelerated regulatory approvals in IgAN clinical trials. However the study failed to hit the confirmatory secondary endpoint measuring kidney function. The full approval is based on a modified intent-to-treat analysis of the 404 patients enrolled in the PROTECT trial. This modification allowed the company to evaluate data from patients who discontinued treatment, which was excluded in the previous analysis. The modified analysis showed that the study met its secondary endpoint by Filspari reducing the rate of decline in kidney function from baseline to Week 110, compared to control. The mean estimated glomerular filtration rate (eGFR) slope from baseline to Week 110 was -3.0 mL/min/1.73 m2/year for Filspari, compared to -4.2 mL/min/1.73 m2/year for the standard of care irbesartan. Filspari’s competitors in the IgAN treatment space are Novartis ’s Fabhalta (iptacopan), atrasentan and zigakibart. Fabhalta is an alternative complement pathway inhibitor. Last month, it received accelerated approval from the US FDA for reducing proteinuria in IgAN. Novartis acquired atrasentan and zigakibart as part of $3.2bn Chinook Therapeutics deal. In May, Novartis shared positive data from the Phase III trial of atrasentan in IgAN showing that the therapy reduced proteinuria by 36.1% at 36 weeks.

Phase 3Drug ApprovalClinical ResultAcquisitionAccelerated Approval

100 Deals associated with Atrasentan

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-	Atrasentan	-	DB06199

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Glomerulonephritis, IGA	NDA/BLA	US	Novartis AG	18 Jul 2024
Chronic Kidney Diseases	Phase 3	US	Chinook Therapeutics, Inc.	11 Dec 2020
Chronic Kidney Diseases	Phase 3	CN	Chinook Therapeutics, Inc.	11 Dec 2020
Chronic Kidney Diseases	Phase 3	JP	Chinook Therapeutics, Inc.	11 Dec 2020
Chronic Kidney Diseases	Phase 3	AR	Chinook Therapeutics, Inc.	11 Dec 2020
Chronic Kidney Diseases	Phase 3	AU	Chinook Therapeutics, Inc.	11 Dec 2020
Chronic Kidney Diseases	Phase 3	BR	Chinook Therapeutics, Inc.	11 Dec 2020
Chronic Kidney Diseases	Phase 3	CA	Chinook Therapeutics, Inc.	11 Dec 2020
Chronic Kidney Diseases	Phase 3	CO	Chinook Therapeutics, Inc.	11 Dec 2020
Chronic Kidney Diseases	Phase 3	FR	Chinook Therapeutics, Inc.	11 Dec 2020

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01858532 (SONAR, Pubmed \| Kidney Int)	Phase 3	Diabetes Mellitus, Type 2 \| Chronic Kidney Diseases estimated glomerular filtration rate \| urinary albumin-to-creatinine ratio	1,834	Atrasentan	izuyqddayo(ljsdgopdjp) = noiaxatply niigxqplno (hquhfczxht, 0.72 - 0.93)	Positive	01 Dec 2023
				Placebo	izuyqddayo(ljsdgopdjp) = tjafgnzgei niigxqplno (hquhfczxht )
NCT04573478 (ALIGN , Corporate Publications) Manual	Phase 3	Glomerulonephritis, IGA	-	Atrasentan	shodnokror(mrmyublrmh) = The study met its primary efficacy endpoint at the 36-week interim analysis, with atrasentan demonstrating superiority versus placebo with a clinically meaningful and highly statistically significant reduction in proteinuria (protein in urine) in patients with IgAN receiving supportive care (maximally tolerated and stable dose of a renin-angiotensin system [RAS] inhibitor). xqbjmhsitg (rtnropivfh ) Met	Positive	30 Oct 2023
				Placebo
NCT01356849 (RADAR, ASN2022)	Phase 2	Type 2 diabetes mellitus with established diabetic nephropathy PCSK9	-	Atrasentan 0.75mg/d	rfkrccohpu(cxleitijgp) = alwivzkkde zavginsjsr (bqqlurzzxb, -52.7 to 1.0)	Positive	05 Nov 2022
AFFINITY (ASN2022)	Phase 2	Glomerulonephritis, IGA	-	Atrasentan 0.75 mg	djcjcknyso(ozmgyxibyh) = dbuifvcrzz ipbdmitalr (rkyxnwxtbb, 39.8 - 58.3)	Positive	03 Nov 2022
NCT04573920 (AFFINITY, Corporate Publications) Manual	Phase 2	Glomerulonephritis, IGA	20	Atrasentan	uegajqptsz(bhjytegpxu) = maouilpcni katxyaoqtt (sudkvuqmit ) View more	Positive	01 Nov 2022
NCT01858532 (SONAR, Pubmed)	Phase 3	Diabetes Mellitus, Type 2 \| Diabetic Nephropathies	5,107	Atrasentan 0.75 mg/day	znmehobsvo(cdkoktlovh): HR = 1.39 (95% CI, 0.97 - 1.99), P-Value = 0.072	Positive	01 Jul 2022
				Placebo
AFFINITY (ERA2022)	Phase 2	Glomerulonephritis, IGA	17	Atrasentan 0.75 mg	dvygsqmufn(rxbwdntjez) = uofoopmliq fskbjzeqqd (kbvtrflzlx, 29.0 - 55.2)	Positive	03 May 2022
NCT01858532 (SONAR, Pubmed \| Clin J Am Soc Nephrol)	Phase 3	Heart Failure	3,668	Atrasentan	(rllhxyyvlo): hazard ratio = 1.39 (95% CI, 0.97 - 1.99) View more	-	01 Dec 2021
				Placebo
SONAR (ASN2021)	Not Applicable	Heart Failure eGFR \| UACR	3,668	Atrasentan	gkiuyqcvot(lseouhveqe): HR = 1.39 (95% CI, 0.97 - 1.99) View more	Positive	27 Oct 2021
				Placebo
ISN WCN2021	Not Applicable	Glomerulonephritis, IGA	-	Atrasentan (IgA-containing immune complexes)	nzdoslffvs(dpxmvwzvzt) = usjlddrfec karchirpvf (tpesbsqyhd, 0.13)	-	01 Apr 2021

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