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But results were not fully durable after treatment cessation

by
Kristen Monaco
,
Senior Staff Writer, MedPage Today

May 28, 2024

An investigational monoclonal antibody appeared to have therapeutic benefits among kidney transplant patients with antibody-mediated rejection, a randomized phase II trial showed.

After 24 weeks, resolution of morphologic antibody-mediated rejection occurred in nine of the 11 participants who received infusions of the CD38 monoclonal antibody felzartamab compared with two of 10 placebo-treated participants (risk ratio 0.23, 95% CI 0.06-0.83), reported Georg Böhmig, MD, of the Medical University of Vienna, and colleagues in the New England Journal of Medicine.

Originally developed for multiple myeloma, felzartamab is a fully human IgG1 monoclonal CD38 antibody that depletes target cells through antibody-dependent cellular cytotoxicity and phagocytosis.

“The results of our study could represent a breakthrough in the treatment of kidney transplant rejection,” said co-author Katharina Mayer, MD, also of the Medical University of Vienna, in a press release. Mayer presented the findings over the weekend at the European Renal Association Congress in Stockholm.

In a statement, Böhmig noted that “there is a large unmet need for a therapy that resolves disease by the Banff classification and preserves kidney function in patients with antibody-mediated rejection. The data presented in this study are very compelling and represent the potential for significant progress to be made in this high-burden disease.”

The resolution of morphologic antibody-mediated rejection observed in the trial was mainly driven by a reduction in microvascular inflammation. Participants in the felzartamab group had a median microvascular inflammation score of 0 compared with 2.5 in the placebo group.

The felzartamab group also had lower molecular scores at 24 weeks, representative of the probability of antibody-mediated rejection, compared with the placebo group (median score 0.17 vs 0.77), as well as lower median levels of donor-derived cell-free DNA (0.31% vs 0.82%, respectively), which is used to diagnose graft injury. Median CD16^bright natural killer cell count in peripheral blood was also lower in the felzartamab group than the placebo group (16 cells/µL vs 54 cells/µL).

“Although this trial was not powered for clinical outcomes, the results suggest a potential stabilization of the eGFR [estimated glomerular filtration rate] slope, which is a surrogate for long-term allograft survival,” the researchers wrote. The 1-year eGFR slope was -0.39 mL/min/1.73 m² in the felzartamab group and -4.53 mL/min/1.73 m² in the placebo group.

However, treatment effects were not durable after discontinuation, with three of nine patients responsive to felzartamab having a recurrence of antibody-mediated rejection by week 52, along with an increase in molecular activity and biomarker levels toward baseline levels. Of the felzartamab-treated patients who experienced resolution, biopsy results showed that 67% maintained resolution at 52 weeks with no additional drug administered.

This suggests that “continuing treatment would be required for long-term prevention of rejection-related graft loss,” Böhmig and colleagues wrote.

The small trial recruited 22 kidney transplant recipients with antibody-mediated rejection — 11 randomized to each group. One placebo patient didn’t finish the study following graft loss caused by rejection at week 14. The median time from kidney transplantation to trial inclusion was 9 years. Median age was 39, 50% were women, 91% were white, and 9% were Asian. Only 27% received their kidney from a living donor.

Most had chronic active antibody-mediated rejection (68%), followed by active antibody-mediated rejection (32%) and additional borderline lesion antibody-mediated rejection (14%). The majority had human leukocyte antigen (HLA) class II-only donor-specific antibody (59%), followed by HLA class I only (32%); few had HLA class I and II (9%).

Nine felzartamab infusions were administered over the course of 6 months at a dose of 16 mg/kg of body weight, which was followed by a 6-month observation period.

Eight felzartamab-treated patients experienced mild or moderate infusion reactions with the first infusion. Treatment-related adverse events occurred in 91% and 64% of the felzartamab and placebo groups, respectively, and were mostly comprised of infections. Nasopharyngitis, COVID-19, and cytomegalovirus viremia occurred more frequently in the felzartamab group.

No fatal adverse events occurred, and no patients discontinued treatment because of adverse events.

“Our findings also raise the hope that felzartamab could counteract the rejection of other donor organs, such as heart or lung transplants,” said Böhmig. “Xenotransplants using genetically modified pig organs could perhaps also move further into the realm of possibility.”

A US soldier used to be sentenced Friday to 14 years in penal complex for attempting to lend a hand the Islamic Assert waste troops.

The sentencing of Cole Bridges, 24, came after his 14 June 2023 guilty plea to terrorism expenses.

Bridges joined the military some five years ago, and used to be assigned as a cavalry scout within the third infantry division essentially based fully in Castle Stewart, Georgia. Earlier than Bridges changed into a soldier, then all some other time, he started researching and ingesting pro-terrorist propaganda – and voiced his give a rob to for IS and jihad on social media, Ny federal prosecutors talked about.

Around October 2020, Bridges started communicating on-line with any individual whom he believed used to be an IS supporter. This person used to be in actuality an FBI undercover employee, authorities talked about.

Bridges told the covert operative that he used to be pissed off with the US defense force and wanted to lend a hand IS. He then gave “coaching and guidance to purported Isis fighters who were planning attacks, alongside side advice about likely targets in Unique York Metropolis”, in accordance with a press delivery on his sentencing.

Bridges moreover gave parts of a US military coaching manual, as smartly as recordsdata on strive towards ways, to the undercover employee. He did so “with the working out that the materials would be worn by Isis in future assault planning”.

In December 2020, Bridges started giving the covert operative instructions in relate that the purported IS militants would know the design target US forces within the Heart East. Bridges moreover shared guidance on the absolute most reasonable means to guard an IS stronghold in a expose to assault US special forces, prosecutors talked about.

This recommendation integrated how chances are high you’ll maybe moreover wire some buildings with explosives, to abolish troops. Early the next 12 months, Bridges gave the undercover employee a video of himself carrying his defense force physique armor “standing in front of a flag on the entire worn by Isis fighters and making a gesture symbolic of give a rob to for Isis,” prosecutors talked about.

About one week later, Bridges sent yet some other video whereby he, “the utilization of a direct manipulator”, voiced a propaganda speech to give a rob to an expected IS assault towards US servicemen, officers talked about.

Bridges’ time in federal penal complex will likely be adopted by 10 years of supervised delivery.

“Cole Bridges worn his US military coaching to pursue a horrifying goal: the brutal waste of his fellow service individuals in a fastidiously plotted ambush,” the Ny US licensed expert Damian Williams talked about in a press delivery. “Bridges sought to assault the very troopers he used to be entrusted to guard and, making this abhorrent conduct mighty extra troubling, used to be desirous to lend a hand other folks he believed were individuals of a lethal foreign terrorist group notion this assault.

“Right here’s a betrayal of the worst inform.”