In RNAi Move, Takeda Fronts $300M to Team Up on Arrowhead Liver Drug

Arrowhead Pharmaceuticals’ gene silencing treatment for a rare liver disease will move through the regulatory process and potential commercialization with the muscle of Takeda Pharmaceutical behind it.

Takeda (NYSE: [[ticker:TAK]]) has agreed to pay $300 million up front in a partnership on Arrowhead (NASDAQ: [[ticker:ARWR]]) drug ARO-AAT as a treatment for alpha-1 antitrypsin-associated liver disease. According to terms of the agreement announced Thursday, Arrowhead and Takeda will co-develop the drug, which is currently in Phase 2/3 testing.

In addition to the upfront cash, Pasadena, CA-based Arrowhead could earn up to $740 million in milestone payments. If the drug is approved, the partners will jointly commercialize the drug in the US, sharing profits equally. Takeda will take the lead commercializing the drug in the rest of the world and will pay Arrowhead royalties from those sales. Speaking on a conference call Thursday, Arrowhead CEO Christopher Anzalone said that Takeda’s experience and global reach gives Arrowhead its best opportunity to commercialize ARO-AAT globally.

The Arrowhead drug emerged from the company’s platform for developing therapies that employ RNA interference, a biological mechanism that stops a gene from producing a disease-causing protein. This approach is sometimes referred to as gene silencing. Alpha-1 antitrypsin deficiency is a rare inherited disorder that causes a deficiency of the protein that gives the disorder its name. That protein, produced by liver cells, blocks enzymes that can break down healthy connective tissue. Deficiency of the healthy form of the protein leads to liver disease in children. In adults, the disorder causes both liver and lung disease.

While there are treatments for the lung problems stemming from the deficiency, there are no FDA-approved drugs for the liver disease, which can lead to fibrosis, cirrhosis, and a higher risk of liver cancer. Arrowhead’s ARO-AAT is designed to stop the liver from producing the mutant protein that causes progressive liver disease. By reducing levels of the mutant protein, the hope is the therapy can halt the progression of the disease, potentially allowing the liver to heal itself.

The Takeda partnership comes less than a month after the release of preliminary data for the open-label Phase 2 portion of the study evaluating the Arrowhead gene-silencing drug. In four patients, Arrowhead reported that levels of the mutant protein were reduced by up to 93 percent. Those protein levels were reduced in the liver by up to 95 percent. The company also reported data showing improvement in fibrosis and other biological indicators of liver injury. More details about the results will be presented next month during the American Association for the Study of Liver Disease meeting.

Based on the early clinical trial results, Arrowhead said last month that it plans to discuss with the FDA ways to streamline or speed up the pivotal portion of the clinical study. Those discussions haven’t happened yet. But Anzalone said that ways clinical development of ARO-AAT could be adjusted include reducing the length of the pivotal study, reducing the size of the study, or considering other endpoints that would be sufficient to support regulatory approval. “At this point, it’s still a bit unclear until we speak with the FDA,” he said.

Alnylam Pharmaceuticals (NASDAQ: [[ticker:ALNY]]) won the first FDA approval for an RNAi drug in 2018 for patisiran (Onpattro), a treatment for the nerve damage suffered by patients who have the rare disease hereditary transthyretin amyloidosis. Nearly a year ago, the Cambridge, MA-based biotech won FDA approval for a second RNAi drug, givosiran (Givlaari), for acute hepatic porphyria. Alnylam also has an RNAi drug candidate for alpha-1 antitrypsin deficiency. In April, Alnylam inked an alliance with Dicerna Pharmaceuticals (NASDAQ: [[ticker:DRNA]]), a deal that calls for the companies to work together to co-develop and potentially co-commercialize one or both of their RNAi drugs for the disorder. Both drugs are currently in Phase 1/2 testing.

Vertex Pharmaceuticals (NASDAQ: [[ticker:VRTX]]) is in the mix, too, with two small molecule drugs in mid-stage development for alpha-1 antitrypsin deficiency. The most advanced of the two, VX-814, is expected to report Phase 2 data by the end of this year or early next year. The second Vertex compound VX-864, began Phase 2 testing in July.

The data for the Arrowhead drug are preliminary, but Takeda sees enough promise in the early results to grab a share of the compound, securing a place in the growing RNAi market. Asit Parikh, head of Takeda’s gastroenterology division, said on the call that earlier regulatory approval of RNAi drugs has reduced the risk of this technology, whose targeted approach should limit side effects. Those factors helped persuade Takeda to grab a share of the Arrowhead drug, which the company sees as the best shot at treating liver disease caused by alpha-1 antitrypsin deficiency.

“I actually believe that this is going to be the first drug out there for patients with this disease and I actually think it’s going to be the strongest drug out there based on what we know so far,” Parikh said.

In a research note, SVB Leerink analyst Mani Foroohar described the deal as a “prudent move” for Arrowhead. The deal locks in value for ARO-AAT, shares some of the development costs, and mitigates risk ahead of the release of data from other drugs in development for alpha-1 anti-trypsin deficiency associated liver disease. Takeda is just the latest big pharmaceutical partner signed on by Arrowhead. The biotech previously licensed a hepatitis B program to Janssen, a Johnson & Johnson subsidiary. Arrowhead also has a partnership with Amgen (NASDAQ: [[ticker:AMGN]]) focused on cardiovascular disease.

Image: iStock/magicmine