3 days ago
Biocurious: Dimerix could be riding big and beautiful kidney drug success earlier than expected
With the FDA's blessing, Dimerix will use phase III trial endpoints that could lead to accelerated approval for its kidney disease drug
Dimerix is confident of phase III success because an expert 'peek' at the blinded data shows it's on the right track
The company is well cashed up, courtesy of four global distribution deals
When it comes to clinical trials, the choice of primary endpoints can mean the difference between a trial failing and a billion-dollar blockbuster drug emerging.
Plenty of drug candidates have looked successful at mid stage, but then floundered because a later stage trial has failed to meet strictly defined goals.
This appears to be the case with Opthea (ASX:OPT) and the recent failure of its two phase III eye disease trials.
In other cases, strictly enforced endpoints mean that a trial is too long and too expensive.
But regulatory attitudes are changing.
In the case of Dimerix (ASX:DXB), the US Food & Drug Administration (FDA) has delivered the kidney disease drug developer a concession on endpoints for its ongoing phase III trial.
The FDA's stance not only means that the endpoints are more likely to be achieved, reducing risk.
It also means the company could win accelerated FDA marketing approval before the study has completed.
'That sparked a lot of interest in the sector because suddenly the trials are more manageable,' says Dimerix chief Dr Nina Webster.
The 286-patient study is testing Dimerix's candidate DMX-200 for the regressive focal segmental glomerulosclerosis (FSGS).
A rare – but not ultra rare – disease, FSGS usually results in end-stage kidney failure.
Endpoints have delayed the endgame
Previously, the FDA had set an endpoint of how well a drug preserves kidney function.
But this meant a trial had to track the patient to kidney failure or death, which could take years.
This makes a trial too long and too costly.
'In rare diseases, no-one is going to do these studies,' Webster says.
About five years ago the FDA became more amenable to the use of 'surrogate' endpoints
These are measures that substitute a true clinical endpoint to expedite drug development.
The FDA allowed the use of the kidney function biomarker, called estimated global filtration rate (eGFR).
Under the dainty banner of 'Parasol' – and, no it's not an umbrella group – experts advised the use of proteinuria as a further alternative endpoint for FSGS.
Proteinuria is kidney proteins seeping into the urine, while eGFR is the rate at which the spuds can cleanse blood.
If proteinuria is present and the eGFR is not up to scratch, they are sure signs the kidneys are not working as they should.
Conversely, if a drug reduces proteinuria or the eGFR 'slope rate' – the rate of decline – it is accepted as being effective.
Parasol promises faster Action
Dubbed Action 3, the Dimerix trial involves two years' treatment, as measured against placebo. The study is due to complete in 2027 when the last patients have been treated.
But Dimerix now is working with Parasol to establish the exact surrogate endpoints required to front the FDA for accelerated marketing approval.
Expedited approval is as allowed for some orphan drugs, such as DMX-200.
'The full study is for two years and that doesn't change,' Webster says.
'Th question is whether we can get interim approval and go to market earlier.'
One possibility is that proteinuria alone could be the accepted endpoint, given proteinuria and eGFR appear to point to the same thing.
That is: deteriorating kidneys.
Dr Webster says an accelerated endpoint must reasonably predict the outcome of the trial.
'The question is, what do we need to see at point X to prove the end at point Y? Parasol is working with us on that.
'We're collecting all of our data on eGFR and proteinuria anyway, so it gives us a lot of flexibility in the program.'
(Other geographies such as Japan and Europe still require an eGFR endpoint).
Surrogate change spurs others …
The FDA's stance on surrogate endpoints could be a double-edged sword for Dimerix, as it also provides succour to potential rivals.
In this vein, a drug called sparsentan (brand name Filspari ) won FDA approval for a kidney condition called IgA nephropathy.
The drug failed its Phase III endpoint for eGFR. But now its owner Travere Therapeutics is having a crack at FDA marketing approval for FSGS using a proteinuria endpoint.
The data from the supportive trial was unblinded, which means the study custodians can't change the endpoints retrospectively.
'But the FDA is in a hard spot with this one because is an area of such high unmet need,' Webster says.
'These patients currently have limited treatment options and Filspari looks like it is doing something for them.
'We are waiting with bated breath in the hope that Filspari is approved and gives hope to these patients.'
Travere has licensed the European and local sparsentan rights to our own CSL (ASX:CSL).
… but we're friends, not rivals
Webster says rather than rivalling DMX-200, sparsentan could be used in unison.
An angiotensin receptor, sparsentan targets high blood pressure – a key cause of kidney disease in the first place.
(High blood pressure causes inflammation which causes scarring and cell death).
Thus, sparsentan needs to be better than the current blood pressure medication.
But DMX-200 works on the secondary inflammatory pathway, with the patients already on blood pressure meds.
'It's not apples for apples with study design, which is why we are compared against the placebo and not a comparator,' Webster says.
In effect, DMX-200 faces a lower comparative hurdle.
'Our drug is complementary, not competitive,' Webster says.
Data 'peek' hints at trial success
While a trial result is never certain, Dimerix is confident it won't meet the fate of Opthea or Percheron Therapeutics (ASX:PER).
(The latter's neurological disease trial also failed to meet primary endpoints).
One reason is that the Action 3 trial already has been subject to a blinded interim analysis by an arm's length expert committee, which peeked at the data.
'Blinded' means that Dimerix, the trial investigators and the patients don't know the results.
In March last year the 72-patient analysis reported that DMX-200 worked better than placebo. As per protocol, the experts did not disclose the extent of this efficacy.
But it was enough for the company to know that it's on the right track.
'We just know at that point in time, we were doing better and that if we carry on that trajectory, we have a shot at the endpoint,' Webster says.
'That was a big moment for us, because we wanted to confirm something similar to our smaller phase II study in a larger cohort of patients.'
FDA approval could come sooner rather than later
Dimerix has received over $65 million of cash, courtesy of four distribution deals that may deliver up to $1.4 billion of milestone payments plus royalties.
While a further capital raising is a case of 'never say never', it's unlikely.
Naturally, most of the milestones are back ended to achievements such as phase III success and FDA approval.
But with accelerated approval possible after the interim analysis, the latter might be sooner than investors think.
Many drug developers view the Trump Ascendancy Mark Two with trepidation.
In contrast, Webster notes Trump nominated kidney disease as a key health priority in his first stab at POTUS.
The financial motive alone is compelling, in that dialysis costs the US health system around US$125 billion annually.
'We are in the sweet spot of being a rare disease (with pricing benefits) and having the potential to reduce US healthcare costs,' Webster says.
