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Alnylam may be gearing up for its biggest commercial launch yet in its nearly 23-year history, but the company’s top scientists believe they are just starting to scratch the full potential of its gene-silencing siRNA technology. Until recently, most of Alnylam’s work has focused on relatively rare diseases in the liver. On Tuesday, the company announced plans to solve the longstanding technical challenge of delivering siRNA therapies to practically any part of the body by 2030. Doing so could open doors to tackling some of the biggest and most notorious diseases. “This is a pretty big inflection point for Alnylam,” chief medical officer Pushkal Garg told Endpoints News in an interview ahead of the company’s R&D presentation. “We have multiple blockbuster opportunities for drugs coming out in the next three to seven years.” The glimpse at Alnylam’s future comes a month ahead of two FDA approval decisions expected in late March: vutrisiran for a form of heart disease called ATTR amyloidosis with cardiomyopathy, and fitusiran for hemophilia A and B. Both drugs target a gene in the liver. Garg said the anticipated approval of vutrisiran in particular “is allowing us to really invest substantially in our R&D engine.” The company has its sights on delivering drugs into the brain, eye, fat cells, kidney, muscles and elsewhere. Alnylam revealed that its growing pipeline now includes Huntington’s disease, a debilitating neurodegenerative condition with no cure. The company also has a growing interest in metabolic diseases, including diabetes. “It’s a crowded space, but on the other hand, it’s a giant field,” Alnylam CSO Kevin Fitzgerald told Endpoints. Alnylam’s stock $ALNY is up 60% since June, when it announced that vutrisiran could reduce deaths and hospitalizations in a disease that may affect 500,000 people worldwide. The quarterly injection will enter a multibillion-dollar market established by daily pills. The company is already planning a sequel to vutrisiran called nucresiran that could be dosed just twice a year and reduce the offending transthyretin protein by more than 95%, potentially making it even more effective than vutrisiran’s roughly 85% reduction, Garg said. “We want to make this a disease that patients don’t have to think about anymore,” Garg said. There are benefits to the business too, he added, noting that Alnylam owes royalties to its partner Sanofi for vutrisiran, but not for nucresiran. A pair of Phase 3 studies of nucresiran will begin later this year. Likewise, the company is building on its success with fitusiran — also partnered with Sanofi — to create a new drug that Garg said “has the potential to be a universal hemostatic agent” for three million people with a variety of rare bleeding disorders. The drug targets a protein called plasminogen that breaks up blood clots. A Phase 2 study is planned for the second half of 2025. Alnylam also revealed details about a massive Phase 3 study to test its experimental drug zilebesiran in 11,000 people with hypertension. Garg believes that a single injection could help patients at risk of heart disease keep their blood pressure low for six months. The brain is the company’s first major foray beyond the liver. Alnylam has previously shown that a single injection of a drug, recently renamed mivelsiran, can lower levels of the amyloid protein linked to Alzheimer’s disease. New data from that ongoing Phase 1 study show that a second dose, given six months after the first, kept amyloid levels down more than 70% after a year. Alnylam announced a new program for Huntington’s disease and argued that it has a unique approach in targeting a particularly toxic part of the gene missed by most other drug developers. The company highlighted two earlier-stage programs targeting genes in the liver and adipose tissue for weight loss and a third gene for insulin sensitization in diabetes. “We’re going to stick to our strength, which is genetically validated targets and biomarkers that allow us to get answers early,” Fitzgerald said. The company also teased its progress on creating new delivery systems. Alnylam previously revealed that a kind of lipid called C16 was key to getting its drugs into the brain for its Alzheimer’s program. But on Tuesday, the company shared little detail on the kinds of molecules it is using to deliver siRNA into the adipose, heart muscle, skeletal muscle and kidney. “We published C16, and now we have a lot of competitors,” Fitzgerald said. “So we’re not going to be talking about the exact mechanisms by which we’re getting into different tissues yet.

Innovative, Nature-inspired Mechanism, Dissolving Blood Clots Without Inducing Bleeding, Shows Promises of Enhanced Safety and Efficacy CAMBRIDGE, MA, USA I September 24, 2024 I Thrombolytic Science, LLC (TSI), a private clinical-stage biotech company focused on developing clot-dissolving therapies for thrombotic diseases, announced today that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for mutant prourokinase, a recombinant fibrinolytic pro-enzyme. A U.S.-based clinical trial will further confirm the safety and tolerability of TSI’s novel mutant prourokinase (mproUK) in healthy volunteers. “We are thrilled to achieve this important milestone with the FDA clearance for our first U.S. clinical trial of mproUK,” said Alexis C. Wallace, MSc. Eng., MBA, CEO of TSI. “Our innovative approach to fibrinolytic therapy has the potential to transform the treatment landscape for life-threatening thrombotic conditions, offering patients a faster, safer, and more effective reperfusion option. Following promising Phase II results from the DUMAS trial in stroke patients in the Netherlands, we’re now advancing to a Phase II trial in the UK for myocardial infarction following MHRA approval. This IND clearance is a significant step toward expanding access to our low-dose fibrinolytic treatment for broader patient populations globally.” In the natural, physiological mechanism of clot lysis, while tissue plasminogen activator (tPA) initiates clot lysis, prourokinase completes the dissolution of the fibrin clot. “This difference is comparable to the starter of a car and its engine.  tPA is like the starter, whereas prourokinase is the engine”, explained Victor Gurewich, MD, TSI co-founder and discoverer of prourokinase. “Physiological fibrinolysis requires a mini bolus of r-tPA followed by an infusion of a low dose of mproUK. In recent clinical studies, this treatment has been shown to be free of bleeding risk and rethrombosis while having the potential to re-establish blood flow earlier and being more cost effective than in-hospital surgical solutions.” About mproUK TSI’s treatment is based on the natural, biological clot dissolving mechanism involving the sequence of tPA and prourokinase, the latter having been stabilized by a single site mutation. This mutation has significantly improved the safety of prourokinase without interfering with its biological clot lysing mechanism of action.  A successful proof of concept clinical trial using native prourokinase in heart attack patients, preceded by a mini dose of tPA was previously published, the PATENT trial. More recently, promising results were obtained with mutant proUK in ischemic stroke patients, the DUMAS trial. About Thrombolytic Science (TSI) Thrombolytic Science, LLC, is a privately held biotech company developing a new-generation clot-dissolving therapy for heart attack, ischemic stroke and other thrombotic diseases, based on the groundbreaking research on prourokinase by its scientific co-founders at BIDMC / Harvard Medical School SOURCE: Thrombolytic Science

Boehringer Ingelheim’s Metalyse (tenecteplase) has been recommended by the National Institute for Health and Care Excellence (NICE) as a treatment option for acute ischaemic stroke (AIS) in adults. The decision could help save the NHS millions of pounds due to Metalyse costing less than the current standard for treating this type of stroke, Actilyse (alteplase), which is also sold by Boehringer in the UK. Strokes are estimated to be responsible for around 100,000 hospital admissions in England every year. Representing around 85% of all stroke cases in the UK, AIS occurs when there is a blockage in a blood vessel, resulting in a restricted blood supply to the brain. Given during the early phases of a stroke, Metalyse is designed to activate the production of plasmin, an enzyme that breaks down blood clots, to help restore blood flow through the blocked artery. NICE’s decision was based on clinical evidence from the large ongoing UK trial, ATTEST-2, which has been investigating whether Metalyse is more effective and safer than Actilyse, along with published results from completed trials. Results demonstrated that Metalyse was as effective as Actilyse in breaking up blood clots or preventing new blood clots from forming after an AIS. Commenting on the recommendation, Helen Knight, director of medicines evaluation at NICE, said: “We know that… it is important that patients receive treatments that can help to reduce the effects of a stroke as quickly as possible. “[This] guidance means that not only will people who have had an AIS be able to access a new treatment option, but the NHS could save millions by switching to it, making it a very effective use of taxpayers’ money.” The recommendation comes after the Medicines and Healthcare products Regulatory Agency approved Metalyse in April to treat AIS within 4.5 hours of the first symptoms appearing, as well as suspected acute cases of myocardial infarction (heart attack) within six hours of symptoms. Most recently, Boehringer and Brainomix entered into a strategic partnership for a collaborative programme to improve the identification and access to treatment for people living with fibrosing lung disease in the US.