MSC Therapy Shows Promise in Diabetic Kidney Disease
No adverse events related to the infusions of stromal cells were reported.
Orbsen Therapeutics’ ORBCEL, an investigational allogeneic bone marrow-derived mesenchymal stromal cell (MSC) therapy being evaluated in the phase 1/2a NEPHSTROM clinical trial (NCT02585622) for the treatment of progressive diabetic kidney disease (DKD) in adults with type 2 diabetes (T2D), has generated promising safety and efficacy data in interim results from the study’s first cohort.
ORBCEL consists of highly purified immunomodulatory stromal cells and is administered intravenously. The first cohort treated 12 participants with ORBCEL at a dose of 80x106 cells and 4 participants with a placebo (Cryostor CS10). It was noted that the safety and tolerability profile was similar for both the ORBCEL and placebo cohorts, with no adverse events (AEs) related to the infusions of stromal cells reported. In terms of efficacy, serum creatinine-based estimated glomerular filtration rate (CKD-EPI, P = 0.034; MDRD, P = 0.034) measurements indicated a statistically significant association between ORBCEL treatment and preservation of kidney function over baseline during the study's 18 month duration, in comparison to the treatment with the placebo. Furthermore, it was noted that, based on monitored blood markers, evidence of stabilization in the proportion of regulatory T-cells in the blood was associated with treatment with ORBCEL, while a tendency for a decrease in the proportion of regulatory T-cells in the blood was observed in patients who received the placebo.
"The current standard of care for DKD patients includes multiple types of drug therapy, such as renin-angiotensin-aldosterone system inhibitors and the more recently approved drug class known as sodium-glucose transporter 2 (SGLT2) inhibitors, which have a proven ability to slow the decline of kidney function,” Guiseppe Remuzzi, director, Mario Negri Institute for Pharmacological Research IRCCS, Bergamo, Italy, said in a statement regarding the news. “However, these medication classes are not tolerated by all patients and are not always effective to fully halt or reverse the progression of kidney injury in DKD. ORBCEL cell therapy might be particularly useful as an additional treatment in patients with rapidly progressive kidney disease caused by diabetes."
The multicenter, double-blind NEPHSTROM study is enrolling patients aged at least 40 years and less than 85 years who have had T2D for at least 3 years. Participants are additionally required to have a urinary albumin excretion of at least 60 µg/min, a urine albumin-to-creatinine ratio of at least 88 mg/g, an estimated GFR (eGFR) of 30 to 50 ml/min/1.73 m2 by the CKD-EPI equation on 2 or more consecutive measurements at least 30 days apart within the previous 6 months, and a documented decline of eGFR of at least -10ml/min/1.73 m2 over the past 3 years or a documented rate of eGFR decline of at least -5 ml/min/1.73 m2 per year based on 3 or more consecutive readings at least 90 days apart in the previous 18 months. Participants must also not have a suspected renal diagnosis other than DKD. Patients with a current resting systolic blood pressure (BP) of 150 mmHg or greater and a current resting diastolic BP greater than or equal to 90 mmHg in a clinical setting, even with treatment with 3 hypertensive agents of different classes; patients who began treatment with a new anti-hypertensive agent, a new lipid lowering agent, or a new hypoglycemic agent within the past 6 months; patients who increased their dose of an anti-hypertensive agent by 100% or more of the previous dose within the previous 3 months; patients with a current HbA1c greater than 75 mmol/mol, a current fasting total cholesterol more than 7 mmol/l, or current fasting total triglycerides more than 3.5 mmol/l will be excluded from participation. Patients who screen positive for clinically significant anti-HLA antibodies will also be excluded. Additional exclusion criteria relate to patient health status, health history, and treatment history.
The study’s primary end point is the number and severity of all pre-specified infusion-associated events and the overall number and frequency of adverse events. Among the study’s numerous secondary end points are measures of GFR, Urinary Albumin/Creatinine Ratio, Urinary albumin excretion, and fasting blood glucose. The study is taking place at locations in Ireland, Italy, and the United Kingdom.
Orbsen Therapeutics has announced its intention to submit the results from the first cohort to a peer-reviewed journal for publication. The company also noted that the trial’s second cohort, which will treat 13 patients, either at a dose of 160x106 cells or with the placebo, completed enrollment in late 2022, and interim data from this cohort is anticipated in the second half of 2023. A phase 2b study for ORBCEL is also in the planning stage, with the company seeking communication with regulatory agencies regarding trial design.
"We're very encouraged by the safety profile and the preliminary efficacy signal that we have seen with our allogeneic cell therapy in patients with diabetes and chronic kidney disease,” Stephen Elliman, chief scientific officer, Orbsen Therapeutics, added to the statement. “Our goal with ORBCEL is to resolve systemic inflammation and improve kidney function, so that these patients will not require dialysis or a kidney transplant. The growing burden of DKD and its impact on healthcare make this an important disease target for Orbsen and our technology."
