AstraZeneca is investing $200 million in the development of Ionis Pharmaceuticals’ drug in late-stage clinical trials for a rare disease affecting the nerves. preliminary data Now, a pivotal study provides some justification for a 2021 deal, and the partners plan to submit regulatory filings to the FDA later this year.
The drug, eplontersen, is in Phase 3 testing for the treatment of nerve pain caused by hereditary transthyretin-mediated amyloid (hATTR). The disease stems from a misfolded version of a protein, transthyretin, that accumulates in body tissues, including nerves. The two main goals of the clinical trial are to measure changes in the concentration of transthyretin in the blood and to evaluate patients on a scale used to measure neuropathy. On both targets, AstraZeneca and Ionis said Tuesday that their drugs resulted in statistically and clinically meaningful changes. The companies did not further detail the changes, but said data from that interim analysis would be presented at a medical meeting later this year.
Those clinical trial results and planned regulatory filings are key to keeping up with Cambridge, Massachusetts-based Alnylam Pharmaceuticals.Last week, that biotech company won FDA approves Amvuttra, its second hATTR therapy. As an injection every three months, Amvuttra offers patients a dosing advantage over Alnylam’s first hATTR drug, Onpattro, which is injected every three weeks. Both are “gene silencing” drugs that stop genes from making disease-causing proteins by using a mechanism called RNA interference.
Like Alnylam, Ionis is designed to block the production of transthyretin. But the Carlsbad, California-based biotech uses antisense oligonucleotides, short synthetic nucleotide chains designed to target genes of interest. Ionis’ eplontersen is administered by injection and is intended to be administered once a month. The drug comes from the company’s Ligand Conjugated Antisense (LICA) technology platform.
In December, AstraZeneca and Ionis announced a partnership Two of the companies will share the development and potential commercialization of eplontersen in the United States. The pharma giant has also secured rights to commercialize the therapy in other parts of the world, with the exception of certain countries in Latin America. In addition to the $200 million upfront payment, Ionis will receive up to $485 million in development and approval milestones and up to $2.9 billion in sales-related milestones.
Ionis already has a presence in the hATTR market. Tegsedi, an Ionis antisense drug approved by the FDA in 2018, is now marketed in much of the world under an agreement with the Swedish company Sobi. But Tegsedi is injected once a week. Eplontersen’s Phase 3 trial was an open-label study comparing the drug to a historical placebo group in Tegsedi’s 2017 pivotal study. The preliminary results, released Tuesday, were from an interim analysis of Week 35. The final analysis of the primary endpoint will be completed at Week 66. All patients will be followed until Week 85, at which point study participants will have the option to enter the open-label extension study.
In a research note to investors on Tuesday, William Blair analyst Myles Minter wrote that preliminary results are a positive sign of Ionis’ ability to compete at ATTR, but that without full data it’s difficult to assess eplontersen’s competitiveness against Alnylam’s drug . Still, the latest results show no worrisome adverse effects, and Ionis management told Minter that the safety profile of eplontersen was similar to the same dose used in Phase 1 testing, which showed no renal or cardiovascular problems — risks that are in Drug label for Tegsedi.
“We think this is a clear win for Tegsedi, which bodes well for the security posture of the wider LICA platform,” Minter said.
Treating neuralgia is just one of the competing frontiers for drugs. When ATTR affects the heart, it can lead to progressive heart failure and death within four years of diagnosis, according to Ionis and AstraZeneca. Alnyam is testing its gene silencing approach in cardiomyopathy. A Phase 3 trial of eplontersen in cardiomyopathy by Ionis/AstraZeneca is ongoing.
In cardiomyopathy caused by hATTR, Ionis/AstraZeneca and Alnylam will compete with Pfizer’s Vyndaqel, a small-molecule drug designed to stabilize transthyretin. The drug generated more than $2 billion in sales last year, according to Pfizer’s financial report. BridgeBio Pharma also aims to provide these patients with alternative treatments. But late last year, an interim analysis of the biotech drug, acoramidis, failed to meet its primary goal of phase 3 testing at 12 months of treatment. The 30-month study was fully funded, so BridgeBio is continuing the study with the hope of achieving better results. Preliminary 30-month data is expected to be released in mid-2023.
Photo: Christopher Furlong, Getty Images
