Biocurious: With its drug candidate AGN-007, Argenica has a licence to thrill

Never say never again: Argenica is girding for a more focused trial of its stroke candidate ARG-007. Pic: Getty Images.

Shaken but not deterred after stroke of misfortune, Argenica says it has a viable path to approval with stroke drug candidate ARG-007
Company working toward phase IIb study, enrolling the most responsive stroke patient cohort
For reasons not fully understood, the incidence of strokes is increasing in Western countries as well as other key markets such as China

 

Different diseases have different levels of recognition and public advocacy – fairly or unfairly.

To Argenica Therapeutics (ASX:AGN) CEO Dr Liz Dallimore, strokes simply aren’t “sexy”, relative to conditions such as motor neurone disease or Parkinson’s disease.

“Maybe people think of stroke as an old person’s disease, something that’s not as exciting as these other conditions,” she posits.

“But it is a huge medical need and a huge burden on healthcare systems.”

According to the Australian Stroke Foundation, an Australian had a stroke every 11 minutes last year – a sharp increase on every 19 minutes six years previously.

“That trend is happening globally, such as in China where strokes have overtaken heart attacks as the number one killer,” Dallimore said.

“This is a huge market opportunity for Argenica.”

While 15 million people globally suffer a stroke each year – 5m of them fatally – there’s no effective treatment beyond thrombolytic (clot removing) drugs.

Given the narrow time window for treatment and the brain’s reliance on oxygen, developing stroke drugs is often seen as too difficult.

With its drug candidate ARG-007, Argenica seeks a licence to kill the voice of the sceptics – and thrill patients who otherwise end up with poor outcomes.

 

No time to die  

Perth-based Argenica was spun out of the Perrin Neuroscience Research Institute after more than a decade of preclinical research.

The company zeroes in on the severe stroke patients who pose the biggest burden on the healthcare system.

“This is where we can attract the highest drug price and the greatest commercial opportunity,” Dallimore said.

But like the true course of love, Argenica’s drug development path has not been linear.

Early last September, Argenica shares tumbled around 60% after the company’s phase II trial did not hit a secondary efficacy endpoint.

The program achieved the primary safety goal.

As recent sector-wide experience shows, there are trial failures and trial setbacks.

After a serious bout of soul-searching – and careful perusing of the trial data – Dallimore is convinced that it is a case of the latter.

Management is working towards a phase IIb trial that rectifies the original problems by enrolling the right patients in the first place.

 

The science of strokes

When someone has a stroke or a traumatic brain injury, the brain releases a neurotransmitter called glutamate.

The more severe the injury, the higher the amount of glutamate released.

Via a knock-on process we are not explaining too well, the brain cells are flooded with calcium and start to die.

ARG-007 is cationic arginine-rich peptide. Arginines are amino acids derived from one’s diet and essential for producing proteins.

The drug candidate is thought to have multiple mechanisms of action, including reducing oxidative stress and calcium influx.

Like James Bond, it’s handy in a crisis.

“What’s so exciting about it is it’s not receptor specific; it’s actually binding to a number of receptors that all result in this calcium influence,” Dallimore said.

“That’s really important for strokes, because in the past the drugs that have only targeted one of those channels have failed in the clinic.”

 

Live and don’t let die  

As with an earlier trial of healthy volunteers, the phase II study showed the treatment was safe.

While investors don’t get too excited about proving safety, it’s important for stroke patients because typically they have co-morbidities such as high blood pressure and atrial fibrillation.

“They are very vulnerable,’ Dallimore said.

The study enrolled 92 patients that had just suffered a large vessel ischaemic occlusion (a blockage rather than a bleed, the most common form of stroke).

Half of them received a placebo.

The trial fell short on its secondary end point of reducing overall brain infarct volume (brain cell death).

“This really surprised us,” Dallimore said.

But with a sub-group of 17 patients with moderate to severe strokes – let’s call it the Goldfingers, er, Goldilocks cohort – the drug showed a 15% improvement.

 

It worked, infarct

“Stroke patients have varying degrees of blood flow,” Dallimore said.

“We saw a benefit in patients that had poor collateral blood flow.”

In this case, ‘collateral’ does not allude to cash or a house deposit. It refers to the blood’s ability to redirect past a blockage (clot) and supply the brain with oxygen, via capillaries and small arteries.

Taking place at emergency departments, the phase II trial involved confirmed ischemic stroke patients being scanned and then delivered the drug – or placebo – pre thrombectomy, via a 10-minute infusion.

The trial showed that even patients with severe blockages had little infarct growth because of good collateral flow.

“So, there’s nothing for our drug to work on,” Dallimore said.

“They’re walking out of hospital at day two like they’ve never had a stroke.”

ARG-007’s effect was most pronounced on those with high brain cell loss at baseline.

“The worse the stroke, the worse the outcome when they leave,” she said.

“Except if you’ve had our drug. It stops that infarct from growing and that’s statistically significant.”

In effect the good ‘collaterals’ diluted AEG-007’s overall efficacy signal and shouldn’t have been on the trial.

“Hindsight is an amazing thing,” Dallimore said.

 

Measure of success

The choice of endpoints for a trial is just as important as the choice of patients, but this is influenced by what the regulators want to see.

In the case of strokes, the US Food and Drug Administration (FDA) and the European and local gatekeepers focus on functional outcomes.

In other words, how well a drug improves quality of life, such as enabling a patient to walk independently.

That’s keepin’ it real – and fair enough too.

The company plans to meet with the FDA to propose a primary efficacy endpoint based on the qualitative Modified Rankin Scale (MRS).

Given the phase II trial was not “powered” enough to deliver on such a qualitative measure, the company used MRS as an exploratory endpoint only.

“We’ll take this protocol to the FDA in the next couple of months,” Dallimore said.

“There’s absolutely nothing controversial in this protocol … so we expect that to go reasonably smoothly.”

 

Money money money

The idealist who said that money doesn’t buy happiness might have been thinking about James Packer – not the cheery James Bond and certainly not the cash-sapping milieu of drug development.

Argenica has $8m of cash, which keeps on the lights. But the company needs considerably more funds to get to the halfway interim (futility) analysis stage.

Dallimore said the company was working hard on potential regional partnering deals – possibly similar to those executed by kidney drug developer Dimerix (ASX:DXB) which bought in $65m of upfront funds.

(Dimerix is forging on after its own trial design setback, but that’s another story).

“We are looking at some non-dilutive funding through grants and deals, to supplement a potential capital raising,” Dallimore stated.

 

What happens next?

Argenica awaits a crucial meeting with the FDA to thresh out the trial parameters and to remove a clinical hold the agency imposed on the program last June.

(Ahead of the phase II trial results, the company pre-emptively lodged an Investigational New Drug application to carry out the follow-up study).

“We should pretty much bed down the protocol in the next couple of weeks and lock in statisticians and all that sort of stuff,” Dallimore said.

“Then we can put forward a formal clinical hold response … and things should happen fairly quickly.”

The company hopes to have a so-called Type A confab with the FDA by the end of June.

Held within 30 days of a request for one, a Type A meeting addresses critical roadblocks in our drug development program.

Dallimore said the likely size of the trial was a “million-dollar question”.

Strictly speaking, it is a multimillion-dollar question.

But she said the study probably would enroll around 300 patients at sites in the US and locally, across two dosages.

“We can run the trial more quickly by setting up more sites, but setting up more sites costs money.”

 

No more Dr No

Dallimore said that by being effective in a patient subgroup that needed the drug the most, ARG-007 was doing exactly what big pharma companies wanted to see.

“This is especially in the case of strokes because the patients are so heterogeneous.”

She said big pharma companies including Genentech, Johnson & Johnson, and Bayer had nominated stroke drugs as being in their “sweet spot” of dealmaking.

A year ago, Merck of Germany assumed commercial development of AptaTargets’ ischaemic stroke candidate Aptoll.

In the meantime, Dallimore said Argenica’s institutional investors had been surprised by the share reaction to last year’s trial news, which was driven by retail shareholders.

“They said we have done everything we said we would do,” she added.

“But we are very much a retail play at the moment.”

 

 

At Stockhead, we tell it as it is. While Argenica and Dimerix are Stockhead advertisers, the companies did not sponsor this article.