Rare Disease Report

Update on DMX-200 Treatment for Focal Segmental Sclerosis

JUNE 12, 2018
Krista Rossi
In a recent exclusive interview with Dimerix CEO, Kathy Harrison, and chief medical officer David Packham, MD, MB, BS (Hons), FRCP, FRACP, Rare Disease Report ® received the latest update on DMX-200, a combination therapy of propagermanium and irbesartan for the treatment of focal segmental sclerosis (FSGS) in addition to chronic kidney disease. DMX-200 was previously granted orphan drug designation by the US Food and Drug Administration (FDA).  

Rare Disease Report® (RDR®): What is DMX-200, and why was it investigated as a possible treatment for FSGS?

Packham: DMX-200 is a combination of 2 therapies; it’s an angiotensin 2 receptor blocker (ARB) with a chemokine receptor blocker (CCR2). We are targeting FSGS because although it is a relatively rare kidney disease, it carries a very bad prognosis, contributes disproportionately to numbers of patients on dialysis, and has a lack of effective treatments. FSGS progresses by at least 3 mechanisms, all of which are targets for our therapy.

These mechanisms are losses of specialized cells in the kidney filters (glomeruli), called podocytes, detrimental hyperfiltration of residual glomeruli, and prevention of progressive inflammation and fibrosis of kidney tissues. The clinical consequence of these 3 mechanisms is a great increase in the amount of protein that leaks into the urine. We know that therapies which reduce proteinuria, by a significant amount of about 30% or more, translate into hard endpoints of improved kidney outcomes.

Drugs like ARBs have been used for many years and constitute a best treatment for proteinuric chronic kidney diseases. This goes back to treating the hyperfiltration of, and glomerular hypertension within, the renal remnant. We know that ARBs can prolong the life of the kidney, with the best evidence of this in diseases like diabetic nephropathy and the condition we are targeting, focal segmental glomerulosclerosis.

A very significant additional mechanism which promotes progression of chronic kidney disease is inflammation in the kidney. By inflammation, we mean an influx of inflammatory cells called monocytes, and the signal it sets up in damaged kidneys so that they come in, cause inflammation, and leave scarring. This is the target of the CCR2 blocker, propagermanium.

Finally, both receptors we are targeting are expressed on podocytes, and our animal experiments suggest that combining the 2 drugs prevents loss of podocytes in models of the disease.

RDR®: How did DMX-200 come into development?

Packham: Dimerix came onto the scene by developing an assay to show how receptors interact. This is a completely different approach in respect of receptors called G-protein-coupled receptors, and that’s the main site of action of most drugs. Dimerix discovered a way of identifying the fact that the receptors existed not only in individual forms but also in complexes called heterodimers. This showed that you not only have to block the individual receptors with the drug but also the complexes, the heterodimers.

In other words, if you use 1 drug, which can affect A or B, and if you use both drugs, you could expect A+B. Because of these heterodimers though, if you use 2 drugs, you not only get A+B but also the effect of blocking the heterodimer (A+B+AB). [Dimerix] developed an assay looking for synergies between existing drugs and found a synergy between an angiotensin receptor blocker and a CCR2 blocker; that’s where the 2 streams come together.

RDR®: How was the underlying and potential efficacy of DMX-200 established?

Packham: [Investigators turned] to the best models of chronic kidney disease, which is a 5/6 nephrectomy in the rodent. They performed the experiments there and found that indeed, if you blocked receptor A, the angiotensin receptor blocker, you had a beneficial effect; and if you blocked receptor B, the CCR2 receptor, you had a beneficial effect. [However], if you used both together, you had an additive effect of reducing proteinuria, reducing influx of inflammatory cells to the kidneys, and very importantly, in terms of focal segmental glomerulosclerosis, you also preserve a type of cell called podocytes, which make up the filters in the kidneys. They’re cells that cannot be replaced, and they are key in the development of focal segmental glomerulosclerosis.

In the phase 2a trial, we looked at 24 patients with the treatment and found that 25% of patients had a 50% reduction in proteinuria, and the drugs were safe.

RDR®: When will additional clinical trials begin?

Harrison: We have now designed 2 phase 2 clinical trials, one in the rare disease focal segmental glomerulosclerosis and one looking at effects on diabetic kidney disease, which affects large patient populations.

We are filing applications for approval, so we would expect the trials to begin very soon. From our meeting with the FDA, we believe following the current proof of concept phase 2 study, we would only be required to complete a single phase 3 study to achieve [potential] accelerated approval within a relatively short number of years.  

RDR®: What would the significance be for this drug approval for this patient population?

Packham: Untreated and without spontaneous remission (which is rare), these patients most oftentimes enter renal failure within 2-5 years. If we are able to correct or improve (achieve complete or partial remission) the abnormal high levels of protein leaking in the urine, you see an increased life span of the kidney. If you can move people from no remission to partial remission or partial remission to complete remission, that’s great because you have added years of life before they have to go on to dialysis treatment.

Focal segmental glomerulosclerosis is the worst type of kidney disease you could get. It’s common in children and young adults, and the outlook is awful because it often recurs after renal transplantation. We believe that by using these 2 drugs together, we may impact the disease at the level of the podocyte. We also attack the disease further downstream by trying to reduce the level of inflammation within the interstitium of the kidney. We believe we could turn non-responders into partial responders and partial responders into responders with this therapy. That’s what we hope to achieve: to move people into a class of better outcomes. By so doing, we could significantly delay or even prevent the need for renal replacement therapy.    
 

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