Forty-five per cent of patients in Dimerix’s (ASX:DXB) successful Phase 2a trial in chronic kidney disease (CKD), on advice from their physician, applied for and were granted access to remain on DMX-200 under Australia’s Special Access Scheme, which allows participants continued access to a therapy after they complete a clinical study.
“This demonstrates physicians’ confidence that DMX-200 was having a positive effect on their patients,” Kathy Harrison, CEO, says in an interview with BioTuesdays.
Ms. Harrison explains that physicians’ recommendations were based on patients classified as responders in the trial; achieving a reduction of proteinuria, or protein leaking into the urine because of damage to the kidneys; or a 50% or greater increase in proteinuria four weeks after dosing ceased, suggesting that DMX-200 may have had a potential benefit in slowing disease progression.
Dimerix, which was spun out of the University of Western Australia in 2004, is currently reformulating DMX-200 for twice daily dosing from three times a day in preparation for a Phase 2b study to begin in Australia before the end of 2017, with data expected in early 2019.
“We met with the FDA last year and their indication to us was that the Phase 2b trial could be supportive of a registration for focal segmental glomerulosclerosis (FSGS), following a single pivotal Phase 3 trial, which will likely be conducted in North America and Europe,” Ms. Harrison says.
“The FDA also suggested that we explore efficacy in a refined patient population in the Phase 2b trial, including a group of patients with FSGS for which we have orphan drug designation and is our target for registration,” she adds. “However, we believe DMX-200’s mechanism of action could also be suitable for a wider range of kidney diseases.”
FSGS is a rare disease that attacks the kidney’s filtering units, or glomeruli, causing serious scarring, which leads to permanent kidney damage and even failure. Much as a coffee filter keeps coffee grounds in, glomeruli filter blood, taking out the water-like part, which becomes urine, and leaving the protein in the blood. When glomeruli become damaged, proteins begin leaking into the urine, resulting in proteinuria.
According to Ms. Harrison, first line therapy is drugs to reduce blood pressure, which can reduce proteinuria but does not stop progression to kidney failure. “There is a huge unmet medical need for a safe treatment, which can significantly reduce proteinuria and prolong the life of the kidney.”
CKD is a growing global health problem, driven by factors like increasing incidence of obesity and diabetes. In the U.S. alone, it affects some 26 million people a year. Medicare spending on end-stage renal disease was nearly $33-billion in 2014.
“If we can further demonstrate in our studies that DMX-200 reduces proteinuria levels and prevents progression to the need for blood dialysis, we will have a very viable therapy and a huge leap forward in treatment options for patients over the current highest standard of care,” Ms. Harrison contends.
She points to estimates from independent analysts that the market potential of a FSGS drug to be $1-billion a year in the U.S. alone. “We have ongoing partnering discussions with Big Pharma and key opinion leaders as they recognize there is limited competition in FSGS.”
DMX-200 is an adjunct therapy, consisting of propagermanium, which is given to patients already on the standard-of-care blood pressure drug, irbesartan. Propagermanium targets inflammation in the kidney. Both drugs have been in use for many years and their safety profile is well understood.
Ms. Harrison explains that the combination of these drugs was identified using Dimerix’s Receptor-HIT discovery platform, which facilitates identification of pairs of different receptors, known as heteromers, that interact when small molecule drugs, peptides or antibodies, bind to them. That compares with traditional drug analysis, which is largely based on single target receptors.
“The technology is particularly well-suited to G-protein coupled receptors (GPCRs), a large and important family of drug targets that play a central role in many biological processes and are linked to a wide variety of diseases,” she points out.
“We believe Receptor-HIT can identify new uses for existing drugs and drive the discovery of new drugs and research programs.”
Ms. Harrison says DMX-200 originated from the discovery by Dimerix’s scientists that a GPCR called, AT1R, which is targeted by irbesartan, forms a GPCR heteromer with CCR2, which is the target of propagermanium, and that this GPCR heteromer is highly relevant in kidney disease.
Dimerix’s Phase 2a study met its primary endpoint of safety and tolerability. In addition, six of the 24 patients who completed the study achieved a greater than 50% reduction in proteinuria during at least one dose level of propagermanium.
“This is a 50% improvement over and above the patients’ stable improvement on standard-of-care medication, irbesartan, which classified them as responders,” Ms. Harrison contends. “This result has been deemed clinically meaningful.”
In major studies conducted by Sanofi and published in the New England Journal of Medicine and Nephrology Dialysis Transplantation, irbesartan reduced proteinuria by 24% to 38% in patients with diabetic nephropathy and proteinuria.
Three further patients in Dimerix’s Phase 2a study experienced an increase in proteinuria of 50% or greater after dosing ceased, compared with their final measure on treatment.
“This increase suggests that DMX-200 may have had a possible benefit in slowing disease progression in these patients,” Ms. Harrison suggests.