NHGRI Initiates Phase 2 Clinical Trial of ManNAc for Primary FSGS
Phase 2 Trial Design and Development Stage
The National Human Genome Research Institute (NHGRI) is recruiting patients with primary focal segmental glomerulosclerosis (FSGS) for the Phase 2 clinical trial NCT06664814 of ManNAc. ManNAc, an investigational drug with the generic name N-acetyl-D-mannosamine, is a metabolic precursor that acts on the N-acetylneuraminic acid (Neu5Ac·sialic acid) biosynthesis pathway regulated by the GNE enzyme, aiming to increase sialylation of glomerular proteins. The single-center trial at the Bethesda NIH Clinical Center will enroll 30 adults and administer 2,000mg of ManNAc orally twice daily for 12 weeks, with a primary completion date expected on November 30, 2027. As an open-label, single-arm study, it focuses more on dose safety and exploratory signals for subsequent randomized trials rather than confirming efficacy.
Biological Rationale Targeting Proteinuria
Reduced sialic acid on glycoproteins such as podocalyxin and nephrin on podocyte surfaces impairs the charge selectivity and structural integrity of the glomerular filtration barrier, leading to proteinuria. ManNAc is the first dedicated precursor in this pathway, aiming to supplement intracellular Neu5Ac production and restore hypo-sialylated glomerular barriers. In the earlier Phase 1 trial NCT02639260, ManNAc was well tolerated without serious adverse events, and proteinuria decreased by 12–52% in the twice-daily dosing group, with a mean adjusted reduction of 9.69% (p < 0.0001). However, due to the small number of patients and short-term results, this Phase 2 trial aims to revalidate the association between UPCR changes and hypo-sialylation observed in kidney biopsies.
Outcome Measures and Patient Selection
The primary endpoint is the reduction rate of urine protein-to-creatinine ratio (UPCR) at 12 weeks. Partial response is defined as a reduction exceeding 40% and an absolute UPCR below 1.5g/g, while complete response is defined as UPCR below 0.3g/g. Eligible patients must have biopsy-confirmed FSGS, with screening UPCR ≥2g/g, 24-hour urine protein ≥2g/day, and eGFR ≥45mL/min/1.73㎡. APOL1 variants and pre-treatment hypo-sialylation levels in glomeruli will be analyzed to distinguish responders based on biomarkers. The sample size of 30 patients and the absence of a control group limit direct superiority over FILSPARI but provide valuable data for precision medicine-based follow-up trials.
Competitive Landscape and Commercial Implications
Standard treatments for FSGS include renin-angiotensin system inhibitors, SGLT2 inhibitors, corticosteroids, and calcineurin inhibitors such as tacrolimus and cyclosporine, but toxicity and incomplete responses remain ongoing challenges. Travere Therapeutics (TVTX) received FDA approval on April 13, 2026, for FILSPARI (sparsentan, an endothelin A and angiotensin II type 1 dual antagonist) as the first approved drug for reducing proteinuria in non-nephrotic syndrome FSGS. Later-stage competitive pipelines include Boehringer Ingelheim’s TRPC6 inhibitor BI 764198 in Phase 3 and Dimerix (ASX:DXB)’s CCR2 inhibitor DMX-200 in Phase 3. The global FSGS drug market was estimated at $972.55 million in 2024, and ManNAc targets combination or biomarker-selected markets with a podocyte glyco-biological mechanism distinct from immunosuppression or hemodynamic modulation.
The Phase 2 trial of ManNAc, although limited to 30 patients, holds research value by expanding the understanding of FSGS beyond immune-mediated disease to a metabolic and glyco-biological target of podocyte hypo-sialylation. In the short term, the 12-week UPCR reduction rate, partial response defined as over 40% reduction and UPCR below 1.5g/g, and pharmacokinetics in patients with eGFR ≥45 will determine eligibility for subsequent randomized trials. Mid- to long-term competitive benchmarks include Travere Therapeutics (TVTX)’s FILSPARI, approved by the FDA in April 2026, and Phase 3 candidates BI 764198 and DMX-200. ManNAc must demonstrate differentiation through APOL1 and biopsy-based hypo-sialylation patient selection. If the 12–52% proteinuria reduction signal observed in Phase 1 is replicated in the $972.55 million global FSGS drug market in 2024, ManNAc could establish value as a non-immunosuppressive combination therapy and precision medicine asset.
Source: ClinicalTrials.gov (api_ct)