After years of research, technology for silencing a gene—stopping it from producing a disease-causing protein—has reached patients. AstraZeneca is now angling for a position in this burgeoning field through an alliance with Silence Therapeutics, a biotech developing such gene-silencing drugs.
According to deal terms announced Wednesday, AstraZeneca (NYSE: AZN) will pay London-based Silence (LON: SLN) $60 million up front. The pharmaceutical giant will also make a $20 million equity investment in its new partner. The companies initially aim to work on five targets over the next three years. AstraZeneca has the option to expand the pact to another five targets. The collaboration covers potential therapies for cardiovascular, kidney, metabolic, and respiratory disorders.
Problem proteins are at the root of many diseases. Pharmaceutical companies have historically tried to treat disease by developing therapies that bind to these proteins and block them. This approach doesn’t always work, or sometimes it doesn’t work well enough. It can also spark side effects. Silence and a growing number of others are developing therapies intended to stop those proteins from being produced in the first place.
The genetic instructions that tell a cell how to make proteins are carried on molecules called messenger RNA (mRNA). Silence’s investigational drugs uses small interfering RNA (siRNA), which are short strands of RNA that enter a cell, find their mRNA targets, and bind to them. Doing so silences a gene and stops it from producing the problem protein. Scientists credited with discovering the technology, called RNA interference (RNAi), were awarded a Nobel Prize in 2006.
Silence’s most advanced internal program is SLN124, an experimental treatment set to begin clinical testing in beta thalassemia and myelodysplastic syndrome, two rare blood disorders. A potential cardiovascular RNAi therapy, SLN360, is in preclinical development. Silence also has partnerships with Mallinckrodt Pharmaceuticals (NYSE: MNK) and Takeda Pharmaceutical (NYSE: TAK). The Mallinckrodt alliance is focused on treating diseases of a part of the immune system called the complement system. The disease target of the Takeda partnership is undisclosed, but Iain Ross, Silence’s executive chairman, said on a conference call that he hopes the company will be able to say more in about a year. Now Silence adds AstraZeneca to its partner list.
“We think it’s a further validation of our proprietary platform,” Ross said. “We’ve already done deals with Mallinkrodt and also Takeda, and we feel this is a very exciting collaboration we’ve put in place.”
In 2018, Alnylam Pharmaceuticals (NASDAQ: ALNY) won the first FDA approval of an RNAi therapy. The Cambridge, MA-based biotech’s drug, patisiran (Onpattro), was approved to treat nerve damage caused by hereditary transthyretin amyloidosis. That approval validated the science underlying RNAi therapies, and showed that such treatments can be delivered to the liver.
Silence also aims to target the liver but developing RNAi treatments for the diseases spelled out under the AstraZeneca collaboration will require the company to also get its siRNA molecules to the heart, kidney, and lungs. John Strafford, Silence’s head of business development, say Silence will work with AstraZeneca to achieve such delivery. The partnership holds Silence responsible for discovery and research work up to the point of nominating drug candidates. Silence will also be responsible for manufacturing up through Phase 1 testing. The research will focus on gene targets selected by AstraZeneca.
AstrraZeneca will take over development of the therapies as they reach the clinic; if they’re approved, the pharmaceutical giant will also handle commercialization. According to the deal terms, Silence could earn up to $400 million in milestone payments for each target, depending on the progress of the program. If these therapies reach the market, Silence would also receive royalties from sales.
Meanwhile, Alynlam continues to press forward in RNAi R&D. The company followed patisiran’s approval with a regulatory nod last November for givosiran (Givlaari), an RNAi treatment for acute hepatic porphyria, a rare metabolic disorder that affects the liver. The company has started a rolling submission seeking FDA approval of lumasiran for primary hyperoxaluria type 1, another rare metabolic condition, which primarily affects the kidneys. Alnylam also has a partnership with Regeneron Pharmaceuticals (NASDAQ: REGN) focused on developing RNAi treatments for eye and neurological disorders.
Other companies developing RNAi therapies include Dicerna Pharmaceuticals (NASDAQ: DRNA), which has partnerships with Roche, Boehringer Ingelheim, and Alexion Pharmaceuticals (NASDAQ: ALXN); Arrowhead Pharmaceuticals (NASDAQ: ARWR); and Arbutus Biopharma (NASDAQ: ABUS).
Silence’s Ross says his company is not actively seeking partners to advance the development of SLN124 and SLN360. For now, the plan is to continue developing those programs internally, though he added that if other companies expressed interest in a partnership, Silence would at least hear them out.
In the near term, the coronavirus pandemic is impinging on the Silence’s development plans. The Phase 1 test of SLN124, which was previously expected to dose its first patient in the first quarter of this year, has halted patient screening, Ross said. The company now estimates it will have preliminary data in the first half of next year. The company is on track to file regulatory paperwork in the second half of this year for clearance to start Phase 1 tests of SLN360.