DUBLIN – Silence Therapeutics plc entered a wide-ranging siRNA-based drug discovery and development deal with Astrazeneca plc that has propelled it toward the front ranks of siRNA platform companies. It is banking an up-front payment of $60 million, another $20 million as an equity investment and up to $400 million in option fees and milestone payments per candidate drug, in an alliance that could entail up to five active programs within three years. What’s more, Cambridge, U.K.-based Astrazeneca has an option to pursue up to five more targets beyond that first batch.

“This is really transformational for Silence. It really puts us on the map,” John Strafford, vice president and head of business development at London-based Silence, told BioWorld. The alliance ranges broadly over cardiovascular, renal, metabolic and respiratory indications. Key to its success, therefore, is the development of novel conjugates that will enable the targeted delivery of siRNA molecules to the appropriate tissues.

The development of N-acetylgalactosamine (GalNac) ligands for selective uptake of siRNA molecules by hepatocytes, through the asialoglycoprotein receptor, has greatly improved the performance of liver-directed siRNA drugs. But extending the success of siRNA to other organs is still a work in progress. Cambridge, Mass.-based Alnylam Pharmaceuticals Inc. had done enough in terms of siRNA delivery to the central nervous system (CNS) and to the eye to convince Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc. to slap down $800 million in cash last year for a broad alliance, which also included some liver-related indications. In a similar vein, Lexington, Mass.-based Dicerna Pharmaceuticals Inc. entered an alliance in 2018 with Eli Lilly and Co., which includes neurodegeneration and pain, as well as liver-associated indications.

John Strafford, vice president and head of business development, Silence

Silence is engaged in its own efforts around tissue targeting, Strafford said, but it will also draw on the experience Astrazeneca has developed both in-house and through its partnerships in mRNA drug development in cardiometabolic disease and cancer with Cambridge, Mass.-based Moderna Inc. and in antisense nucleotide drug development with Ionis Pharmaceuticals Inc., of Carlsbad, Calif. “This is a tough nut to crack. This collaboration positions us well to achieve it,” Strafford said.

Astrazeneca will be responsible for nominating target genes, while Silence will be responsible for the design of siRNA molecules and for the production of material for GLP toxicology studies and phase I studies. For each program, Astrazeneca will pay an option fee of $10 million at the point of candidate nomination, and could pay up to $140 million in development milestones and up to $250 million in commercial milestones. Silence will receive tiered sales royalties ranging from a high single-digit to a low double-digit percentage. It also has an option to negotiate co-development rights on two programs.

A blue-chip big pharma deal such as this one is a real boost to the competitive standing of Silence’s siRNA platform. The company, whose roots lie in a German outfit called Atugen, was one of the early movers in the field, but it failed to make much progress the first time round. Indeed, Astrazeneca bought into the company as far back as 2007, as part of a respiratory disease deal worth up to $400 million, but, that collaboration foundered, as did all the others in the field at that time, owing to the immaturity of the technology.

Rob Quinn, CFO, Silence

That Silence can land a deal on the scale of the current agreement indicates that it has managed to keep pace with its bigger and more advanced rivals, like Alnylam, Dicerna and Pasadena, Calif.-based Arrowhead Pharmaceuticals Inc., in developing a platform that can deliver stable siRNA molecules that have a long duration of action. Its own pipeline is still preclinical. A planned trial start in the present quarter of its lead candidate, SLN-124, which knocks down transmembrane protease, serine 6, and which is in development for treating iron overload in patients with beta-thalassemia and myelodysplastic syndrome, has been derailed by the COVID-19 pandemic. “We had some patients lined up for screening and were due to begin dosing very soon,” Chief Financial Officer Rob Quinn told BioWorld. The company is instead submitting a new protocol, with altered inclusion and exclusion criteria and additional clinical sites. Its guidance on an interim readout has shifted from the second half of 2020 to the first half of 2021.

It is still on track to begin clinical development later this year of SLN-360, which silences the apolipoprotein(a) component of lipoprotein(a), a genetically validated target in dyslipidemia and cardiovascular disease. “We see that as the jewel in the crown,” Quinn said. “We’re going to file an IND in the second half of this year.” Interim data could arrive around mid-2021. “We’re keen to show the world we have a competitive drug here,” he said. Studies in nonhuman primates indicate knockdown of more than 90% within weeks. “It’s rapid, and it’s really long-lived,” Quinn said.

SLN-360 is the last unencumbered asset in its class, Quinn said. Ionis affiliate Akcea Therapeutics Inc. and partner Novartis AG are in phase III with an antisense molecule, TQJ-230 (AKCEA-APO(a)-LRx). Amgen Inc. and Arrowhead plan to move AMG-890, a GalNac-conjugated siRNA into a phase II trial in subjects with elevated Lp(a) later this year.

Silence has no plans to seek a deal for this program as yet and may even decide to take the molecule the whole way. The company, which exited 2019 with £33.5 million in cash, now has additional resources to dedicate to the program. It has undergone a major leadership transition over the past 18 months, and a CEO search is ongoing. It is also hiring 44 employees, in areas such as clinical development, project management and manufacturing. “I think we were perhaps a bit of a sleepy AIM company,” Quinn said.

Shares in Silence (London:SLN) gained as much as 49% on the news Wednesday, March 25, but later shed much of those gains to close at £4.74 (US$5.60), up 16.75% on the previous close of £4.06. The companies did not disclose the price at which Astrazeneca has bought into the stock, but it is about £3.96 per share. The equity component of the deal involves the issue of about 4.3 million new shares.