Safety and Efficacy of ONT0l in Lupus

1. Summary of study intervention – including number of patients, enrollment period and duration of follow-up.

25 eligible lupus nephritis (III, IV, or combination III/IV+V) patients who have no or incomplete response after beginning treatment with mycophenolate mofetil will be enrolled over the course of 5 years. AND 36 active SLE (SLEDAI  ≥ 6), with one active non-renal clinical manifestation, who have failed at least 1 disease modifying anti-rheumatic drug (DMARD) therapy (not including hydroxychloroquine and corticosteroids) patients will be enrolled over the course of 2-5 years (total of 61 participants). Patients will be enrolled for 86 days total: up to 28 days screening, 28 days on study drug, and 30 days follow up. After screening, they will be given the study drug ONT01 (as an add-on to mycophenolate mofetil and other standard of care lupus medication) for 28 days, beginning with a dose of 200mg ONT01 twice a day, and increasing by 200mg twice a day at every visit until the target of 800mg twice a day. Participants will continue taking one of the two highest tolerated doses, between 400 mg and 800 mg twice a day. Adverse events, tolerability, disease metrics, and biomarkers of treatment will be assessed. 7 visits are required by patients over the next 10-12 weeks, and will occur at HSS main campus.

2. Inclusion/Exclusion Criteria:

Inclusion Criteria:

1. ≥ 18 years of age and able to provide informed consent to participate
2. Diagnosis of SLE and have fulfilled the ACR classification criteria for SLE during the course of their disease
3. Active non-renal SLE at time of visit, with one active non-renal clinical manifestation

                                                              i.      Active non-renal SLE is defined as having a SLEDAI of 6 or greater (with at least 1 non-renal non-serological clinical domain)

           OR

                                                            ii.      Active nephritis defined as having a no or partial response after initial induction and maintenance therapy with mycophenolate mofetil (and other standard of care therapies) for 3 months or more for class III, IV, or combination III/IV+V nephritis

1.      Active LN is defined as follows: a. kidney biopsy showing Class III, IV, V, III+V, or IV+V, within 1 year from screening, AND b. 24-hour urine protein/creatinine ratio >=1g/g at screening, AND c. absence of partial renal response (PRR)

2.      Partial renal response (PRR) is defined as a. 24-hour UPCR improved by >=25% after 3 months from the start of induction standard of care (SOC) therapy (baseline), or >= 50% after 6 months from the induction therapy (UPCR), AND b. 24-hour UPCR<2g/g if baseline was < 3g/g, OR < 3g/g if baseline at induction was >= 3g/g. AND d. EGFR>=60 ml/min/1.73 M2 or no less than 80% of Baseline eGFR (at induction) AND e. No intercurrent rescue therapy, death, or early SOC treatment discontinuation or study withdrawal

3.      No response (NR) is defined as a. no achievement of at least a partial renal response, OR b. use of intercurrent rescue therapy, OR c. death

4. Female patients who are women of childbearing potential must agree to use a highly effective form of contraception during the study and for at least 120 days after last exposure to study drug. Male patients with female partners of childbearing potential must use effective barrier contraception (i.e., condoms) during the study and for at least 120 days after last exposure to study drug. Also, patients may not proceed with sperm or egg donation during the study and for at least 120 days after the last exposure to study drug.

Exclusion Criteria: 

a.       Any condition, including any uncontrolled disease (eg, asthma, interstitial lung disease, pulmonary arterial hypertension, morbid obesity), that in the Sponsor-Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct or evaluation

b.       Active central nervous system SLE associated with significant cognitive impairment leading to inability to provide informed consent and/or comply with the protocol

c.       Comorbidities requiring systemic corticosteroid (CS) therapy, such as asthma or inflammatory bowel disease. Systemic is defined as oral, rectal or any injectable route of administration (thus stable dosing by other routes is allowed, including inhaled, topical, ophthalmic, otic, and intranasal).

d.      Active clinically significant viral, bacterial or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks of or during the Screening Visit, or completion of oral anti-infectives within 2 weeks before or during the Screening Visit.

e.       History of positive human immunodeficiency virus (HIV), hepatitis C antibody and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+), and/or hepatitis B core IgG and/or IgM antibody (+) at the Screening Visit.

f.        History, or current diagnosis, of active tuberculosis (TB), or untreated latent TB infection (LTBI), determined by a positive QuantiFERON test at the Screening Visit

g.      History of malignancy (hematologic or solid tumor) within 10 years prior to Screening Visit, except adequately treated basal cell or squamous cell carcinomas of the skin (no more than 3 lesions requiring treatment in lifetime) or adequately treated carcinoma in situ/cervical intraepithelial neoplasia of the uterine cervix

h.      Immunization with live or live-attenuated vaccines within 1 month before or during the Screening period

i.        Initiation of, or change in, dosing of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker within 2 weeks before the Screening Visit or during the Screening period

j.        Treatment with Voclosporin (Lupkynis) or cyclophosphamide (Cytoxan) at time of screening

k.      Treatment with other investigational agents within the last 3 months or 5 half-lives, or as per washout requirement from the previous protocol, whichever is longest, prior to the Screening Visit.

l.        Clinically significant abnormalities in laboratory tests, unless attributable to active SLE at the Screening Visit

                                                              i.            Aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase level > 2.5 × upper limit of normal (ULN), or

                                                            ii.            Total bilirubin > 1.5 × ULN, or

                                                          iii.            Hemoglobin < 5.0 mmol/L [9 g/dL], or

                                                          iv.            White blood cells < 2.5 × 109/L, or

                                                            v.            Absolute neutrophil count < 1500 /mm3, or

                                                          vi.            Platelets < 75 × 109/L

m.    Clinically significant chest imaging (e.g. X-ray, computed tomography or magnetic resonance imaging [MRI]) abnormalities per Investigator opinion (e.g. interstitial lung disease) or evidence of active TB on chest X-ray. Chest imaging study must have been performed in 3 months prior to the Screening Visit or during the Screening period

n.      Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.

o.      Patients are unable or unwilling to adhere to the contraception requirements outlined in inclusion criteria d.

                  Contact Information for the Study (Full Name, email address, phone number)

• • • • • Christele Felix, felixc@hss.edu, 646.714.6196