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An investigative treatment targeting APOL1 activity significantly improved proteinuria APOL1-mediated kidney disease (AMKD), a proof-of-concept phase IIa study found.

In a single-arm, open-label study, treatment with oral VX-147 -- a small molecule acting as an APOL1 function inhibitor -- significantly reduced urine protein to creatinine ratio (UPCR) by 47.6% (95% CI -60 to -31.3%) by week 13, reported Glenn Chertow, MD, MPH, of Stanford University School of Medicine in Palo Alto, California.

Starting at an average baseline UPCR of 2.21 g/g, patients on VX-147 had an average UPCR at week 13 of 1.27 g/g -- meeting the study's primary endpoint -- Chertow said at a late-breaking presentation at the National Kidney Foundation Spring Clinical Meetings.

"These results provide the first clinical evidence that inhibition of APOL1 function, the gain of function mutation, can reduce proteinuria in APOL1-mediated kidney disease, and I believe mark a milestone in the understanding of APOL1 as a therapeutic mechanism," he explained.

"It's exciting to think about this approach as a precision-medicine approach," Chertow noted. "Nephrology in general has fallen a bit behind oncology, cardiology, and several other medical subspecialties. It's exciting to see developments coming in glomerular disease."

"This is the first of many, we hope," he added.

This investigational treatment was clinically effective even in patients considered nephrotic, which was defined as a UPCR between 2.7 g/g to under 10 g/g plus an eGFR of 27 mL/min/1.72 m² or higher. Starting at an average baseline UPCR of 3.47 g/g, these nephrotic patients dropped down to a mean UPCR of 1.83 g/g by week 13, representing a 47.7% drop.

Similar findings were reported in a subgroup of patients considered to be subnephrotic, defined as a UPCR between 0.7 g/g to under 2.7 g/g plus an eGFR of 27 mL/min/1.72 m² or higher. These patients dropped down to a mean UPCR of 1.10 by week 13, after starting at a baseline average of 1.84 g/g, for an average 47.5% drop, he stated.

This is clinically relevant as patients who carry two APOL1 mutations and chronic kidney disease have a consistently quicker progression to end-stage kidney disease, Chertow explained. While the specific mechanism behind this association isn't fully understood, he said it's thought to be due to enhanced APOL1 pore function that leads to progressive glomerular dysfunction, proteinuria, and subsequently kidney failure.

The study included 16 patients (three in the nephrotic range; 13 in the sub-nephrotic range) with biopsy-proven focal segmental glomerulosclerosis, two APOL1 mutations, UPCR ≥0.7g/g, and eGFR ≥27mL/min/1.73m². The average age was 38.8 and more than half had the G1/G1 APOL 1 genotype, 37.5% had the G1/G2 genotype, and only one patient had the G2/G2 genotype.

All participants were given VX-147 orally once daily for 13 weeks: the first 2 weeks at a dose of 15 mg and then the remaining 11 weeks at 45 mg. This was added on top of standard of care. Half of patients were on an ACE inhibitor, nearly half were on angiotensin receptor blockers, and a few patients were also on an immunosuppressant or systemic corticosteroids. Patients had a 28-day safety follow-up visit.

All adverse events (AEs) were graded mild to moderate and none led to death or treatment discontinuation. The most common AEs reported included headache, back pain, nausea, blood bicarbonate decrease, diarrhea, dizziness, dysphasia, and fatigue.

Chertow noted that a of VX-147 was announced on April 6.

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