DUBLIN – Alnylam Pharmaceuticals Inc. is on track to secure its third FDA approval in successive years, as its siRNA drug, lumasiran, hit all its marks in a phase III trial in patients with primary hyperoxaluria type 1 (PH1). The drug is already undergoing regulatory review and has a Dec. 3 PDUFA action date. It is undergoing accelerated assessment in Europe as well.

“This is now our fourth drug that appears to have delivered transformative data,” Akshay Vaishnaw, president of R&D at Cambridge, Mass.-based Alnylam, told BioWorld.

Analysts were bullish on its approval prospects. “Once again, Alnylam’s strategy to develop an RNAi therapeutic for a genetically validated target panned out with potency and clinical benefits,” Jefferies analyst Maury Raycroft wrote in an investor note. “We are confident in FDA approval of lumasiran,” noted Piper Sandler analyst Edward Tenthoff.

PH1, an ultra-rare inherited condition, is caused by mutations in the AGXT gene, which encodes alanine-glyoxalate aminotransferase, a liver enzyme that ordinarily catalyzes the conversion of glyoxalate to glycine. In PH1, glyoxalate is instead converted by another enzyme, glycolate oxidase (GO), to oxalate. That accumulates in the form of calcium oxalate crystals in patients’ kidneys and leads to the frequent formation of kidney stones, deposition of calcium (nephrocalcinosis) in the renal tissue and, eventually, to end-stage renal disease. Additional complications in other organs, including the heart, bone and the eyes, arise as the kidney becomes saturated and calcium oxalate starts to build up in other sites. Lumasiran targets expression of the GO gene in order to reduce levels of oxalate.

“Up to now, we’ve only had liver transplant as a cure for this disease,” Jaap Groothoff, head of the department of pediatric nephrology at Emma Children’s Hospital, part of the University of Amsterdam’s academic medical center, in the Netherlands, told BioWorld. Many patients also need to undergo kidney transplant as well. Groothoff was principal investigator on the Illuminate-A study. His colleague, Sander Garrelfs, presented the data at a virtual version of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) International Congress over the weekend.

The study assigned 39 pediatric and adult PH1 patients, in a 2-to-1 ratio, to a drug treatment or a placebo arm. Those in the drug treatment group attained a mean reduction of 53.5% urinary oxalate levels measured over a 24-hour period after six months of treatment, as compared with those on placebo. The drug was dosed at three-monthly intervals.

Patients also attained a mean reduction of 65.4% in urinary oxalate levels at six months vs. their individual levels at baseline. A majority of patients in the drug treatment group exhibited a response. Of the 25 evaluable patients (there was one drop-out), 21 (84%) attained near-normal urinary oxalate levels, defined as no more than 1.5 times the upper limit of normal. Thirteen of the 25 (52%) were considered to be in the normal range. “Potentially, that should lead to less kidney failure in the end,” Groothoff said. The trial participants all had substantially higher levels of urinary oxalate at baseline. “Most of them were between three and four times the upper limit of normal,” he said. None of those in the placebo group demonstrated any such reductions.

Akshay Vaishnaw, president R&D, Alnylam

It will, he said, take two to three years for the clinical benefits of the therapy to become apparent. Given the central role of oxalate in the disease pathology, it would be surprising if none accrued. “We know that it’s a key biomarker, linked to progression to renal failure,” Vaishnaw said. An exploratory analysis of clinical endpoints showed preliminary signs of efficacy. “Three patients saw some degree of improvement in nephrocalcinosis,” he said. In contrast, none of those in the placebo group did, and one showed signs of worsening.

On the safety front, no serious adverse events occurred during the study. The most common side effect was mild injection site reaction in about one-third of patients who received the drug. But Alnylam can also take comfort from genetic evidence. There are a number of families with no functioning GO enzyme but who exhibit no obvious phenotype.

The study includes a 54-month extension period to evaluate its continued safety and efficacy. Two other phase studies are underway as well. Illuminate-B, an open-label phase III study, is evaluating lumasiran in infants and young children, and Illuminate-C, a single-arm phase III trial, is studying the extrarenal effects of the drug in advanced patients who already have progressed to kidney failure. “We’re hoping to show benefits to other organs as well,” Vaishnaw said.

Rapidly maturing RNAi platform

Alnylam is not alone in PH1. Its closest rival is Lexington, Mass-based Dicerna Pharmaceuticals Inc., which is in a pivotal phase II trial in all three forms of PH with nedosiran (DCR-PHXC), an RNAi drug that targets lactate dehydrogenase, the final common pathway for oxalate production. “Lactate accumulating in the system is generally not a good thing,” Vaishnaw said. “Is that target associated with real safety in the long run?” Dicerna’s molecule is preferentially taken up by liver cells, so significant systemic accumulation may not occur. Either way, Alnylam will have some share of any upside that may arise. It and Dicerna recently concluded a cross-licensing agreement under which each will pay the other sales royalties. But it will take some time before its potential will become apparent. Dicerna’s Phyox 2 study has been disrupted by the COVID-19 pandemic.

Several other approaches are also in development. Amarna Therapeutics BV, of Leiden, the Netherlands, is developing an SV40-based gene therapy; Novome Biotechnologies, Inc., of South San Francisco, is developing engineered bacteria intended to colonize the gut and break down oxalate. Stockholm-based Oxthera AB is in phase II with Oxabact – an enteric bacterial species called Oxalobacter formigenes – which preferentially metabolizes oxalate. The results, so far, are “not very promising,” Groothoff said.

The lumasiran data provide further evidence of Alnylam’s rapidly maturing RNAi platform. The molecule incorporates both its N-acetylgalactosamine conjugation technology, which ensures preferential liver uptake, and its enhanced stability chemistry, which provides for an extended duration of activity. The company gained its first FDA approval – for Onpattro (patisiran) in hereditary transthyretin-mediated amyloidosis – in August 2018. Last November, it gained FDA approval for Givlaari (givosiran) in acute hepatic porphyria. Inclisiran, which Basel, Switzerland-based Novartis AG gained through its $9.7 billion acquisition of The Medicines Co. last November, is another Alnylam-originated siRNA drug. It, too, is on the brink of approval, in cardiovascular disease. Alnylam has already monetized about half of its anticipated royalties for inclisiran, in a $2 billion deal with the New-York-based private equity firm Blackstone Group Inc.

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