inaxaplin (VX-147) / Vertex - LARVOL DELTA

AMPLITUDE, a Ph2/3 Adaptive Trial of Inaxaplin in APOL1-mediated Kidney Disease (ERA 2025) - No abstract available

Nephrology • Renal Disease

Clinical implications of apolipoprotein L1 testing in patients with focal segmental glomerulosclerosis: a review of diagnostic and prognostic implications. (PubMed, Ann Med Surg (Lond)) - "APOL1-associated kidney damage primarily affects podocytes, accelerating glomerulosclerosis. Emerging treatments, such as inaxaplin, reduced proteinuria by 47%, with 40% achieving remission in FSGS cases linked to APOL1."

Journal • Review • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Infectious Disease • Nephrology • Pediatrics • Renal Disease

AMPLITUDE: Phase 2/3 Adaptive Study of VX-147 in Adult and Pediatric Participants With APOL1- Mediated Proteinuric Kidney Disease (clinicaltrials.gov) - P2/3 | N=466 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Phase classification: P3 ➔ P2/3

Phase classification • Nephrology • Pediatrics • Renal Disease

Phase 2b Open-label Study of Inaxaplin in Participants With Proteinuric APOL1 Mediated Kidney Disease (clinicaltrials.gov) - P2 | N=45 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

AMPLITUDE: Phase 2/3 Adaptive Study of VX-147 in Adults With APOL1-mediated Proteinuric Kidney Disease (clinicaltrials.gov) - P3 | N=466 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Phase classification: P2/3 ➔ P3

Phase classification • Nephrology • Renal Disease

Vertex Reports Fourth Quarter and Full Year 2024 Financial Results (Businesswire) - "Fourth Quarter 2024 Results...Product revenue increased 16% to $2.91 billion compared to the fourth quarter of 2023, primarily driven by the continued performance of TRIKAFTA/KAFTRIO. Net product revenue increased 17% to $1.84 billion in the U.S...The multiple ascending dose (MAD) portion of the Phase 1/2 study of VX-522, a nebulized CFTR mRNA therapy, is underway, with data expected in the first half of 2025; Vertex has completed enrollment of children 5 to 11 years of age with SCD or TDT in two global Phase 3 studies of CASGEVY and expects to complete dosing of this age group in 2025; Vertex continues to enroll and dose patients with primary AMKD in the Phase 3 portion of the AMPLITUDE global Phase 2/3 pivotal clinical trial of inaxaplin...Vertex expects to complete enrollment in the interim analysis cohort in 2025 and apply for potential accelerated approval in the U.S. after this cohort reaches 48 weeks of treatment, assuming a positive interim analysis."

Commercial • P1/2 data • Trial status • Beta-Thalassemia • Cystic Fibrosis • Renal Disease • Sickle Cell Disease

Phase 2b Open-label Study of Inaxaplin in Participants With Proteinuric APOL1 Mediated Kidney Disease (clinicaltrials.gov) - P2 | N=45 | Not yet recruiting | Sponsor: Vertex Pharmaceuticals Incorporated

New P2 trial • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Evaluation of the Pharmacokinetics and Safety of Inaxaplin in Participants With Mild or Moderate Hepatic Impairment (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Vertex Pharmaceuticals Incorporated | Active, not recruiting ➔ Completed

Trial completion • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Hepatology

Evaluation of the Pharmacokinetics and Safety of Inaxaplin in Participants With Mild or Moderate Hepatic Impairment (clinicaltrials.gov) - P1 | N=36 | Active, not recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology

AMPLITUDE: A Phase 2/3 Adaptive Trial of Inaxaplin in APOL1-Mediated Kidney Disease (KIDNEY WEEK 2024) - "The high prevalence of 2 APOL1 variants in participants with recent African ancestry and proteinuric CKD reinforces the importance of APOL1 genotyping to optimize kidney disease management and enable referral to clinical trials of APOL1-targeted therapies. Our Ph2/3 trial will evaluate the effects of IXP on preserving kidney function and reducing proteinuria in a broad AMKD population."

Late-breaking abstract • P2/3 data • Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Nephrology • Renal Disease

Small Molecule Inhibition of APOL1 Channel Activity Protects Podocytes from Mitochondrial Dysfunction, Cell Death, and Barrier Disruption Induced by APOL1 Risk Variants (KIDNEY WEEK 2024) - "We sought to examine the impact of APOL1 variants in podocytes and the potential impact inhibition of APOL1-mediated ion flux could have on these effects. To enable this effort, we developed tetracycline inducible, human immortalized podocyte lines expressing APOL1 G0 (reference allele), APOL1 G1 or APOL1 G2 and examined cell survival following APOL1 induction using a cell death assay. We also studied the potential for APOL1 variants to disrupt cell adhesion, cell-cell junctions and mitochondrial function and the ability of APOL1 ion channel inhibition to modulate these effects. APOL1 G1 and G2 induction led to a loss in podocyte viability that was rescued by treatment with Compound 3, a close analog of our clinical candidate inaxaplin. These data highlight the critical importance of APOL1-mediated ion flux in APOL1 driven cell injury and suggest that damaged podocytes can be recovered to restore their critical filtration barrier."

Human Immunodeficiency Virus • Infectious Disease • Metabolic Disorders • IFNG

Small Molecule APOL1 Channel Inhibitor Reduces Proteinuria, Rescues Podocyte Injury, and Reverses eGFR Decline in an APOL1-Mediated Kidney Disease Mouse Model (KIDNEY WEEK 2024) - "Here we demonstrate that APOL1 channel inhibition by Compound 3, a close analog of the clinical candidate inaxaplin, reduces proteinuria and glomerulopathy and reverses eGFR decline after APOL1-mediated glomerular damage is well established."

Preclinical • Glomerulonephritis • Nephrology • Renal Disease • IFNG

Evaluation of the Pharmacokinetics and Safety of Inaxaplin in Participants With Mild or Moderate Hepatic Impairment (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology

Genetic Causes of Nephrotic Syndrome and Focal and Segmental Glomerulosclerosis. (PubMed, Adv Kidney Dis Health) - "Achieving molecularly informed diagnoses also holds substantial potential for personalizing medicine, including the development of targeted therapeutics. Illustrative examples include coenzyme Q10 for ADCK4-associated NS and inaxaplin, a small molecule that inhibits apolipoprotein L1 channel activity, though larger studies are required to confirm benefit."

Journal • Review • Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Genetic Disorders • Glomerulonephritis • Nephrology • Renal Disease

Evaluation of the Pharmacokinetics and Safety of Inaxaplin in Participants With Mild or Moderate Hepatic Impairment (clinicaltrials.gov) - P1 | N=40 | Not yet recruiting | Sponsor: Vertex Pharmaceuticals Incorporated

New P1 trial • Hepatology

A Study to Evaluate Pharmacokinetics (PK) and Safety of Inaxaplin in Participants With Renal Impairment (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Vertex Pharmaceuticals Incorporated | Active, not recruiting ➔ Completed

Trial completion • Renal Disease

A Study to Evaluate Pharmacokinetics (PK) and Safety of Inaxaplin in Participants With Renal Impairment (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Recruiting ➔ Active, not recruiting

Enrollment closed • Renal Disease

Genetic Testing in Patients with Focal Segmental Glomerulosclerosis (NKF-SCM 2024) - "Nephrologists rank the APOL-1 targeting treatment inaxaplin among their top three most desired agents to be approved, while their interest in the product has also nearly doubled over time (35% in 2021 to 64% in 2023). Other pipeline products of high interest include sparsentan and atrasentan. Genetic testing can be a non-invasive and oftentimes a cost-effective way to diagnose patients with multiple kidney diseases, including those beyond FSGS. Improved access and education around the benefits of genetic testing for CKD patients is key to early intervention and will ultimately lead to better renal outcomes."

Clinical • Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Glomerulonephritis

A Review of Focal Segmental Glomerulosclerosis Classification With a Focus on Genetic Associations. (PubMed, Kidney Med) - "Currently, no specific treatments have been approved to treat genetic FSGS; however, interventions targeting underlying cofactor deficiencies have shown potential in some cases. Furthermore, encouraging results have emerged from a phase 2 trial investigating inaxaplin, a novel small molecule APOL1 channel inhibitor, in APOL1-associated FSGS."

Journal • Review • Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Nephrology • Renal Disease

Safety and Tolerability of the APOL1 Inhibitor, Inaxaplin, following Single- and Multiple-Ascending Doses in Healthy Adults. (PubMed, Glomerular Dis) - "These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD."

Journal • Chronic Kidney Disease • Nephrology • Pain • Renal Disease

A Study to Evaluate Pharmacokinetics (PK) and Safety of Inaxaplin in Participants With Renal Impairment (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Trial completion date: Dec 2023 ➔ Jun 2024 | Trial primary completion date: Dec 2023 ➔ Jun 2024

Trial completion date • Trial primary completion date • Renal Disease

APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease. (PubMed, J Clin Invest) - "Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that Interferon gamma (IFNγ)-mediated induction of G1 caused K+ efflux, activation of GPCR-IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease."

Journal • Chronic Kidney Disease • Nephrology • Renal Disease • IFNG

AMPLITUDE: Phase 2/3 Adaptive Study of VX-147 in Adult and Pediatric Participants With APOL1- Mediated Proteinuric Kidney Disease Mediated Proteinuric Kidney Disease (clinicaltrials.gov) - P2/3 | N=466 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated

Trial completion date • Trial primary completion date • Nephrology • Pediatrics • Renal Disease

APOL1 G1-Mediated Cation Transport Inhibits Amino Acid Transport and Increases Endoplasmic Reticulum Calcium Release, Causing Podocytopathy (KIDNEY WEEK 2023) - "These findings established APOL1-mediated Na+/K+ transport as the proximal driver of podocyte injury, and that Ca2+ signaling and protein synthesis are potential therapeutic targets for APOL1 nephropathy."

Metabolic Disorders • Nephrology • Renal Disease • EIF2A • EIF2S1 • TSC2

A Study Evaluating the Relative Bioavailability and Food Effect of a Tablet Formulation of VX-147 (clinicaltrials.gov) - P1 | N=21 | Completed | Sponsor: Vertex Pharmaceuticals Incorporated | Recruiting ➔ Completed

Trial completion • Focal Segmental Glomerulosclerosis • Glomerulonephritis