RNA therapeutics targeting the liver have been a success story for biopharma, but Arrowhead reminded investors on Friday that going elsewhere might be trickier. Signs of lung inflammation in an animal study were enough for the group to pause a phase 1/2 trial of its cystic fibrosis RNA interference project ARO-ENaC.
Arrowhead reckons the halt might be temporary, but the signs are not good: Ionis recently discontinued a similarly acting antisense asset, Ionis-Enac-2.5-Rx, also after preclinical toxicology findings.
The latest setback raises the question of whether there might be an issue with the target, or the delivery of oligonucleotides to the lung. However, biopharma might not have too much to worry about: according to Evaluate Pharma the only other inhaled RNA therapeutic in clinical development is Toray/Bonac’s TGF-beta-inhibiting TRK-250.
And the slow pace of development – the project went into phase 1 in idiopathic pulmonary fibrosis in 2018 – suggests that it might not go much further.
Sirnaomics is taking a similar approach with its inhaled version of STP707, which targets both TGF-beta and Cox-2; however, that asset is still preclinical. And, despite promises to go into the clinic this year, Vir and Alnylam have deprioritised VIR-2703, an inhaled RNAi project for Covid-19.
Still, there might be breath left in the lung-targeted approach: Ionis said at the time of the Ionis-Enac-2.5-Rx discontinuation that it had a number of other pulmonary research programmes ongoing. And Arrowhead also has preclinical lung-targeted projects in COPD and Covid-19.
Outside the liver
But Arrowhead’s stumble highlights the difficulty of getting RNA therapies to work outside the liver in general. Here there is more activity: Ionis, for one, is going big in neurological diseases, where its antisense projects are largely given intrathecally.
A big test for this approach will be upcoming pivotal data with the group’s Biogen-partnered ALS asset tofersen. However, a black mark against the intrathecal delivery of antisense therapies came with the failure of Ionis and Roche's tominersen earlier this year in Huntington’s; one theory for the flop was that the molecule did not sufficiently penetrate the deep brain tissues involved in the disease.
Ophthalmic approaches have also garnered interest: Pharmamar recently started a phase 3 trial of tivanisiran, an RNAi eye drop for dry eye disease in Sjögren’s syndrome, while Ionis has an intravitreally injected antisense candidate, ION357, for autosomal dominant retinitis pigmentosa.
And the latter group’s oral gastrointestinal antisense asset ION253, partnered with Johnson & Johnson, is in phase 1. It will be interesting to see if any of these approaches succeed; if not, RNA therapeutics could be limited to liver-directed targets for the foreseeable future.
Arrowhead fell 26% on Friday, which seems overdone given that the sellside had not ascribed any value to ARO-ENaC, and that most of its pipeline is liver-directed. Still, the company is worth around $6.5bn, largely on the back of promising but early data from a handful of patients receiving its alpha-1 antitrypsin deficiency project ARO-AAT. It has much to prove.
This story has been updated to correct Arrowhead's market cap at the time of publication.