Alnylam sets up 3rd potential RNAi approval with a showcase of positive lumasiran data
A week after nabbing a priority review, Alnylam has released pivotal data for their latest late-stage experimental drug — setting the stage for the RNA-targeting biotech to potentially win their 3rd FDA approval in as many years.
In the 39-person trial, patients with an ultra-rare liver condition PH1 (primary hyperoxaluria type 1) were given either placebo or the Alnylam drug lumasiran. Patients with PH1 overproduce a natural metabolic end-product, urinary oxalate, potentially leading to kidney stones and in many cases kidney failure at a young age, along with damage across the body.
Of the 25 patients who received lumasiran, 21 — or 84% — saw their oxalate levels fall to near the normal range, and just over half saw their numbers fall inside the normal range. That compared to 0% in the placebo group. Overall, patients on the treatment arm saw their levels fall 65.4% on average – a 53.5% reduction when compared to placebo.
“Until now we had no good therapy for this disease,” lead investigator Jaap Groothoff, who heads pediatric Nephrology at the Emma Children’s Hospital in Amsterdam told Endpoints News. “This is the first drug that really showed to decrease oxalate production in these patients to a level we think might very effective and might prevent them from having kidney failure.”
Like Alnylam’s other drugs, lumasiran uses RNA interference (RNAi), a technique for silencing genes by delivering a matching sequence. Specifically, lumasiran silences the gene for an enzyme used in the production of oxalate, called glycolate oxidase. The biotech’s RNAi rival-turned-partner Dicerna is also working on a drug for the condition, targeting a different enzyme, called LDH, in the production process.
Unlike lumasiran, their drug is being designed to work for all three types of primary hyperoxaluria, although Alnylam executives are confident they have the better medicine, citing safety concerns about the Dicerna drug. They are also several months ahead, with Dicerna yet to release pivotal results or submit an NDA.
“LDH deficiency can lead to a buildup of lactate in the body and we don’t know the safety consequences of that,” Alnylam R&D chief Akshay Vaishnaw told Endpoints. “Of course we hope there are no safety consequences, but that case has to be proven as they accumulate more data.”
Questions still remain for Alnylam’s drug as well. In agreement with the FDA and EMA, Alnylam tested changes in a biological underpinning for the disease, rather than a symptom. Groothoff said the drug should allow patients to reduce their fluid intake — which can be up to 6 liters per day to reduce symptoms — but follow-up trials will examine whether lumasiran can reduce kidney stones or, more crucially, whether the drug’s effects will be durable and if it can forestall kidney damage. “We hope that it will lead to a lower number of patients in kidney failure,” Groothoff said. “There’s no reason to believe that [the drug] would wean off after some time, but we have to see.”
For Alnylam, the latest drug is part of the culmination of a strategy they turned to at the beginning of the previous decade, Vaishnaw said. That’s when, after 10 years of research, they figured out ways to get their RNAi sequences into cells. That was easiest to do in the liver – a natural first target, because it filters all substances in the blood – and they focused on developing drugs for rare, well-defined genetic diseases found there.
That led to the approval of the first RNAi drug, Onpattro, in 2018, for a form of amyloidosis and to the second, Givlaari, in 2019, for acute hepatic poryphia. Both drugs also came with price tags around $500,000, although they could be lowered based on how effective they were or how many patients ultimately had the rare disease. Vaishnaw declined to comment on potential pricing for the lumasiran, but noted PH1 patients could go through multiple organ transplants and life on immune-suppressive drugs or dialysis.
“These are tremendous burdens to these patients,” he said. “This is what we’re trying to alleviate, and I think that is returning a lot of value.”
Lumasiran, though, may be the last drug in that early strategy. Although there are other rare liver disease candidates in the pipeline, Alnylam is nearing the regulatory stage for drugs that target other parts of the body and could have a larger impact. Although both drugs still go after targets in the liver, inclisiran – the cholesterol drug co-developed by Alnylam and recently submitted to the FDA by Novartis – and a Sanofi-partnered drug for hemophilia drug are both nearing market.
The company is also working on a Covid-19 candidate with Vir Biotechnology that directly delivers RNAi as an inhalant directly to the lungs. It is set to enter the clinic at the end of the year. And further out, Vaishnaw said, the company has figured out ways of attaching molecules called ligands to RNA as homing missiles, allowing it to be delivered in the nervous system and elsewhere. The company last year signed an $800 million-deal with Regeneron for central nervous system disorders, including Alzheimer’s. They also have a preclinical NASH program and a Phase I hepatitis B drug.
“There’s a lot of work to do over the next 10 years,” Vaishnaw said.