A CIRM-funded clinical trial to help kidney transplant patients avoid the need for anti-rejection or immunosuppressive medications has completed enrollment and transplantation of all patients.
Medeor Therapeutics’ MDR-101 Phase 3 multi-center clinical trial involved 30 patients; 20 of them were treated with MDR-101, and 10 control subjects were given standard care. CIRM awarded Medeor, based in South San Francisco, $18.8 million for this research in January 2018.
More than 650,000 Americans suffer from end-stage kidney disease – a life-threatening condition caused by the loss of kidney function. For these people the best treatment option is a kidney transplant from a genetically matched, living donor. Even matched patients, however, face a lifetime on immunosuppressive drugs to prevent their immune system from rejecting the transplanted organ. These drugs can be effective at preventing rejection, but they come at a cost. Because they are toxic these medications increase a transplant patient’s life-time risk of cancer, diabetes, heart disease and infections.
Medeor Therapeutics developed its MDR-101 therapy to reprogram the patient’s immune system to accept a transplanted kidney without the need for long term use of immunosuppression drugs.
The company takes peripheral blood stem cells from the organ donor and infuses them into the patient receiving the donor’s kidney. This creates a condition called “mixed chimerism” where immune cells from the donor help the patient’s immune system adapt to and tolerate the donor’s kidney.
After a standard kidney transplant, the patient is given a combination of three anti-rejection medications which they typically have to remain on for the rest of their lives. However, the Medeor patients, by day 40 post-transplant, are only taking one medication and the hope is that immunosuppression is discontinued at the end of one year.
“Chronic kidney disease and kidney failure are a growing problem in the US, that’s why it’s so important that we find new ways to reduce the burden on patients and increase the odds of a successful transplant with long term benefit,” says Maria T. Millan, M.D., President and CEO of CIRM. “Medeor’s approach may not only reduce the likelihood of a patient’s body rejecting the transplanted organ, but it can also improve the quality of life for these people and reduce overall health care costs by eliminating the need to stay on these immunosuppressive medications for life.”
In an earlier Phase 2 trial, a majority of patients achieved mixed chimerism. Approximately 74 percent of those patients have been off all immunosuppressive drugs for more than two years, including some who continue to be off immunosuppressive medications 15 years after their surgery.
“Today’s news is a tremendous milestone not only for Medeor but for the entire transplant community. This is the first randomized, multi-center pivotal study designed specifically to stop the use of all immunosuppressive anti-rejection drugs post-transplant. This therapy can be a true game changer in our efforts to transform transplant outcomes and help patients live healthier lives,” said Dan Brennan, MD, Chief Medical Officer at Medeor Therapeutics.
If the results from this pivotal clinical trial show that MDR-101 is both safe and effective, Medeor may apply to the Food and Drug Administration (FDA) for approval to market their approach to other patients in the U.S.
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Acute graf-versus host disease (aGVHD) is one of the major problems following allogeneic peripheral blood stem cells transplantation (allo-PBST). For instance, allogenic hematopoietic stem cells transplantation (All of SCT ) has important curative therapy for high-risk haematological maglinancies but severe and or steroid-refractory aGVHD remains a significant limitation to optimal outcome. In human, the presence of donor T cells may activate antigen presenting cells (APCs) to efficiently present alloantigen to donor T cells, while releasing cytokines (IL-12, IL-23,IL-6, IL-27, IL-10,TGFβ) that expand and differentiate both pathogenic and regulatory donor T cells. The concurrent of costimulatory signals at the APC-T cells interface and subsequent coinhibitory signals are critical to the acquisition of effector T cell function and ensuring secretion of pathogenic cytokines (IL-17, IFN-g, TNFα,GM-CSF) plus cytolytic deregulation pathway effectors(perforin & granyzym). Therefore, deregulated of cytokines production occurs as a cascade during sequential monocyte and T cell activation are responsible for many of manifestation of aGVHD. The conditioning regimen leads to damage and activation of host tissues and induces the secretion of inflammatory cytokines. There are many studies shown that cytokine deregulation in the pathogenic and clinical aGVHD. Tanaka et al reported the increase of IFN-g in mixed leukocytes culture between donor and host PBMC which correlated with GVHD development in corresponding patients. Clinical trial to investigate pathogenic of human aGVHD in 30 patients underwent allo-PBSCT showed significantly increase in transcription of IL-2 ,IFN-g, IL-12 andIL-18 in PBMC during onset of aGVHD. Roy et al examined an increase expression of IL-2,IL-4 and IFN-g in PBMC and skin biopsy of allo-BMT patients in the onset of aGVDH. Carayol et al showed that patients after allo-BMT had an increase of mRNA IFN-g in PBMC of patients at the beginning of aGVHD. However, IL-2 and IFN-g were detected in skin biopsies. On the other hand, the spontaneous increase of IL-10 production in unrelated bone marrow transplantation recipients was associated with fewer transplant-related complications including aGVDH. Takasuka et al revealed that marked elevation of plasma IL-10 in the patients who recovery after BMT and severe aGVDH. That observation supported the hypothesis that an increase of IL-10 production by rectpients’ cell during the early post transplantation period reduces the clinical manifestation of aGVDH. Therefore, IFN-g and IL-10 are good prognosis indicator to determine the clinical pathogenic of aGVHD.
Medeor Therapeutics developed MDR-101 therapy to reprogram the patient’s immunsystem to accept a transplanted kidney without the need for longterm use of immunosuppressive drugs. After a standard kidney transplant, the patient is given a combination of three anti-rejection medications. However, the Meteor patients received 1 medication after 40 days of post-transplant. Results of phase 2 trial showed that a majority of patients achieve mixed chimerism. Approximately of 74% of patients have been off all immunosuppressive drugs for more than 2 years and some patients can continue for 5 years after surgery.
It is important to note that, most immunosuppressive drugs are highly toxic and patients receive a multiple of immunosuppressive drugs for 40 days after a standard kidney transplant may hinder the recovery of immune cells. The PBMC of patients required a period of time for recovery and the status of health is varying from one individual to the other. After 40 days of post-transplantation, patients receiving the donor’s kidney are infused with blood stem cells from the organ donor. The consequent of Medeor therapy produces 3 possibilities of event which might occur in immunity of patients . -Population of PBMC in donor is dominant than recipient. -The equal amount of PBMC in donor and recipient. -Population of PBMC in recipient is dominant than donor.
The dominant effect of PBMC in donor may seriously affect multiple organs of recipient from functioning in longterm . However, the dominant effect of PBMC in recipient may induce rejection of transplanted donor’s organ in future. The expression of IFN-g and IL-10 in PBMC are good prognosis indicators to determine the clinical pathogenic of aGVHD in patients.