An Open-Label Phase 2 Study of N-Acetyl-D-Mannosamine (ManNAc) in Subjects With Podocyte Diseases

• INCLUSION CRITERIA:

Individuals must meet all the following inclusion criteria to be eligible to participate in this study:

1. Prior kidney biopsy demonstrating FSGS, MCD, or MN obtained within 10 years prior tothe screening visit.

2. Age >=18 years weighing more than 50 kg.

3. If the patient is on any immunosuppressive therapy, he/she should be on them for atleast 3 months prior to study evaluation and should be on a stable dose for at least 4 weeks before start of trial, with no plans to alter the regimen during 12 weeks ofstudy period, except to stabilize levels and/or for any safety concerns.

4. Subjects will be allowed to continue with standard of care (SOC)non-immunosuppressant antiproteinuric agents to include RAAS inhibitors,mineralocorticoid antagonists (MRA), sodium-glucose co-transporter-2 inhibitors (SGLT2i), non-dihydropyridine calcium channel blockers (NDHP-CCBs), Sparsentan, andglucagon-like peptide-1 (GLP-1) receptor agonists, in addition to other SOC adjuvanttherapies such as diuretics, if they are able to maintain a stable dose throughoutthe trial. Subjects and their primary nephrologists will be encouraged to optimizetheir SOC treatments as much as possible prior to trial commencement. Subjects mustbe on a stable dose for at least 4 weeks before start of trial. Subjects shouldattempt to keep stable doses of both immunosuppressants and anti-proteinuric drugsthroughout trial duration, to avoid confounding effects. Patients not receiving anyof these SOC agents either due to allergy or intolerance will still be eligible.

5. Subjects must have a spot random urine PCR of >=2 g/g on each of 3 measurementscollected on at least 2 separate days during screening and baseline period plus a 24-hr urine protein collection of >=2 g/day. The rationale for using this degree ofproteinuria is that proteinuria beyond this threshold value significantly increasesthe risk of progressive decline of renal functions in the absence of effectivetherapies to mitigate this risk. Conversely, this threshold value could also allowfor the selection of a cohort of patients who are most likely to benefit from ManNActherapy.

6. Subjects with an estimated glomerular filtration rate (eGFR) >=30 mL/min/1.73/m^2using the race-free CKD-EPI 2021 equation based on creatinine and cystatin-C. Therationale is that below this eGFR threshold, sialic acid, the key metabolite ofManNAc markedly accumulates and may potentially result in systemic toxicity. Priorpharmacokinetic studies have shown that renal elimination of sialic acid isprimarily through glomerular filtration, and it is neither reabsorbed nor secretedin the renal tubules. Hence decline in eGFR below 30 mL/min/1.73m^2 directlycorrelates with markedly rising blood sialic acid levels, in addition, thesesubjects may not benefit as much from ManNAc therapy as they have advanced diseasepathology, which may be irreversible. Future studies with personalized precisionManNAc dosing may benefit the patient population with eGFR <30 mL/min/1.73m^2.

7. Subjects of reproductive potential must be willing to use at least one effectiveform of birth control throughout the trial period, unless they have had a permanentbirth control procedure/intervention including but not limited to hysterectomy,tubal ligation and/or vasectomy. These may include the following: barrier methods (such as condoms), oral or depot injection (for example, Norplant or Depo-Provera)contraception medication, and/or intrauterine devices.

8. Evidence of a personally signed and dated informed consent indicating that thepatient has been informed of all pertinent aspects of the study and theirwillingness to comply with all aspects of the study and their willingness to complywith all aspects of the study protocol, including treatment plan, laboratory tests,baseline and follow-up visits and procedures that include completion of dailydiaries to record symptoms and medication intake.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Individuals who are unwilling or unable to provide informed consent.

2. Individuals who, at screening, have unstable nephrotic syndrome based on review ofrecords and clinical assessment by investigators will be excluded. The rationale for this criterion is that patients presenting with unstable nephroticsyndrome may need to be initiated on various medications includingimmunosuppressives as well as non-immunosuppressive drugs which can significantlychange the level of proteinuria. Additionally, fluid shifts due to diuretic use fortreating edema can alter GFR which could confound the pharmacokinetics andpharmacodynamics of the investigational drug.

3. Individuals who acutely require optimization of volume status with intravenousdiuretics to control volume overload, as this may result in fluid shifts between theintravascular space and the remainder of extracellular fluid volume. This mightalter drug pharmacokinetics and pharmacodynamics as mentioned above in # 2.

4. Individuals with a psychiatric illness or neurological disease that in the judgementof the investigators would interfere with the ability to adhere with therequirements of this protocol. This includes, but is not limited to,uncontrolled/untreated psychotic depression, bipolar disorder, schizophrenia,substance abuse or dependence, antisocial personality disorder, panic disorder, orbehavioral problems, which might interfere with effective communication.

5. Vulnerable individuals, including those with impaired cognitive function or areincarcerated.

6. Individuals whose renal biopsy show evidence of an additional pathology other thanFSGS, MCD, and/or MN.

7. Renal biopsy showing interstitial fibrosis and tubular atrophy (IFTA) >50% perbiopsy report.

8. Individuals with uncontrolled hypertension with blood pressures consistently >140/90mmHg on 3 or more community clinic blood pressure measurements.

9. Individuals with clinical evidence of any type of active infection including but notlimited to HIV, Hepatitis B and/or Hepatitis C or patients who are positive onscreening test for HIV including antibody or viral load, HBV surface antigen and/orHCV antibody. If a patient is positive for HCV antibody, then an HCV viral load willbe measured to identify subjects with active infection. Additional tests may includethose to screen for active CMV, Infectious Mononucleosis (Epstein-Barr Virus),parvovirus B19 and/or COVID-19 infection as per investigator judgement.

10. Individuals with evidence and/or documented history of progressive deterioration ofliver functions, including the production of clotting factors, removal of toxicmetabolic products, bile excretion for at least 6 months, routine hepatic laboratoryindices including but not limited to (AST, ALT, or GGT) greater than 3 times theupper limit of normal, and/or individuals with a documented history and/or diagnosisof chronic liver disease.

11. Individuals with hypertriglyceridemia >500 mg/dL.

12. Individuals with a documented history of malignancy (identified within the last 5years and/or on active therapy at time of screening).

13. Individuals with a documented history of Type I or Type II Diabetes Mellitus

14. Individuals with a documented history of any cardiac, connective tissue, and/orhematologic diagnoses that, in the judgment of the investigators, may be associatedwith FSGS, MCD, and/or MN.

15. Individuals who are currently taking, or who have taken within the last 6 months,medications known or suspected to cause drug-induced podocytopathies, includinginterferons, lithium, heroin, and anthracyclines, will be excluded at the discretionof the investigators.

16. Individuals who are pregnant, will be breastfeeding or refuse birth control anytimeduring the study.

17. Individuals who have received treatment with another investigational drug,investigational device, or approved therapy for investigational use less than 60days prior to planned ManNAc dosing.

18. Individuals with hypersensitivity to ManNAc.

19. Individuals who have been treated with ManNAc, sialic acid, IVIG, and/or othersupplements containing sialic acid (e.g., sialyllactose) less than 60 days prior toplanned ManNAc dosing.

20. Individuals who received a renal or any other solid organ and/or bone marrow/stemcell transplantation.

21. Individuals who, in the judgment of the investigator, have a condition that placesthe subject at increased risk for AEs or have any other illness or clinicalcondition that might confound the results of the study or pose an additional risk inadministering study drug to the subject.

22. Patients who need systemic immunosuppressive or glucocorticoid therapy for non-renalindication at any time throughout the trial.

23. Any patient receiving B-cell depleting therapy, monoclonal antibody therapy,cyclophosphamide, and/or plasmapheresis within 6 months of screening.

24. A documented history of active alcohol and/or substance abuse within the past 2years.

25. Any patient with rapidly progressing glomerulonephritis (RPGN) and/or crescenticglomerulonephritis on renal biopsy.