- Safety concerns in animal tests led Arrowhead Pharmaceuticals to suspend testing of a closely watched drug for cystic fibrosis, the latest setback for an RNA-based medicine against the genetic lung disease.
- Arrowhead stopped an early-stage human trial of the drug, known as ARO-ENaC, after researchers observed "unexpected signals of local lung inflammation" in a toxicology study in rats. The biotech will only resume testing if "there is an acceptable path forward for further clinical investigation," its chief medical officer, Javier San Martin, said in a July 2 statement.
- The surprising announcement is the third disappointing result for an RNA-based cystic fibrosis treatment since March, a reflection of the difficulty drugmakers face in safely and effectively delivering the medicines into the lungs. Arrowhead, which has three lung drugs in its pipeline, lost a quarter of its market value on the news Friday.
RNA interference, a Nobel Prize-winning method of silencing genes before they can make harmful proteins, came of age in the last decade because of the liver.
The large organ, which filters blood, is where Alnylam Pharmaceuticals finally succeeded with an RNAi drug after nearly two decades of ups and downs. Each of its three subsequently approved drugs are either infused into the blood or injected into muscle or fatty tissue before heading to the liver. The first, Onpattro, is encased in a delivery tool known as a lipid nanoparticle. The others are linked to a molecule that ferries them to their targets.
While RNAi drug developers are still focused on the liver, some are experimenting with ways to broaden the reach of their drugs by targeting other organs. The lungs, which are principally affected by several prominent diseases including cystic fibrosis, are one such target. Multiple drugmakers have launched research programs for RNA-based medicines delivered via an inhalable mist.
In taking on lung diseases, however, each of those companies has signed up for a tough task. Delivering medicines to the lungs is difficult because of the various defenses the body uses to keep drugs out or remove them if they get there.
Several programs have now run into setbacks. Moderna and Vertex, for instance, have been working together since 2016 to develop a messenger RNA-based drug for cystic fibrosis. They still don't have one near clinical trials, and have cited challenges with delivery as the key reason why. A treatment from Translate Bio, meanwhile, wasn't effective in an early trial, though the biotech hasn't given up. Ionis Pharmaceuticals scrapped a cystic fibrosis program in March after worrying safety signals in animal tests.
Now Arrowhead, too, has flagged safety concerns. Arrowhead said it hasn't observed signs of lung inflammation in human testing, with CEO Chris Anzalone adding in a statement that the company remains "committed" to its lung drug platform.
"This may delay our pulmonary program a bit, but it's just part of drug development," Anzalone said. Ionis, too, is still going after lung diseases, just not cystic fibrosis.
But the string of setbacks for RNA drugs in cystic fibrosis raises questions about the approach's viability. Mani Foroohar, an analyst at SVB Leerink, noted the negative toxicology results from two different RNA platforms suggests the problems either relate to the target they share — a sodium channel in the lungs known as ENaC — or the safety of RNA drugs "in the lungs as a whole." Multiple small molecule drugs targeting ENaC have previously failed.
"The extent to which these [toxicology] signals curtail development of future lung-targeted programs across the ... space remains to be seen, but they certainly highlight the sensitive and challenging drug delivery environment in the lungs," Foroohar wrote.
Initial human data from ARO-ENaC had been expected imminently but will now be delayed, according to Jefferies analyst Maury Raycroft, who spoke with Arrowhead executives.
Arrowhead's setback is a reprieve of sorts for Vertex, which sells four market-leading cystic fibrosis medicines. Arrowhead still poses a competitive challenge to Vertex on another front, however, as its experimental RNAi drug for the rare genetic disease alpha-1 antitrypsin deficiency is ahead of Vertex's programs.
Arrowhead on Tuesday separately disclosed early results for a kidney cancer drug in early testing.
Correction: A previous version of this story mistakenly indicated that all three marketed Alnylam drugs are delivered with lipid nanoparticles.