An Open-Label Phase 2 Study of N-Acetyl-D-Mannosamine (ManNAc) in Subjects With Primary Focal Segmental Glomerulosclerosis

• INCLUSION CRITERIA:

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

• Prior kidney biopsy demonstrating FSGS obtained within 5 years prior to thescreening visit.

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

• If the patient is on immunosuppressive therapy (e.g., prednisone, cyclosporine,tacrolimus or mycophenolate mofetil) he/she should be on these medications for atleast 3 months prior to study evaluation and should be on a stable dose of themedication for at least 4 weeks before start of trial, with no plans to alter theregimen during 12 weeks of study period, except to stabilize levels and/or for anysafety concerns.

• 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), 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.

• Subjects must have a spot random urine PCR of >= 2g/g on each of 3 measurementscollected on at least 2 separate days during screening period plus a 24-hr urineprotein collection of >= 2g/day. The rationale for using this degree of proteinuriais that proteinuria beyond this threshold value significantly increases the risk ofprogressive decline of renal functions in the absence of effective therapies tomitigate this risk. Conversely, this threshold value could also allow for theselection of a cohort of patients who are most likely to benefit from ManNActherapy.

• Subjects with an estimated glomerular filtration rate (eGFR) >=45 mL/min/1.73/m^2using the race-free CKD-EPI 2021 equation based on creatinine and cystatin-C [Inkeret al, 2021]. The rationale is that below this eGFR threshold, sialic acid, the keymetabolite of ManNAc markedly accumulates and may potentially result in systemictoxicity. Prior pharmacokinetic studies have shown that renal elimination of sialicacid is primarily through glomerular filtration, and it is neither reabsorbed norsecreted in the renal tubules. Hence decline in eGFR below 45 mL/min/1.73m^2directly correlates with rising blood sialic acid levels [Fuentes et al, 2020], inaddition, these subjects may not benefit as much from ManNAc therapy as they haveadvanced disease pathology, which may be irreversible. Future studies withpersonalized precision ManNAc dosing may benefit the patient population with eGFR <45 mL/min/1.73m^2.

• 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.

• 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:

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

• Individual presenting for initial therapy of uncontrolled nephrotic syndrome whichwe define as proteinuria as measured by spot urine protein:creatinine ratio >3g/g or 24-hour urine protein excretion of >3.5g/day with symptomatic peripheral edema orpulmonary edema, hypoalbuminemia (serum albumin <3.0g/dl), electrolyte disturbances (related or unrelated to medical therapy), and/or active thromboembolism (initiatedon systemic anticoagulation in the last 3 months). The rationale for this criterionis that patient presenting for initial therapy for uncontrolled nephrotic syndromemay need to be initiated on various medications including immunosuppressives as wellas non-immunosuppressive drugs which can significantly change the level ofproteinuria. Additionally, fluid shifts due to diuretic use for treating edema canalter GFR which could confound the pharmacokinetics and pharmacodymanics of theinvestigational drug.

• 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.

• 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.

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

• Individuals whose renal biopsy shows evidence of an additional pathology along withFSGS.

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

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

• 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.

• 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.

• Individuals with hypertriglyceridemia >500 mg/dL.

• Individuals with a documented history of malignancy (identified in last 5 years oron active therapy at time of screening).

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

• Individuals with documented history of hematological conditions commonly associatedwith FSGS such as sickle cell disease and myeloproliferative disorders.

• Individuals with a documented history of cardiac conditions commonly associated withFSGS such as congenital cyanotic heart disease. Individuals with a documentedhistory of connective tissue disorders commonly associated with FSGS such as SLE andmultiple sclerosis.

• Individuals taking medications (either currently or within the last 6 months)associated with FSGS such as interferons, lithium, androgenic steroids, sirolimus,heroin, anthracyclines and bisphosphonates.

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

• 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.

• Individuals with hypersensitivity to ManNAc.

• 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.

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

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

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

• Any patient receiving rituximab, cyclosphosphamide and/or plasmapheresis within 6months of screening.

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

• Any patient with collapsing FSGS variant on renal biopsy.

• Individuals with clinical history suggesting a post-adaptive FSGS such as those withneonatal history of low birth weight, congenital anomaly of the kidney or urinarytract (CAKUT) based on renal ultrasound findings or history of nephrectomy,vesicoureteral reflux or obesity as defined by Body Mass Index (BMI) > 40kg/m^2.