Arrowhead delivers in the lung
Early clinical data with an inhaled RNA interference candidate look promising, but there is still much to prove.
Getting RNA-based therapies into the lung has proven difficult in the past. So it is no wonder that early clinical data from Arrowhead yesterday, suggesting target engagement with one of its inhaled projects, caused excitement among investors, with the group’s stock closing up 12%.
Arrowhead’s chief executive, Chris Anzalone, admits that it is still early days. But if the company really has cracked lung delivery this could open up opportunities in diseases including asthma, COPD and, perhaps most tantalisingly, cystic fibrosis.
Arrowhead has several inhaled projects in the clinic, and there could be many more to come. “We don't see two or three or four drugs in the lung space, we see eight or nine or 10,” Anzalone tells Evaluate Vantage.
These could now draw interest from potential partners, although the chief exec believes that Arrowhead will be able to commercialise at least some of its lung-targeted assets alone, should they make it to market.
Rage against asthma
The data released yesterday come from the healthy volunteer portion of a phase 1/2 study of ARO-RAGE, designed to reduce production of the receptor for advanced glycation end products (Rage). The receptor is involved in inflammation.
A total of 50 subjects received one or two doses of ARO-RAGE, at 10mg, 20mg, 44mg, 92mg and 184mg, while 10 received placebo. Data are available from the first four dose cohorts, and show reductions in soluble Rage in both serum and bronchoalveolar lavage fluid.
There was a dose-dependent lowering of Rage, Arrowhead said, with the most impressive seen in those who received two doses of 92mg – these subjects had a mean maximum reduction of 80% in serum. Those receiving placebo, meanwhile, had a mean 1% drop in serum soluble Rage. Similar results were seen in bronchoalveolar lavage fluid.
More detailed data will be presented at the group’s R&D day on 1 June. Anzalone describes the initial results as a “great leap forward” for Arrowhead. “The fact we're getting [knockdown of] Rage suggests that we will get it for other targets.”
One question now is whether the project will work similarly in patients; asthma sufferers are now being dosed in the second part of the study, and results could come by the end of the year.
Anzalone is confident, saying “there’s no reason to believe that it should be different in patients”. However, caution could be warranted, particularly as the mucus seen with various lung diseases has hampered delivery of RNA therapies.
The chief exec does not expect this to be a roadblock, noting that Arrowhead’s RNAi particles are small enough to penetrate the mucus matrix. “We've done in vitro studies with actual human CF mucus, and we can get through that. We expect we should be able to get through mucus, regardless of whether it’s patients or healthy volunteers.”
But he adds: “The larger question is, is 80% knockdown going to be enough for disease-modifying effects? And we'll see about that.”
There are also questions around the target given the failure of other Rage inhibitors, such as VTV Therapeutics’ azeliragon in Alzheimer’s with and without diabetes.
Anzalone reckons previous disappointments were down to difficulties in hitting Rage with small molecules. “There's good consensus that, if you can reduce the expression of Rage, you can broadly decrease the inflammatory response.”
As well as asthma, ARO-RAGE could have utility in COPD and cystic fibrosis. Meanwhile, the group’s second-generation asset against the epithelial sodium channel alpha subunit, known as ARO-ENaC2, is further behind. “It's not clear if and when that will make it back into the clinic,” Anzalone says.
|Arrowhead's lung hopefuls|
|ARO-RAGE||Receptor for advanced glycation end products||Asthma, CF, COPD||Ph1/2 in healthy/asthma pts; healthy volunteer data Apr 2023|
|ARO-MUC5AC||Mucin 5AC||Asthma, CF, COPD||Ph1/2 in healthy/asthma pts; preliminary data due H1 2023|
|ARO-MMP7||Matrix metalloprotease 7||IPF||Ph1/2 in healthy/IPF pts; data due 2023|
|ARO-ENaC2||Epithelial sodium channel alpha subunit||CF||Preclinical|
|CF=cystic fibrosis; COPD=chronic obstructive pulmonary disease; IPF=idiopathic pulmonary fibrosis. Source: Evaluate Pharma & clinicaltrials.gov.|
The first-gen ARO-ENAC asset, which was being developed for cystic fibrosis, was dropped after being linked with lung inflammation in an animal study. Anzalone highlights ARO-RAGE’s improved potency, which allows less frequent dosing and therefore, he says, less potential for inflammation.
“With ARO-ENAC we were dosing daily for three days, every two weeks.” ARO-RAGE is being dosed monthly, and could be given even less frequently, “so we’re using a substantially smaller amount of material”.
ARO-RAGE looks well tolerated, with no severe adverse events and no dropouts in the relatively small number of subjects dosed so far, but Anzalone admits that this will need to be confirmed with more regular dosing.
As for competition, there are plenty of others hoping to develop inhaled RNA and gene therapies for cystic fibrosis, including that disease’s major player Vertex, but all are at a similarly early stage. For now, Arrowhead looks to have edged to the front of the pack.
This story has been updated to correct the number of healthy volunteers who received ARO-RAGE and placebo.