Novartis is making a $100 million, $61.3 per share equity investment in Ionis Pharmaceuticals and will pay Ionis and the latter’s Akcea Therapeutics subsidiary $75 million upfront as part of a worldwide option and collaboration agreement to develop the latter’s Phase I/IIa-stage cardiovascular disease candidates AKCEA-APO(a)-LRx and AKCEA-APOCIII-LRx. Both drugs have been developed using Ionis’s antisense technology and are in development for reducing cardiovascular risk in patients with high levels of lipoproteins Lp(a) and ApoCIII.

Ionis and Akcea aim to carry out a Phase II dose-ranging study for each candidate to select the optimal dose and evaluate alternative dosing schedules for prospective Phase III studies. At the end of each Phase II study, Novartis will be able to exercise its licensing and commercialization option for the relevant candidate. Upon exercise, the Swiss drug maker will pay a $150 million license fee for its option to each drug and take on worldwide development and commercialization activities, including a global Phase III cardiovascular outcome study in a high-risk population. Ionis and Akcea could receive development and commercial milestones of $600 million for APO(a)-LRx and $530 million for AKCEA-APOCIII-LRx, plus tiered sales royalties topping 20%. Novartis will also have to make an additional $50 million equity investment in either Ionis or in Akcea within the next 18 months.

“AKCEA-APO(a)-LRx and AKCEA-APOCIII-LRx are novel potential therapies to address the broad opportunities that still exist to treat cardiovascular disease, despite currently available therapies,” commented Paula Soteropoulos, Akcea Therapeutics CEO. “We are advancing our pipeline of novel drugs to treat previously inadequately treated lipid disorders by pursuing indications that drive the greatest near- and long-term value. This strategic partnership allows us to move more rapidly to Phase III cardiovascular outcomes studies with both therapies than our original development plan.”

“Lp(a) and ApoCIII are potent, genetically validated cardiovascular risk reduction targets,” added Vasant Narasimhan, global head of drug development, and CMO at Novartis. “Novartis is building a robust cardiovascular portfolio of targeted therapies to address unmet medical need of high-risk patients. The importance of predictive biomarkers in achieving successful cardiovascular outcomes will also be essential in the future payer environment.”

Akcea Therapeutics was established as a wholly owned subsidiary of Ionis in early 2015 to focus on developing antisense drugs for treating cardiometabolic diseases caused by lipid disorders. A prior Phase I/IIa study evaluating AKCEA-APO(a)-LRx in healthy volunteers with elevated Lp(a) levels showed that treatment can reduce Lp(a) by up to 99%. AKCEA-APOCIII-LRx is currently being evaluated in a Phase I/IIa study in healthy volunteers with elevated triglycerides.

Akcea’s lead candidate volanesorsen is designed to reduce production of the liver protein ApoC-III. The antisense drug is in Phase III development for the treatment of familial chylomicronemia syndrome (FCS) and familial partial lipodystrophy (FPL). In December 2016, the firm reported positive data from the Phase III Compass study evaluating volanesorsen in 113 patients with severe hypertriglyceridemia. Compass is one of four global studies in the Phase III development program. Reporting on the trial in December Akcea said that it anticipated regulatory filings for volanesorsen in the U.S., Europe, and Canada, during 2017.

The Novartis deal for AKCEA-APO(a)-LRx and AKCEA-APOCIII-LRx comes just 2 days after Ionis reported positive data from a Phase II study with its own antisense drug IONIS-GCGRRx in 79 patients with type 2 diabetes.

In December 2016 Ionis’s flagship drug, Spinraza™ (nusinersen) received FDA approval for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. Biogen exercised its option to develop and commercialize Spinraza in August 2016. Also in December 2016, Ionis reported earning a $28 million milestone payment from AstraZeneca, relating to completion of IND-supporting studies and licensing of the KRAS-targeting antisense drug IONIS-KRAS-2.5Rx (AZD4785).

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