Welcome to your weekly digest of approaching regulatory and clinical readouts. The amyloidosis market has heated up in recent months with clinical trial wins for Pfizer, and Anylam and Ionis scoring regulatory approvals. The next boost could come from phase II results from Eidos Therapeutics' AG10 in cardiomyopathy, due to be presented on November 10 as a late-breaker at the AHA conference.
Although Eidos is substantially lagging its nearest rivals it will hope that AG10’s previously reported ability to stabilise pretty much 100% of plasma transthyretin (TTR), with a clean safety record, could keep it in the amyloidosis race. Still, the company's stock has slumped since Pfizer presented impressive data with its similarly acting project, tafamidis, at the ESC meeting in August (ESC 2018 – Pfizer impresses with tafamidis, but amyloidosis battle goes on, August 27, 2018).
TTR normally circulates in the blood as a four-part molecule, but in transthyretin amyloidosis (ATTR) the molecule breaks down into its individual parts, which accumulate in parts of the body as amyloid fibrils. Symptoms depend on where the fibrils build up and include polyneuropathy (ATTR-PN) as well as cardiomyopathy (AATR-CM).
AG10 binds to and stabilises TTR, preventing it from splitting. Eidos’s phase II trial is testing 400mg and 800mg doses of AG10 against placebo in patients who have had at least one prior hospitalisation for heart failure, or clinical evidence of heart failure, with a primary endpoint of safety and tolerability. Secondary endpoints include TTR stabilisation.
There are no approved products for ATTR-CM specifically. Alnylam’s Onpattro and Ionis’s Tegsedi were recently approved in ATTR-PN, but there are toxicity issues with Tegsedi, and Onpattro's safety in cardiac patients has been questioned. Tafamidis, meanwhile, is approved for ATTR-PN in Europe; in the US Pfizer has told Vantage that it plans to seek approval in ATTR-CM first, with ATTR-PN potentially following.
Analysts at Barclays believe that the amyloidosis indication is big enough for multiple entrants, but realistically Eidos will have to hope that its asset rapidly advances through the clinic and maintains a squeaky clean safety record if it is to take any meaningful share.
Avoiding the Nash crush
Competition also built up in a separate space, the liver disease Nash, with last week’s deal between Pfizer and Novartis sweeping away any doubt over whether big pharma was interested. Investors in unpartnered biotechs wishing to compete might take this as a considerable threat, and this perhaps explains the undemanding valuation of a player like Conatus.
However, Conatus itself already boasts its own deal with Novartis, which opted in to its sole asset, emricasan, last year. Emricasan now faces an important mid-stage test, with readout of its Encore-PF trial expected by the end of the year.
Conatus’s strategy is interesting: emricasan is initially being positioned as a treatment not for Nash, but rather for a manifestation of this disease. Encore-PF enrolled 240 Nash patients who also had severe portal hypertension, and measures as primary endpoint the mean change in hepatic venous pressure gradient for three emricasan doses versus placebo; secondaries do not include any Nash measures, according to clinicaltrials.gov.
Portal hypertension is the main driver underlying chronic liver disease patients’ progression to cirrhosis, Stifel analysts reckon, which is why decreasing it is relevant. Emricasan is also in studies in Nash fibrosis and decompensated Nash cirrhosis, and these should read out next year, giving the group what it hopes will be a comprehensive data package.
Another interesting point is emricasan’s pharmacology; the asset is a caspase inhibitor, a mechanism more commonly associated with apoptosis and oncology. Stifel says that a reduction in hepatic venous pressure gradient of 10-20%, or to below 12mmHg, would be clinically meaningful.
In an earlier exploratory study emricasan failed to show a benefit on portal hypertension but did work in a subgroup of patients with severe hypertension at baseline – hence the design of Encore-LH. If the study reads out positively Novartis has already pledged to put emricasan monotherapy and a farnesoid X receptor (FXR) agonist combo into phase III.
More broadly, the choice of endpoint could point the way towards approval in a less competitive space than Nash itself.
|Study||Disease/primary endpoint||Trial ID||Readout|
|Encore-PH||Nash with severe portal hypertension/24wk chg in HVPG||NCT02960204||End of 2018|
|Encore-NF||Nash fibrosis/fibrosis improvement without Nash worsening||NCT02686762||H1 2019|
|Encore-LF||Nash cirrhosis/event-free survival||NCT03205345||Mid-2019|