Argenica Therapeutics (ASX:AGN)<\/a> CEO Dr Liz Dallimore, strokes simply aren\u2019t \u201csexy\u201d, relative to conditions such as motor neurone disease or Parkinson\u2019s disease.<\/p>\n\u201cMaybe people think of stroke as an old person\u2019s disease, something that\u2019s not as exciting as these other conditions,\u201d she posits.<\/p>\n
\u201cBut it is a huge medical need and a huge burden on healthcare systems.\u201d<\/p>\n
According to the Australian Stroke Foundation, an Australian had a stroke every 11 minutes last year \u2013 a sharp increase on every 19 minutes six years previously.<\/p>\n
\u201cThat trend is happening globally, such as in China where strokes have overtaken heart attacks as the number one killer,\u201d Dallimore said.<\/p>\n
\u201cThis is a huge market opportunity for Argenica.\u201d<\/p>\n
While 15 million people globally suffer a stroke each year \u2013 5m of them fatally \u2013 there\u2019s no effective treatment beyond thrombolytic (clot removing) drugs.<\/p>\n
Given the narrow time window for treatment and the brain\u2019s reliance on oxygen, developing stroke drugs is often seen as too difficult.<\/p>\n
With its drug candidate ARG-007, Argenica seeks a licence to kill the voice of the sceptics \u2013 and thrill patients who otherwise end up with poor outcomes.<\/p>\n
\u00a0<\/p>\n
No time to die\u00a0\u00a0<\/p>\n
Perth-based Argenica was spun out of the Perrin Neuroscience Research Institute after more than a decade of preclinical research.<\/p>\n
The company zeroes in on the severe stroke patients who pose the biggest burden on the healthcare system.<\/p>\n
\u201cThis is where we can attract the highest drug price and the greatest commercial opportunity,\u201d Dallimore said.<\/p>\n
But like the true course of love, Argenica\u2019s drug development path has not been linear.<\/p>\n
Early last September, Argenica shares tumbled around 60% after the company\u2019s phase II trial did not hit a secondary efficacy endpoint.<\/p>\n
The program achieved the primary safety goal.<\/p>\n
As recent sector-wide experience shows, there are trial failures and trial setbacks.<\/p>\n
After a serious bout of soul-searching \u2013 and careful perusing of the trial data \u2013 Dallimore is convinced that it is a case of the latter.<\/p>\n
Management is working towards a phase IIb trial that rectifies the original problems by enrolling the right patients in the first place.<\/p>\n
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The science of strokes<\/p>\n
When someone has a stroke or a traumatic brain injury, the brain releases a neurotransmitter called glutamate.<\/p>\n
The more severe the injury, the higher the amount of glutamate released.<\/p>\n
Via a knock-on process we are not explaining too well, the brain cells are flooded with calcium and start to die.<\/p>\n
ARG-007 is cationic arginine-rich peptide. Arginines are amino acids derived from one\u2019s diet and essential for producing proteins.<\/p>\n
The drug candidate is thought to have multiple mechanisms of action, including reducing oxidative stress and calcium influx.<\/p>\n
Like James Bond, it\u2019s handy in a crisis.<\/p>\n
\u201cWhat\u2019s so exciting about it is it\u2019s not receptor specific; it\u2019s actually binding to a number of receptors that all result in this calcium influence,\u201d Dallimore said.<\/p>\n
\u201cThat\u2019s really important for strokes, because in the past the drugs that have only targeted one of those channels have failed in the clinic.\u201d<\/p>\n
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Live and don\u2019t let die\u00a0\u00a0<\/p>\n
As with an earlier trial of healthy volunteers, the phase II study showed the treatment was safe.<\/p>\n
While investors don\u2019t get too excited about proving safety, it\u2019s important for stroke patients because typically they have co-morbidities such as high blood pressure and atrial fibrillation.<\/p>\n
\u201cThey are very vulnerable,\u2019 Dallimore said.<\/p>\n
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).<\/p>\n
Half of them received a placebo.<\/p>\n
The trial fell short on its secondary end point of reducing overall brain infarct volume (brain cell death).<\/p>\n
\u201cThis really surprised us,\u201d Dallimore said.<\/p>\n
But with a sub-group of 17 patients with moderate to severe strokes \u2013 let\u2019s call it the Goldfingers, er, Goldilocks cohort \u2013 the drug showed a 15% improvement.<\/p>\n
\u00a0<\/p>\n
It worked, infarct<\/p>\n
\u201cStroke patients have varying degrees of blood flow,\u201d Dallimore said.<\/p>\n
\u201cWe saw a benefit in patients that had poor collateral blood flow.\u201d<\/p>\n
In this case, \u2018collateral\u2019 does not allude to cash or a house deposit. It refers to the blood\u2019s ability to redirect past a blockage (clot) and supply the brain with oxygen, via capillaries and small arteries.<\/p>\n
Taking place at emergency departments, the phase II trial involved confirmed ischemic stroke patients being scanned and then delivered the drug \u2013 or placebo \u2013 pre thrombectomy, via a 10-minute infusion.<\/p>\n
The trial showed that even patients with severe blockages had little infarct growth because of good collateral flow.<\/p>\n
\u201cSo, there\u2019s nothing for our drug to work on,\u201d Dallimore said.<\/p>\n
\u201cThey\u2019re walking out of hospital at day two like they\u2019ve never had a stroke.\u201d<\/p>\n
ARG-007\u2019s effect was most pronounced on those with high brain cell loss at baseline.<\/p>\n
\u201cThe worse the stroke, the worse the outcome when they leave,\u201d she said.<\/p>\n
\u201cExcept if you\u2019ve had our drug. It stops that infarct from growing and that\u2019s statistically significant.\u201d<\/p>\n
In effect the good \u2018collaterals\u2019 diluted AEG-007\u2019s overall efficacy signal and shouldn\u2019t have been on the trial.<\/p>\n
\u201cHindsight is an amazing thing,\u201d Dallimore said.<\/p>\n
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Measure of success<\/p>\n
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.<\/p>\n
In the case of strokes, the US Food and Drug Administration (FDA) and the European and local gatekeepers focus on functional outcomes.<\/p>\n
In other words, how well a drug improves quality of life, such as enabling a patient to walk independently.<\/p>\n
That\u2019s keepin\u2019 it real \u2013 and fair enough too.<\/p>\n
The company plans to meet with the FDA to propose a primary efficacy endpoint based on the qualitative Modified Rankin Scale (MRS).<\/p>\n
Given the phase II trial was not \u201cpowered\u201d enough to deliver on such a qualitative measure, the company used MRS as an exploratory endpoint only.<\/p>\n
\u201cWe\u2019ll take this protocol to the FDA in the next couple of months,\u201d Dallimore said.<\/p>\n
\u201cThere\u2019s absolutely nothing controversial in this protocol \u2026 so we expect that to go reasonably smoothly.\u201d<\/p>\n
\u00a0<\/p>\n
Money money money<\/p>\n
The idealist who said that money doesn\u2019t buy happiness might have been thinking about James Packer \u2013 not the cheery James Bond and certainly not the cash-sapping milieu of drug development.<\/p>\n
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.<\/p>\n
Dallimore said the company was working hard on potential regional partnering deals \u2013 possibly similar to those executed by kidney drug developer Dimerix (ASX:DXB)<\/a> which bought in $65m of upfront funds.<\/p>\n(Dimerix is forging on after its own trial design setback, but that\u2019s another story).<\/p>\n
\u201cWe are looking at some non-dilutive funding through grants and deals, to supplement a potential capital raising,\u201d Dallimore stated.<\/p>\n
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What happens next? <\/p>\n
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.<\/p>\n
(Ahead of the phase II trial results, the company pre-emptively lodged an Investigational New Drug application to carry out the follow-up study).<\/p>\n
\u201cWe should pretty much bed down the protocol in the next couple of weeks and lock in statisticians and all that sort of stuff,\u201d Dallimore said.<\/p>\n
\u201cThen we can put forward a formal clinical hold response \u2026 and things should happen fairly quickly.\u201d<\/p>\n
The company hopes to have a so-called Type A confab with the FDA by the end of June.<\/p>\n
Held within 30 days of a request for one, a Type A meeting addresses critical roadblocks in our drug development program.<\/p>\n
Dallimore said the likely size of the trial was a \u201cmillion-dollar question\u201d.<\/p>\n
Strictly speaking, it is a multimillion-dollar question.<\/p>\n
But she said the study probably would enroll around 300 patients at sites in the US and locally, across two dosages.<\/p>\n
\u201cWe can run the trial more quickly by setting up more sites, but setting up more sites costs money.\u201d<\/p>\n
\u00a0<\/p>\n
No more Dr No<\/p>\n
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.<\/p>\n
\u201cThis is especially in the case of strokes because the patients are so heterogeneous.\u201d<\/p>\n
She said big pharma companies including Genentech, Johnson & Johnson, and Bayer had nominated stroke drugs as being in their \u201csweet spot\u201d of dealmaking.<\/p>\n
A year ago, Merck of Germany assumed commercial development of AptaTargets\u2019 ischaemic stroke candidate Aptoll.<\/p>\n
In the meantime, Dallimore said Argenica\u2019s institutional investors had been surprised by the share reaction to last year\u2019s trial news, which was driven by retail shareholders.<\/p>\n
\u201cThey said we have done everything we said we would do,\u201d she added.<\/p>\n
\u201cBut we are very much a retail play at the moment.\u201d<\/p>\n
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\ufeff\u00a0<\/p>\n
At Stockhead, we tell it as it is. While Argenica and Dimerix are Stockhead advertisers, the companies did not sponsor this article. <\/p>\n","protected":false},"excerpt":{"rendered":"Never say never again: Argenica is girding for a more focused trial of its stroke candidate ARG-007. Pic:…\n","protected":false},"author":2,"featured_media":666530,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[34],"tags":[64,63,137,500],"class_list":["post-666529","post","type-post","status-publish","format-standard","has-post-thumbnail","category-healthcare","tag-au","tag-australia","tag-health","tag-healthcare"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts\/666529","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/comments?post=666529"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts\/666529\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/media\/666530"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/media?parent=666529"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/categories?post=666529"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/tags?post=666529"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}