inaxaplin (VX-147) / Vertex - LARVOL DELTA

APOL1 kidney disease: a critical narrative review of molecular mechanisms, clinical heterogeneity, and the emerging therapeutic landscape. (PubMed, Int Urol Nephrol) - P2/3 | "APOL1 is the clearest current example of a genetically defined, mechanism-targetable kidney disease, but its evidence base is uneven. The genetic association is firmly established; whereas much of the mechanistic literature derives from overexpression systems, several downstream pathways remain contested, and every APOL1-targeted therapy is so far supported only by short-term, surrogate-endpoint data. The principal unresolved issues are the determinants of incomplete penetrance, the absence of a validated progression biomarker and of any model reproducing the common slowly progressive phenotype, and the long-term efficacy and safety of APOL1-directed therapy. Genotype-guided risk stratification is therefore best regarded as clinically reasonable but not yet proven, and routine population-level screening is not currently supported."

Heterogeneity • Journal • Review • Cardiovascular • Chronic Kidney Disease • Diabetic Nephropathy • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Human Immunodeficiency Virus • Hypertension • Infectious Disease • Metabolic Disorders • Nephrology • Renal Disease

Inaxaplin in Participants With Proteinuric APOL1 Mediated Kidney Disease With or Without Comorbidities (clinicaltrials.gov) - P2 | N=42 | Completed | Sponsor: Vertex Pharmaceuticals Incorporated | Active, not recruiting ➔ Completed | Trial completion date: Dec 2026 ➔ Jul 2026 | Trial primary completion date: Dec 2026 ➔ Jul 2026

Trial completion • Trial completion date • Trial primary completion date • Chronic Kidney Disease • Nephrology • Renal Disease

Expression of Apolipoprotein L1 Risk Variants at the Plasma Membrane and Haplotype-Dependent Cytotoxicity. (PubMed, J Am Soc Nephrol) - "This study demonstrated APOL1 to be a membrane protein involved in the influx of Ca2+ from the extracellular medium. Increased activity of APOL1 led to markedly increased cytotoxicity, which supports the gain-of-function theory. This effect was prevented by the presence of N264K variant or treatment with the APOL1 inhibitor VX-147."

Journal • Nephrology • Renal Disease

Inaxaplin in Participants With Proteinuric APOL1 Mediated Kidney Disease With or Without Comorbidities (clinicaltrials.gov) - P2 | N=42 | Active, not recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Recruiting ➔ Active, not recruiting

Enrollment closed • Chronic Kidney Disease • Nephrology • Renal Disease

Pharmacokinetics and Safety of a Single Dose of Inaxaplin in Participants With Severe Renal Impairment or With Mild or Moderate Hepatic Impairment (NKF-SCM 2026) - "CONCLUSION No clinically meaningful differences in IXP PK were observed in patients with renal impairment or with mild to moderate hepatic impairment up to and including a CP score of 7. Therefore, no dose adjustment of IXP is anticipated in these populations."

Clinical • PK/PD data • Hepatology • Nephrology • 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 | Trial completion date: Jun 2026 ➔ May 2030 | Trial primary completion date: May 2026 ➔ Jun 2028

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

Emerging Therapeutic Strategies for APOL1-Mediated Kidney Disease (AMKD) (KIDNEY WEEK 2025) - "Results Small molecule inhibitors, such as Inaxaplin, have demonstrated early efficacy in reducing proteinuria by counteracting APOL1-induced ion dysregulation...Additionally, JAK-STAT inhibitors, like Baricitinib, may help to reduce inflammation that directly contributes to renal injury. Conclusion Emerging APOL1-targeted therapies show promise in slowing disease progression by addressing key molecular mechanisms. With time, these treatments could become the first disease-modifying options for APOL1 kidney disease, while broader factors like genetics and lifestyle also warrant investigation."

Inflammation • Metabolic Disorders • Nephrology • Renal Disease

Small Molecule Inhibitors of APOL1 Reverse Dysfunctional Signaling Mediated by APOL1 Risk Variants in Immortalized Human Podocytes (KIDNEY WEEK 2025) - "Differentiated podocytes were treated with doxycycline to induce APOL1 expression, concurrently with either APOL1 inhibitor MZ-302 (a structural analog of MZE829) or MZ-303 (synthesized inaxaplin). Consistent with these findings, cell painting analyses revealed that APOL1 RV-induced morphological perturbations were also mitigated by small molecule APOL1 inhibitors. Conclusion These findings underscore the therapeutic potential of APOL1 small molecule inhibitors in mitigating APOL1-driven podocyte injury and provide mechanistic insights into podocyte dysfunction in AKD."

Glomerulonephritis • Inflammation • Nephrology • Renal Disease

Inaxaplin for a Broad Population with APOL1-Mediated Kidney Disease and Comorbid Conditions: Phase 2 Proof-of-Concept Study (KIDNEY WEEK 2025) - "Safety will be evaluated. Conclusion The AMPLIFIED study will provide safety and efficacy data on the potential for IXP to treat a diverse population of AMKD patients with concurrent significant comorbidities associated with proteinuric kidney disease."

Clinical • P2 data • Chronic Kidney Disease • Diabetic Nephropathy • Focal Segmental Glomerulosclerosis • Genetic Disorders • Glomerulonephritis • Hematological Disorders • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Lupus Nephritis • Metabolic Disorders • Nephrology • Renal Disease • Sickle Cell Disease • Type 2 Diabetes Mellitus

Inaxaplin (VX-147) Mitigates APOL1-Mediated Preeclampsia (KIDNEY WEEK 2025) - "Furthermore, inaxaplin restored BP (93.49± 6.60 vs. 106.38± 5.50 mmHg; n=7-9; p<0.01) and fetal weight (1.051 ± 0.097 vs. 0.607 ± 0.169 g; n=10; p<0.01) and reduced albuminuria by 57.9±7.5% (n=5; p<0.01) in pregnant G2/G2 females. Conclusion These findings demonstrate that humanized APOL1 mice carrying high-risk alleles spontaneously develop preeclampsia, and that inaxaplin treatment mitigates APOL1-mediated preeclampsia."

Anesthesia • Cardiovascular • Gynecology • Hypertension • Nephrology • Renal Disease • IFNG

Phase 2a Study of VX-147 in Adults With APOL1-mediated Focal Segmental Glomerulosclerosis (clinicaltrials.gov) - P2 | N=16 | Completed | Sponsor: Vertex Pharmaceuticals Incorporated | Phase classification: P2a ➔ P2

Phase classification • Focal Segmental Glomerulosclerosis • Glomerulonephritis

APOL1 Mediated Kidney Disease: A Review and Look Toward the Future. (PubMed, Kidney Med) - "Recent clinical trials have focused on the different postulated mechanisms of cellular toxicity, and one promising candidate, inaxaplin, has advanced to a phase 3 study. This mini-review discusses the development of APOL1 risk alleles, clinical implications of a high-risk genotype, and a suggested framework for nephrologists to pursue genetic testing in countries where it is easily accessible."

Journal • Review • Nephrology • Renal Disease

Discovery of inaxaplin as a precision medicine approach for APOL1-mediated kidney disease (ACS-Fall 2025) - "In that population, treatment with inaxaplin for 13 weeks, on top of standard of care, resulted in a rapid, statistically significant, and clinically meaningful 47.6% reduction in proteinuria. These data highlight the potential of APOL1 channel inhibition for the treatment of APOL1-mediated kidney disease."

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

AMPLITUDE, a Ph2/3 Adaptive Trial of Inaxaplin in APOL1-mediated Kidney Disease (ERA 2025) - "The high prevalence of two 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 Phase 2/3 trial will evaluate the effects of inaxaplin on preserving kidney function and reducing proteinuria in a broad AMKD population."

Chronic Kidney Disease • Diabetic Nephropathy • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Metabolic Disorders • Nephrology • Renal Disease

APOL1-Mediated Kidney Disease (AMKD) (Vertex Press Release) - "Vertex has discovered and advanced multiple oral, small molecule inhibitors of APOL1 function, pioneering a new class of medicines that targets the underlying genetic driver of this kidney disease; Vertex expects to complete enrollment in the interim analysis cohort of the Phase 3 portion of the AMPLITUDE trial of inaxaplin in the second half of 2025. Vertex will conduct the pre-planned interim analysis once this cohort has been treated for 48 weeks, with potential to file for accelerated approval in the U.S. if the results are supportive; Vertex continues to enroll and dose patients in the AMPLIFIED Phase 2 study of inaxaplin in people with AMKD and diabetes or other co-morbidities."

Trial status • 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