ProKidney LP (ProKidney), a leading clinical-stage cellular therapeutics company focused on the treatment of chronic kidney disease (CKD) and the prevention of end-stage renal disease (ESRD) requiring dialysis or transplant, today published data from a patient study confirming the mechanistic action of its lead candidate REACT™ with cell marker analysis.
The paper, published in Kidney International Reports, describes observed improvements in renal function and a wide array of clinical parameters in patients with moderate to advanced diabetic CKD treated with REACT™.
ProKidney’s decade-long research, performed in multiple diseased animal models that were treated with the active biological ingredient found in REACT™, demonstrated repair of diseased kidneys and the improvement of kidney function. Extensive structural, functional, and biochemical analyses, including biopsies and dissection of the treated animal organs, highlighted that REACT™ has the potential to promote the development of new functional kidney structures, including glomeruli and tubules, as well as reduce fibrosis and inflammation. In addition, proteomics, genomic, and metabolomic analyses performed on the animal tissues support the mechanism of repair, new kidney tissue formation, and improvement in renal function promoted by the active biological ingredients in REACT™. While similar extensive tissue analyses cannot be performed on the kidneys of subjects in clinical trials, analyses of blood and urine are consistent with the findings in the animal studies.
“The translational analyses published in this paper are major foundational discoveries in understanding REACT’s™ mechanism of action and what it could mean for CKD patients and their caregivers. This publication is further evidence that REACT™ may successfully stabilize and improve kidney function in patients with moderate to severe diabetic CKD,” said Dr. Tim Bertram, CEO and Founder of ProKidney. “We are actively enrolling diabetic CKD patients in the Phase 3 REACT™ program, which has been aligned with regulatory authorities in the U.S. and Europe. We intend to bring this first ever autologous cell therapy for CKD through regulatory review and make it available to patients as expeditiously as possible.”
REACT™ is an autologous cell therapy produced from a patient’s own kidney cells that is comprised of a proprietary mixture of progenitor cells that have been selected and cultured so they can be placed back into the patient’s kidney to restore the natural healing processes. REACT™ does not require immunosuppression, which is required for allogeneic (from another person) kidney or cellular transplants. ProKidney’s treatment involves a minimally invasive procedure, starting with a standard kidney biopsy, followed by in vitro amplification of selected renal cells (SRCs), the active biological ingredient in REACT™, that are able to harness the body’s intrinsic ability to repair and restore damaged kidney tissue. The injection procedure of REACT™ is done on an outpatient basis with placement in the cortex of the patient’s kidney. This procedure has been shown to be well-tolerated when compared to kidney biopsy, a standard diagnostic procedure.
ProKidney’s RMCL-002 multi-center, randomized Phase 2 trial enrolled 81 stage 3/4 CKD diabetic patients who received two injections in the same kidney six months apart, is ongoing and is evaluating safety, efficacy, and durability of REACT™. A paper describing the 81 subject study was published in March 2022 in the American Journal of Nephrology. Of the 81 subjects in RMCL-002, 22 subjects have consented to have further phenotypic and proteomic, genomic, and metabolomic analyses of the cells comprising their personalized REACT™ product. The results of these analyses were published in The Kidney International Report mentioned above.
All 22 subjects had moderate-to-advanced type 2 diabetic CKD. Annualized estimated glomerular filtration rate (eGFR) slopes pre- and post-REACT™ injection were compared. Fluorescent Activated Cell Sorting (FACS) analysis for renal progenitor lineages in REACT™ and vascular endothelial growth factor A (VEGF-A) analysis were performed. Annualized eGFR slope was -4.63 ml/min per 1/73 m² pre-injection and this showed a statistically meaningful improvement (P=0.015) post-injection. Around 30% of patients achieved stabilization of kidney function and seven had an eGFR slope of >0 ml/min per 1.73 m² post-injection.
Selected renal cells were found to have cell markers from ureteric bud, mesenchymal cap, and podocyte sources and there was production of VEGF, a growth factor associated with maintaining normal nephron function and repair. Improvements were observed in a wide range of clinical parameters pre- and post-injection, including serum creatinine, phosphorus, calcium, and hemoglobin.
No SAEs were associated with the biopsies and REACT™ injections. Other unrelated serious adverse events in this study were common in this population due to the comorbidities of advanced diabetic CKD and metabolic syndrome but were similar in number and characteristics to other historical CKD trials.
The conclusions in the Kidney International Report suggested that the selected renal cells in REACT™ may be able to stabilize and improve kidney function, potentially halting or reversing type-2 diabetic CKD progression or may initiate neo kidney like tissue development to stabilize and improve kidney function and halt type 2 D-CKD progression.
About The Phase 3 Clinical Program for REACT™
In October 2021, the FDA granted ProKidney’s REACT™ Regenerative Medicine Advanced Therapy (RMAT) designation, after reviewing more than seven years of data collected from over 100 REACT™–treated patients with stages 3/4 diabetic CKD and moderate-to-severe albuminuria and guided ProKidney on a registrational clinical program and potency assay development. This program is designed to generate efficacy and safety data in two randomized, sham-controlled, blinded studies with a primary composite endpoint under a Time-to-Event design. The trials in total will include approximately 1,200 subjects globally, and a clinical evidence package based on this design may provide the necessary evidence of safety and effectiveness to support a Biologics License Application (BLA) for commercialization of REACT™.
The Phase 3 program will be conducted in multiple centers in the United States, Europe, Latin America, and Asia Pacific. Study subject demographics will be consistent with previous trials involving REACT ™, including patients at high-risk-of-end-stage kidney disease: Type 2 diabetic mellitus, CKD stage 3/4, not on renal dialysis, eGFR 20-50 ml/min/1.73 m2, and UACR ranging from 300-5000 mg/g. The robust safety profile of REACT™ after two injections in the same kidney in clinical studies thus far supports an effort to enhance efficacy potential by injecting subjects in both kidneys in the Phase 3 program. This broader injection pattern holds the potential to achieve greater efficacy as the therapy will be delivered into the patients’ two kidneys – 2x the kidney mass as compared to Phase 2.
Study subjects in the treatment arm will undergo a kidney biopsy and then be injected in each kidney once with a three-month interval in between injections. Study subjects randomized to the standard of care arm of the study will receive sham biopsies and injections. Following either the second REACT™ or sham injections, subjects in the treatment or standard of care arms will be followed clinically until they reach one of the three components of the primary composite endpoint. Specifically, the primary composite endpoint for this Phase 3 clinical program is the time from the first injection to the earliest of:
At least 40% reduction in estimated glomerular filtration rate (eGFR), which is a measure of how well the kidneys are working;
eGFR<15mL/min/1.73m² sustained for 30 days and/or chronic dialysis, and/or renal transplant; or
Death from renal or cardiovascular causes.
In addition to the primary endpoint, a set of key secondary endpoints will be included to evaluate trends in proteinuria, quality of life, other kidney associated laboratory parameters, and other metrics.
Eligible participants from the control standard of care arms of both Phase 3 trials, will be offered the opportunity to enroll into a new Phase 2 trial to allow them to be injected with REACT™ after completing the Phase 3 trial or after experiencing one of the qualifying events highlighted above. This is expected to facilitate the recruitment of study subjects by allowing them to access the potential benefits of REACT™, and at the same time expand the clinical evidence for REACT™’s efficacy and safety profile.