News and Analysis

Novartis has agreed to license and develop Arrowhead Pharmaceuticals’ preclinical stage small interfering RNA (siRNA) therapy ARO-SNCA, a potential treatment for Parkinson’s disease and other synucleinopathies, plus additional targets, through a collaboration that could generate more than $2.2 billion for the Pasadena, CA, RNA interference (RNAi)-based drug developer.
The collaboration is aimed at developing treatments based on Arrowhead’s Targeted RNAi Molecule (TRiM) platform, which, according to the company, enables it to develop new therapies faster, more cost-effectively, and with potentially lower risk compared to traditional approaches by applying a toolbox of RNAi delivery technologies, chemistries, structures, and manufacturing techniques.

In February, Arrowhead presented positive preclinical data for an obesity candidate based on the TRiM platform, ARO-ALK7, an RNAi therapeutic targeting Activin receptor-like kinase 7 (ALK7) being developed as a potential treatment for obesity. ARO-ALK7 is designed to be administered subcutaneously and cross the blood-brain barrier.
Arrowhead reported that a single subcutaneous dose of ARO-ALK7 led to dose-dependent and durable reductions in ALK7 mRNA in abdominal fat, with approximately 80% knockdown achieved at 0.3 mg/kg, and approximately 91% knockdown achieved at 1.5 mg/kg. A 75% knockdown was still observable after 12 weeks, the company added, in data that was presented in a poster at the Keystone Symposia on Obesity and Adipose Tissue, held February 23–26 in Banff, AB, Canada.
Since then, Arrowhead has launched a Phase I/IIa trial (NCT06937203) in New Zealand that is assessing ARO-ALK7, with healthy obese subjects receiving single and multiple escalating doses of ARO-ALK7 monotherapy. Plans call for researchers to study combinations of ARO-ALK7 with Eli Lilly’s tirzepatide in obese patients with and without type 2 diabetes. Lilly markets trizepatide for type 2 diabetes as Mounjaro® and for weight management, including obesity as Zepbound®.

ARO-ALK7 is the first RNAi candidate to enter the clinic, which targets a gene expressed in adipose tissue, according to the company.
Potential “leap forward”

“Our TRiM platform has generated impressive preclinical results demonstrating delivery to CNS, including distribution to deep brain regions, after subcutaneous administration,” Arrowhead’s president and CEO, Christopher Anzalone, PhD, said in a statement. “The potential translation of these results in upcoming clinical trials would represent an important leap forward for neurodegenerative diseases and gene targets in the CNS that have been historically difficult to address.”
Investors sent Arrowhead shares up 14% in early afternoon trading at 1:50 p.m. ET, as shares climbed to $25.11 from Friday’s close of $22.03. Novartis’ shares on the SIX Swiss Exchange dipped 0.3% to CHF 101.20 ($126.01) from CHF 101.54 ($126.43) on Friday.
“While preclinical data for ARO-SNCA is sparse, NVS taking on the asset (and attendant OpEx [operating expense] and development risk) is a tailwind to ARWR, and keeps focus on sHTG and the late-stage pipeline,” Mani Foroohar, MD, senior managing director, genetic medicines and a senior research analyst with Leerink Partners, wrote in a research note.
sHTG is short for severe hypertriglyceridemia (sHTG), for which Ionis Pharmaceuticals announced positive results from two pivotal Phase III trials of its RNA-targeted olezarsen, which is designed to lower the body’s production of apoC-III, a protein produced in the liver that regulates triglyceride metabolism in the blood. Ionis said the 617-patient CORE trial (NCT05079919) and 446-patient CORE2 trial (NCT05552326) showed an up to 72% placebo-adjusted mean reduction in fasting triglycerides, and an 85% reduction in acute pancreatitis events with favorable safety and tolerability—results that Ionis termed “highly statistically significant.”

“For competitor ARWR, CORE data makes clinical differentiation an uphill battle (favoring IONS’ first-mover advantage),” Foroohar observed, adding that the CORE and CORE2 data “shifts the onus on ARWR to execute clinically and commercially to keep pace with IONS.”
However, Foroohar raised Leerink’s 12-month price target on Arrowhead shares 9.5%, from $21 to $23, based on Arrowhead integrating the upfront payment and milestones from its collaboration with Novartis.
Exclusive worldwide license

Arrowhead has given Novartis an exclusive worldwide license to research, develop, manufacture, and commercialize ARO-SNCA. The pharma giant will select additional collaboration targets outside of Arrowhead’s current pipeline to be developed using the TRiM platform.
For all programs licensed under the agreement, Arrowhead has agreed to conduct and complete preclinical research activities necessary to enable a clinical trial application (CTA) filing, with Novartis then assuming sole control over development, manufacturing, medical affairs, and commercialization activities.
“We see Arrowhead’s TRiM technology as having great potential to achieve the type of widespread and effective delivery in key brain structures that will be necessary to see the full benefit of RNA medicines in neurodegeneration,” stated Fiona Marshall, PhD, Novartis’ president of biomedical research.
For Novartis, ARO-ALK7 marks a second effort to develop a Parkinson’s treatment by targeting alpha-synuclein. Last December, Novartis and collaboration partner UCB acknowledged that their oral small molecule, alpha-synuclein misfolding inhibitor minzasolmin, failed the Phase IIa ORCHESTRA proof of concept trial (NCT04658186) by not meeting its primary clinical endpoint of improvement in Parkinson’s as measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), and not meeting numerous secondary endpoints.
Novartis has agreed to pay Arrowhead $200 million upfront and up to $2 billion in payments tied to achieving milestones, plus royalties on commercial sales. The transaction is expected to close later in the second half of this year, subject to the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 and other customary conditions.
“We look forward to working with Novartis to bring ARO-SNCA for the treatment of synucleinopathies, such as Parkinson’s disease, into clinical trials as soon as possible and to collaborate on additional programs in the future,” Anzalone added.
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