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New Therapies for Consideration in the Future

New Therapies for Consideration in the Future

Several new areas of drug development are ongoing including inhibitors of hepcidin production or action, anti-interleukin-6 specific antibodies (Ziltivekimab), anti-inflammatory biologicals, and activin receptor ligand traps (1).

A phase 1/2, placebo-controlled trial examined the effects of intravenous ziltivekimab every 2 weeks for 12 weeks vs placebo, in 61 people on haemodialy sis with a single nucleotide polymorphism of the TMPRSS6 gene (putatively increases susceptibility to IL-6–mediated inflammatory effects). Ziltivekimab led to a significantly greater reduction of high-sensitivity C-reactive protein and ESA usage and ESA resistance index. There was also an increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin (2). Future trials may define its benefit.

PRS080#022, a PEGylated (polyethylene glycol bound) anticalin protein, antagonizes hepcidin with picomolar affinity (3). Two first-in-human randomised, double-blind phase 1 trials of PRS-080#22; a single intravenous infusion of placebo or PRS-080#22 was administered to 48 healthy volunteers (phase 1a) and 24 patients on hemodialysis (phase 1b) at different doses (0.08-16 mg/kg for the phase 1a study and 2-8mg/kg for the phase 1b study) in successive dosing cohorts. This led to a dose dependent reduction in serum hepcidin levels, mobilisation of serum iron with increased serum iron concentration and transferrin saturation. There was impact on ferritin or haemoglobin. This drug was safe and effective but further clinical studies are needed. Neutralising hepcidin with a monoclonal antibody (mAb) may prevent ferroportin internalization, restore iron efflux from cells, and allow transferrin-mediated iron transport to the bone marrow. A multi-centre, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of a fully humanized mAb (LY2787106) with high affinity for hepcidin in cancer patients with anaemia (4). Thirty-three patients with hepcidin levels ≥5 ng/mL received LY2787106 either every 3 weeks (19 patients, dose range 0.3–10 mg/kg) (part A) or weekly (14 patients, dose 10 mg/kg) (part B). Consistent dose-dependent increases in serum iron, and transferrin saturation were seen at the 3 and 10 mg/kg dose levels, typically peaking within 24 h after LY2787106 administration and returning to baseline by day 8. LY2787106 resulted in transient iron mobilization, thus supporting the role of hepcidin in iron regulation (4).

Haemojuvelin (HJV), encoded by the HEF2 gene, a glycosylphosphatidylinositol-linked membrane-associated protein (expressed in liver, skeletal muscle and heart), binds to bone morphogenic proteins (BMPs) and enhances their effectiveness to activate the BMP-SMAD (small mothers against decapentaplegic) signalling pathway to stimulate hepcidin transcription in hepatocytes (5, 6).

Currently animal data is available suggesting that BMP6 is a key endogenous regulator of hepcidin (7, 8). Deletions in genes encoding the ligand BMP6, the BMP coreceptor HJV, the BMP Type I receptors ALK2 and ALK3, or the intracellular signalling molecule SMAD4 (9-11), all independently resulted in inappropriately suppressed hepcidin expression and tissue iron overload. Recent studies examining te use of anti-haemojuvelin antibodies have demonstrated improvements in anaemia (12). Pre-clinical models have clearly shown that anti-HJV antibodies have the potential to modulate hepcidin and improve Hb in inflammatory and non-inflammatory conditions (13). A recent phase 1b/2a multi-center, open-label clinical trial of DISC-0974, a monoclonal antibody (mAB) targeting hemojuvelin, in people with myelofibrosis or chronic kidney disease is ongoing (NCT05320198). Initial findings have shown a dose-dependent decreases in hepcidin across all treated patients. These reductions in hepcidin corresponded to dose-dependent increases in serum iron.

Aptamers are synthetic single-stranded oligonucleotides that bind ligands with high affinity, representing a novel class of oligonucleotide structures suitable for blocking purposes (14). Spiegelmers are mirror image aptamers. Spiegelmers are attractive therapeutic agents and NOX-H94 is a polyethylene glycol conjugated (PEGylated) spiegelmer that targets and binds to human hepcidin (15). The first human trial is currently underway (15, 16).

A study characterizing the molecular mechanism of ferroportin disease with parenchymal iron overload and resistance to hepcidin, the thiol form of Cys326 in ferroportin was found to be essential in hepcidin–ferroportin interaction. An antiferroportin mAb which binds to the extracellular loop of ferroportin, can block the hepcidin–ferroportin interaction, while maintaining ferroportin function (17). This strategy would promote ferroportin activity and allow continuous iron influx, potentially preventing iron-restrictive erythropoiesis due to hepcidin excess. Human studies are awaited.

SGLT2 inhibitors have been shown to increase Hb in people with chronic kidney disease and/ or heart failure (18-23). The increased Hb in people treated with SGLT2 inhibitors seems to be independent of diuretic use or as a result of intravascular volume depletion causing haemoconcentration (24, 25). Data suggest that SGLT2 inhibitor administration is associated with transient increases in serum EPO concentrations (30%–40%), an increase in reticulocyte counts or haematocrit levels (26) and a decrease in ferritin and hepcidin, indicating erythropoietic stimulation (27- 30). However, more information is needed to better understand the mechanisms of action underlying these effects and their clinical relevance.

References

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