Clinical trial recommendations for potential Alport syndrome therapies

Abstract

Alport syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport syndrome community, as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry representatives, academic researchers, clinicians, regulatory agency representatives, and—most critically—patients with Alport syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations. Alport syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport syndrome community, as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry representatives, academic researchers, clinicians, regulatory agency representatives, and—most critically—patients with Alport syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations. Alport syndrome (AS) is a progressive, hereditary, type IV collagen disorder defined and caused by mutations in the autosomal COL4A3 and COL4A4 genes and the X-linked COL4A5 gene. Its primary kidney manifestations that result in end-stage kidney disease (ESKD) are glomerulosclerosis, tubular atrophy, and interstitial fibrosis.1Kashtan C.E. Ding J. Garosi G. et al.Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport Syndrome Classification Working Group.Kidney Int. 2018; 93: 1045-1051Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar To date, effective therapy for AS is limited to the off-label use of renin-angiotensin-aldosterone system blockade drugs such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. However, retrospective studies suggest that this standard of care merely delays the onset of ESKD.2Gross O. Licht C. Anders H.J. et al.Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.Kidney Int. 2012; 81: 494-501Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar,3Stock J. Kuenanz J. Glonke N. et al.Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations.Pediatr Nephrol. 2017; 32: 131-137Crossref PubMed Scopus (24) Google Scholar Thus, preventative or curative therapies for AS currently do not exist. Because AS is estimated to affect fewer than 200,000 people in the United States,4National Organization for Rare DisordersRare Disease Database: Alport Syndrom.https://rarediseases.org/rare-diseases/alport-syndrome/Date accessed: April 23, 2020Google Scholar it meets US Food and Drug Administration (FDA) and US Orphan Drug Act orphan disease criteria.5Pub L No. 97-414, 96 Stat 2049 et seq. (1983) as amended by Pub L No. 98-551, 98 Stat 2815, 2817 (1984), which added a numeric prevalence threshold to the definition of rare diseases.Google Scholar The true incidence of AS is unknown and is highly dependent upon disease definition. Historically, an AS diagnosis was equated primarily with males with X-linked disease, and secondarily, either males or females with autosomal-recessive disease, or with females with COL4A5 ± mutations who were characterized as carriers of X-linked AS but were not directly affected by AS.6Savige J. Ariani F. Mari F. et al.Expert consensus guidelines for the genetic diagnosis of Alport syndrome.Pediatr Nephrol. 2019; 34: 1175-1189Crossref PubMed Scopus (74) Google Scholar The currently accepted AS diagnosis uses a more inclusive genetic-based approach that recognizes that women with X-linked disease are, indeed, patients, and that the autosomal-recessive and -dominant forms of AS are more prevalent than previously understood.1Kashtan C.E. Ding J. Garosi G. et al.Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport Syndrome Classification Working Group.Kidney Int. 2018; 93: 1045-1051Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Of note, the AS community no longer accepts the term carrier in reference to women with X-linked AS, as they themselves are affected. Furthermore, an increasing body of genetic research involving whole-exome sequencing shows that a nontrivial proportion of cases of idiopathic glomerulosclerosis and other types of chronic kidney disease are in fact associated with mutations in COL4A3, COL4A4, or COL4A5, consistent with AS.7Wang M. Chun J. Genovese G. et al.Contributions of rare gene variants to familial and sporadic FSGS.J Am Soc Nephrol. 2019; 30: 1625-1640Crossref PubMed Scopus (26) Google Scholar, 8Groopman E.E. Marasa M. Cameron-Christie S. et al.Diagnostic utility of exome sequencing for kidney disease.N Engl J Med. 2019; 380: 142-151Crossref PubMed Scopus (267) Google Scholar, 9Mann N. Braun D.A. Amann K. et al.Whole-exome sequencing enables a precision medicine approach for kidney transplant recipients.J Am Soc Nephrol. 2019; 30: 201-215Crossref PubMed Scopus (56) Google Scholar, 10Gribouval O. Boyer O. Hummel A. et al.Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults.Kidney Int. 2018; 94: 1013-1022Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 11Lata S. Marasa M. Li Y. et al.Whole-exome sequencing in adults with chronic kidney disease: a pilot study.Ann Intern Med. 2018; 168: 100-109Crossref PubMed Scopus (108) Google Scholar, 12Gast C. Pengelly R.J. Lyon M. et al.Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2016; 31: 961-970Crossref PubMed Scopus (149) Google Scholar Thus, although AS is still a rare disorder, it is more heterogeneous and prevalent than previously believed. As recently as 2016, not a single clinical trial had investigated any potential AS therapy beyond renin-angiotensin-aldosterone system -blockade. However, because of several unrelated factors, there is now a dramatic increase in AS-relevant biopharmaceutical research. Such factors include, but are not limited to, a growing body of natural history data, regulatory and financial incentives to create therapies for rare disorders,5Pub L No. 97-414, 96 Stat 2049 et seq. (1983) as amended by Pub L No. 98-551, 98 Stat 2815, 2817 (1984), which added a numeric prevalence threshold to the definition of rare diseases.Google Scholar recent discoveries in antifibrotic therapies, availability of preclinical models that mimic AS disease in patients, a clearer genotype–phenotype relationship versus other causes of chronic kidney disease, and pathophysiologic similarities between AS and a wider spectrum of glomerular disease, including diabetic nephropathy. At the time of this writing, Sanofi Genzyme was continuing its Regulus Therapeutics’ HERA AS study13US National Library of MedicineStudy of SAR339375 in patients with Alport Syndrome (HERA).https://clinicaltrials.gov/ct2/show/NCT02855268Date accessed: April 23, 2020Google Scholar and Reata Pharmaceuticals had successfully completed enrollment for Phase 3 of its CARDINAL AS study14US National Library of MedicineA phase 2/3 trial of the efficacy and safety of bardoxolone methyl in patients with Alport Syndrome—CARDINAL.https://clinicaltrials.gov/ct2/show/NCT03019185Date accessed: April 23, 2020Google Scholar (see Table 1). In addition, several other compounds, compound families, and mechanisms of action have been researched preclinically as potential AS therapies.15Omachi K. Miner J.H. Alport syndrome therapeutics: ready for prime-time players.Trends in Pharmacol Sci. 2019; 40: 803-806Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar,16Torra R. Furlano M. New therapeutic options for Alport syndrome.Nephrol Dial Transplant. 2019; 34: 1272-1279Crossref PubMed Scopus (29) Google ScholarTable 1Current Phase 2 and 3 trials enrolling patients with ASDrug/sponsorTarget and theorized mechanismTrial phase and designMain eligibility criteriaSAR339375/Sanofi13US National Library of MedicineStudy of SAR339375 in patients with Alport Syndrome (HERA).https://clinicaltrials.gov/ct2/show/NCT02855268Date accessed: April 23, 2020Google ScholarAnti-microRNA-21Theorized mechanism: antifibroticPhase 2: randomized, double-blind, placebo-controlledEnrollment target: 4548 weeks randomized + 48-week open-label extensionAge 18–55 yrMale or femaleConfirmed AS diagnosis eGFR >35 ml/min per 1.73 m2EITHER:1.eGFR decline of ≥4 ml/min per 1.73 m2 per yr2.Proteinuria >2000 mg/g3.Male age 18–23 yr with eGFR <90 ml/min per 1.73 m2Bardoxolone methyl/Reata Pharmaceuticals14US National Library of MedicineA phase 2/3 trial of the efficacy and safety of bardoxolone methyl in patients with Alport Syndrome—CARDINAL.https://clinicaltrials.gov/ct2/show/NCT03019185Date accessed: April 23, 2020Google ScholarActivates Nrf2 pathway and inhibits nuclear factor-κB pathwayTheorized mechanism: antioxidant, mitochondria-protective, anti-inflammatoryPhase 2/3/:Phase 2: open-labelEnrollment: 3012 weeks + open-label extensionPhase 3: randomized, double-blind, placebo-controlledEnrollment: 18748 weeks randomized + 4-week washout + 48-week open-label extensionAge 12–60 yrMale or femaleConfirmed AS diagnosis; eGFR ≥30 and ≤90 ml/min per 1.73 m2;albumin-to-creatinine ratio ≤3500 mg/gAS, Alport syndrome; eGFR, estimated glomerular filtration rate. Open table in a new tab AS, Alport syndrome; eGFR, estimated glomerular filtration rate. The Alport Syndrome Foundation (ASF) is the primary advocacy organization for the US AS community. In addition to serving as an interactive educational advocate, the ASF coordinates and funds research into potential AS therapies and cures. Considering the recent surge in the AS investigational pipeline, the ASF has created AS clinical trial recommendations resulting from 2 coordinated activities:(i)An externally led patient-focused drug development meeting with the US FDA, held jointly by the ASF and the National Kidney Foundation in August 2018.17Alport Syndrom Foundation and National Kidney FoundationThe Voice of the Patient: Externally Led Patient-Focused Drug Development Meeting on Alport Syndrome.http://www.fda.gov/media/132537/downloadDate accessed: April 23, 2020Google Scholar(ii)An ASF-hosted workshop with key stakeholders at the American Society of Nephrology Kidney Week in October 2018. This paper summarizes recommendations resulting from the latter (“the Workshop”). The Workshop was hosted with support from Retrophin, Reata Pharmaceuticals, and Regulus Therapeutics. The 60 attendees included representatives from the biopharmaceutical industry, academic research laboratories, clinicians, and regulatory agencies, along with patients with AS, and caregivers and family members of patients with AS. The Workshop first summarized the current understanding of AS from the clinical and patient perspectives, as well as concerns and expectations from the FDA and industrial sponsors. Participants then divided into working groups, with each focusing on 1 of the following: preclinical research, clinical trial design, clinical trial outcomes, pediatric concerns, and patient concerns pertaining to conventional medications. Although nonconventional therapies such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9- and adeno-associated virus–mediated gene therapy, stem cell therapy, organoid or regenerative medicine therapies, and others are certainly concerns of the AS community, these were not discussed and are thus not mentioned further here. What follows are the Workshop’s consensus recommendations for conventional drug preclinical research and clinical trial design and outcomes in AS. This document does not establish legally enforceable responsibilities unless specific regulatory or statutory requirements are cited. 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Because is more for trials that and are to to such as and trial should an to to the and to their trial are to trial in the of the In addition, should to to that to increase and in future on the and natural history the and increase the and patient in the As per clinical trial should for an open-label trial and consistent with the safety AS patients who not eligibility criteria or were to should for and consistent with the investigational safety This paper is to the consensus recommendations for the design and of AS clinical trials for conventional as discussed by the AS community of patients, researchers, clinicians, biopharmaceutical industry representatives, and regulatory body representatives at a workshop held in October 2018.