Kidney disease trial shows two drugs are better than one

By Lauren Davis
Tuesday, 05 June, 2018

Kidney disease trial shows two drugs are better than one

Clinical-stage biotech company Dimerix is on a mission to treat chronic kidney disease and, with the help of lead therapeutic candidate DMX-200, it just might succeed. With a Phase 2 trial conducted in 2017 yielding promising results, the company is now set to more deeply investigate the therapeutic effects of DMX-200 on a hugely underserved disease.

Kidney Health Australia states that around one in 10 Australians aged 18 years and over has indicators of chronic kidney disease (CKD), such as reduced kidney function and proteinuria — the presence of the protein albumin in the urine. People with CKD have a two- to three-fold greater risk of cardiac death than those without it, according to the organisation, and those requiring blood dialysis cost the Australian healthcare system a whopping $100,000 per annum per patient.

The good news is that, when managed with effective treatment, deterioration in kidney function can be reduced by as much as 50%. The bad news is that the current treatment option is decades old, and does not actually reverse the disease — it merely slows its progression.

“At the moment, the treatment option for all kidney diseases generally is to lower the blood pressure of the patient, and that serves to take the pressure off the kidney, the kidney being a filter,” Dimerix CEO Kathy Harrison told Lab+Life Scientist. “If you in effect turn the hose down, turn the pressure down, then it stops the pressure on those filters and damaging those filters, which reduces the amount of protein leakage through the kidney.

“But it doesn’t reverse the disease, and in fact patients still generally progress in some forms of the disease, such as the rare disease FSGS [focal segmental glomerulosclerosis]. In the case of a disease like FSGS, patients can progress to complete kidney failure and therefore dialysis within 1–2 years, if they have the severe form of the disease, and kidney transplant is unsuccessful 40% of the time, in that they have the transplant, put a healthy kidney in, and the disease recurs. So there’s no good treatment options at all for FSGS.

“Things like diabetic kidney disease [DKD], they’re slower progressing, but eventually the patient’s kidneys will deteriorate and they will end up on dialysis. So it’s a massively underserved condition — the treatments that are used have been used for decades.”

So what makes DMX-200 so promising? As explained by Harrison, it all started when Dimerix used its Receptor-Heteromer Investigation Technology (Receptor-HIT) assay platform to identify a pair of receptors that function in a joint manner (interact) when ligands, small molecule drugs, peptides or antibodies bind to them.

“We know that the angiotensin receptor and the chemokine 2 receptor — which are the receptors that are important in DMX-200 — actually interact with each other from what we’ve seen in the assay with Receptor-HIT,” Harrison said. “When they interact together, they transactivate each other, so they actually turn each other on to have this additional signalling which occurs when they’re operating as a unit. What we find then, if you try to use an antagonist or a blocker to stop one of the receptors operating — for example, you use an angiotensin receptor blocker to try to turn the angiotensin receptor off — it actually won’t turn off unless you block the chemokine 2 receptor.”

The signals sent out by these receptors typically cause inflammation, which is a major contributor to the progression of chronic kidney disease. To solve this problem, Dimerix added a safe anti-inflammatory drug, propagermanium, to the standard of care treatment, irbesartan — an angiotensin receptor blocker that lowers blood pressure. Together, the two drugs work synergistically to block the signals of both angiotensin and chemokine 2 — with impressive results.

“We saw that when you just blocked one [receptor] or the other, you saw some reduction in protein in the urine,” Harrison said. “But when you had them together, you saw a much bigger reduction, and similar things in the pathology of the kidney as well.”

Harrison said DMX-200 is particularly effective because patients with kidney disease are already taking an angiotensin receptor blocker, so they are able to take propagermanium as an adjunct therapy rather than something with its own agenda.

“It’s also important because we are able to keep the patients on that angiotensin receptor blocker, which is really important for managing their blood pressure. It’s a very safe treatment, adding to what they’re already taking but having this synergistic effect because of the way that we understand the two receptors operating in the cell.”

Dimerix is not the only company currently investigating chronic kidney disease, but Harrison believes it has some advantages over its competitors. She noted, “One of those competitors, what they do is they switch the patient off their angiotensin receptor blocker to put them onto their drug. So we believe ours is a much safer way of operating.”

Another company is taking an approach more closely aligned with Dimerix’s, but utilising a chemical antigen instead. Harrison said, “The compound we’re using, propagermanium, is registered in Japan for treatment of chronic hepatitis B. So it’s been used in a chronic setting for a couple of decades, so we know that it’s very safe… Whereas for people bringing in a chemical antigen that doesn’t have that history of use, obviously there’s always a higher risk that something else might happen that you’re not expecting.”

Last year Dimerix completed a Phase 2a ‘all comers’ clinical trial, where DMX-200 was studied in patients with a group of diseases in the broad category of CKD. In addition to meeting the primary safety endpoint across the study, a subgroup with DKD showed a clinically and statistically significant efficacy response, reducing proteinuria by more than 50% in 25% of patients. In fact, following completion of dosing, a number of patients applied to remain on DMX-200 under the Therapeutic Goods Administration’s (TGA) Special Access Scheme.

Dimerix had already planned to undertake a Phase 2a trial for patients with FSGS, for which the company has received Orphan Drug designation (ODD) in the US. But the data in patients with DKD was also sufficiently compelling to support a follow-up trial in a larger patient group. The company thus announced two trials — one covering DKD and another covering FSGS.

The upcoming FSGS Phase 2a trial is set to study the effects of DMX-200 in around 10 patients, with endpoints including safety and efficacy (proteinuria reduction). The DKD Phase 2b trial will meanwhile study the effects of DMX-200 in around 40 patients, with the primary endpoint being a change in 24-hour albumin creatinine ratio (ACR) based on identified patient responses in the 2017 study. Both the DKD and FSGS trials will commence at the same time and be run across the same 10 or so sites across Australia, using the same principal investigators and same vendors — a measure that will enable the company to conduct both trials without seeking any additional funding.

“What happened was, we raised through a shareholder placement around $3 million, which closed in January,” said Harrison. “And then with our oversubscribed placement, which we were expecting to raise $2.5 million, we actually raised $4.5 million. So that means that the total raised was $7.5 million, instead of the $5.5 million that we were expecting, and the $5.5 million was what we were planning to use to progress the FSGS study all the way through to being Phase 3-ready, through the next set of trials and all the processes that go with that.

“Because we raised the extra money, we felt that we could now also do the diabetic kidney disease study at the same time. So we’ve looked pretty carefully about how we’re doing this, and producing synergies by having the same sites. We believe we’ll be able to get through these studies on that funding.”

A randomised, double blind, placebo-controlled crossover design was selected as the most appropriate format for both trials — meaning that every patient will receive irbesartan for at least three months prior to and throughout the trial, and will receive DMX-200 or a placebo at different periods of the study. By receiving DMX-200 and placebo in an order that is both randomised and blind to patient and investigators, safety and efficacy data can be collected for every patient on each trial. This also enables each patient to act as their own control, mitigating the impact of variability in disease behaviour from patient to patient.

“We have selected the most robust method of ensuring accurate detection of an efficacy signal for both our FSGS and DKD trials,” said Associate Professor David Packham, Chief Medical Officer at Dimerix. “As every patient will receive both study drug and placebo with a six-week washout period between treatments, we will be able to assess individual patient responses and avoid confounding factors due to differences in the natural history of the diseases under study between patients. Further, the fact that all participants who complete the trial are certain of having received trial drug for one of two treatment periods will make this much more attractive to patient participation and recruitment.”

Dimerix plans to be recruiting for both studies in Q3 2018, with preliminary data expected for the DKD study in Q3 2019 and for FSGS in Q4 2019. From there, according to Harrison, it could be just a few years until DMX-200 makes its way to market.

“For FSGS, because of the orphan indication, assuming that we went into a pivotal Phase 3, we believe, based on our discussions with the FDA, that a Phase 3 could potentially have an accelerated approval if everything went well within 12 months of starting the study,” she said. “So I guess you’re looking at not that many years down the track.

“Diabetic kidney disease is obviously a much larger indication, a much more complex pathway. What we would hope is that this trial would help solidify the results that we had in the Phase 2a trial, and get some more strength around those, and out-license that.”

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