Alnylam’s RNAi-Based Therapy Lumasiran Impresses in Phase 3 Primary Hyperoxaluria Trials

By T. Chakraborty, Ph.D.

On June 7th, Alnylam Pharmaceuticals announced encouraging phase 3 results of their RNAi based therapy, Lumasiran in Type 1 Primary Hyperoxaluria. The data was presented at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) International Congress.

Primary Hyperoxaluria (PH)

PH is estimated to affect 1 out of 58,000 individuals globally. Type 1, which is characterized by mutations in the AGXT gene, is the most common form accounting for 80 percent of cases. Mutations affect the liver enzyme alanine glyoxylate aminotransferase (AGT), which is responsible for processing glyoxylate. The dysfunctional AGT results in excessive oxalate production, which in turn forms deposits of calcium oxalate crystals in the kidneys and urinary tract. This ultimately leads to the formation of kidney stones, nephrocalcinosis, severe illness, and death.

Current treatment options are scant and involve either dialysis or organ transplantation approaches, which have high mortality rates and limited organ donors. Even though a small subset of patients responds to vitamin B6 therapy, there exists no other approved pharmaceutical therapy for PH1.

AGTX, a peroxisomal enzyme, has been shown to detoxify glyoxylate. One of the major substrates of glyoxylate production is glycolate via peroxisomal glycolate oxidase (GO). Preclinical studies using transgenic mice have shown that GO is a safe target for reducing glycolate in PH1, thereby reducing the level of toxic glyoxylate [3].

Lumasiran, an RNAi Based Therapy for PH1 Treatment

RNA interference (RNAi) is a host induced cellular mechanism where gene expression is silenced by RNA molecules. This revolutionary discovery resulted in the award of the Nobel prize in 2006, and the technique is now routinely used by scientists in genetic research. Alnylam has been one of the early companies that have used this biological process to bring RNAi therapeutics, a new category of drugs to the market. Lumasiran is a Small interfering RNA (siRNA) that targets hydroxyacid oxidase 1 (HAO1), the gene that encodes for GO.

Phase 3 ILLUMINATE-A Trial

The trial consisted of 39 patients receiving either Lumasiran or a placebo. The primary endpoint was urinary oxalate concentration. Patients receiving the drug had a 53.5 % reduction in urinary oxalate levels compared to the placebo group, while there was a 65.4% decrease from baseline urinary oxalate levels. Further, secondary endpoints were also met in this clinical trial. 84% of patients had near-normalization of urinary oxalate levels.

In a sub-group analysis, Lumasiran showed improvements in basal kidney functions as compared to placebo. The number of kidney stone events between patients receiving Lumasiran and placebo was comparable, but this may be attributed to the relatively short duration of the study. Despite that, three patients receiving Lumasiran demonstrated unilateral and bilateral improvements in nephrocalcinosis at six months, while none showed improvement in the placebo group.

There were no safety issues associated with the Lumasiran administration. All adverse events reported were moderate, and the major side effects included injection site reactions, headache, rhinitis, and upper respiratory tract infection. Lumasiran administration did not have clinically relevant changes in laboratory parameters (including liver function tests), vital signs, and electrocardiograms.

Based on these exciting data, Alnylam has filed a New Drug Application (NDA) with the FDA and EMA. The NDA has been granted a Priority Review with an action date of December 3, 2020.

“We are very pleased to report positive Phase 3 results from the ILLUMINATE-A study of lumasiran. The substantial and sustained reductions in urinary and plasma oxalate reported demonstrates that lumasiran addresses the underlying pathophysiology of PH1 by reducing the production of the toxic metabolite responsible for the clinical manifestations of this serious and progressive disease” said Akshay Vaishnaw, M.D., Ph.D., President of R&D.

“We believe lumasiran has the potential to have a favorable impact on disease manifestations, including nephrocalcinosis and renal stones, and overall disease progression, which we are continuing to evaluate in the ongoing ILLUMINATE program. The ILLUMINATE-A study represents the sixth positive Phase 3 study for an investigational RNAi therapeutic, and we believe it further highlights the transformational potential of this modality as a whole new class of medicines. Assuming favorable regulatory reviews, we look forward to bringing Lumasiran to patients with PH1 around the world”.

In 2019, Cambridge, MA-based Dicerna Pharmaceuticals, Inc., was granted a Breakthrough Therapy designation by FDA for the RNAi-based drug DCR-PHXC, which at that time was the only RNAi-based therapy for the treatment of all types of PH. These successful trials demonstrate the efficacy and safety of RNAi based therapy not only for PH but also give hope to other untreatable genetic disorders.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: GIVLAARI to Enter European Market Following EMA Approval

References

1. https://ghr.nlm.nih.gov/condition/primary-hyperoxaluria#statistics
2. https://investors.alnylam.com/press-release?id=24906
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886931/
4. https://clinicaltrials.gov/ct2/show/NCT03681184

Author

Tulip Chakraborty

Related Post

Prime

Breaking Genetic Shackles: In Vivo Gene Editing Technologies Broaden the Path to Rebirth for Rare Diseases

2026-09-10

Trials & Approvals

FDA Approval of First-in-Class Treatment Marks New Era for Alexander Disease Treatment

2026-09-07

Trials & Approvals

FDA Approves Gilead’s Bixlenvo as a Once-Daily Single-Tablet Regimen for Virologically Suppressed Adults Living with HIV

2026-09-01