Alnylam, the king of commercialization of RNAi therapy, pushes blockbuster products to be launched soon

The encouraging efficacy and safety results of vutrisiran in phase III clinical trials have further strengthened researchers' confidence in the potential of RNAi therapy
.

Approval of three listed RNAi drugs from Alnylam

Onpattro

Onpattro was approved in the United States and the European Union on August 10 and August 30, 2018, respectively, becoming the first RNAi drug approved for marketing in the 20 years since the RNAi phenomenon was discovered
.
Subsequently, Onpattro was approved to be launched in Germany, Japan, the United Kingdom, Canada, Brazil and other countries for the treatment of hATTR amyloidosis
.

The industry is very optimistic about Onpattro's commercial prospects
.
EvaluatePharma, a pharmaceutical market research organization, predicts that Onpattro's sales will reach 1.
308 billion U.
S.
dollars in 2024
.

 Givlaari

On November 21, 2019, Alnylam's Givlaari (givosiran) was approved by the FDA for the treatment of adult patients with acute hepatic porphyria (AHP)
.

Givlaari is a subcutaneous N-acetylgalactosamine combined with RNAi therapy.
It is the second new RNAi drug approved by the FDA after Onpattro
.

AHP is a rare genetic disease.
Due to the defects of representative enzymes in the process of heme production, patients are prone to abnormally high levels of neurotoxic porphyrin precursor accumulation under specific predisposing factors
.
The disease can cause severe pain and paralysis, respiratory failure, seizures, and changes in mental state
.
Because the attack is acute and sudden, sometimes it may even cause permanent nerve damage and death
.

The approval of Givlaari is based on a phase III clinical trial involving 94 patients with acute hepatic porphyria: 48 patients were treated with Givlaari and 46 patients were treated with placebo.
The results showed that compared with patients receiving placebo, Givlaari Group porphyria reduced by 70%
.

Oxlumo

On November 23, 2020, the FDA approved Alnylam's Oxlumo (Lumasiran) to be marketed for the treatment of patients with primary hyperoxaluria type 1 (PH1).
This is Alnylam's third RNAi therapy approved by the FDA
.

Primary hyperoxaluria type I (PH1) is a super rare disease.
The cause is a deficiency of alanine peroxy-glyoxylate aminotransferase in the liver, which leads to excessive production of oxalic acid, and excessive production of oxalic acid leads to renal failure (Oxalic acid is mainly excreted in urine, so the kidney is the main target organ for its deposition), the clinical manifestations are hyperoxaluria and repeated urinary calculi, with significant morbidity and mortality
.

Oxlumo is a subcutaneously injected RNAi drug equipped with an ESC-GalNAc delivery platform that targets the mRNA of the HAO1 gene encoding glycolate oxidase (GO) in the liver.
It reduces the expression of GO to reduce liver oxalate.
Produced
.

Oxlumo's approval is mainly based on positive data from a phase III study ILLUMINATE-A
.
ILLUMINATE-A is a randomized, double-blind, placebo-controlled trial that enrolled 30 patients with PH1 aged ≥6 years
.
In December 2019, Alnylam announced some data on ILLUMINATE-A: Compared with placebo, Oxlumo reached the primary efficacy endpoint in 24-hour urine oxalate excretion in 3 to 6 months
.
The study also achieved statistically significant results on all six secondary endpoints, while also showing encouraging safety and tolerability
.

Before Oxlumo was approved, the only treatment option for PH1 was to use a method called "overhydration," which involves diluting oxalate with an excess of liquid
.
The use of Oxlumo only requires subcutaneous injection once every three months, which can greatly reduce the patient's treatment pain
.

  Keep improving

——Unique RNAi targeted delivery platform to avoid off-target effects

RNAi therapy has also encountered unique challenges in its development
.
This includes how to target RNAi therapies to be delivered to cells, avoid toxic side effects caused by off-target effects, and so on
.
Based on more than ten years of research and development work, Alnylam has made considerable progress in targeted delivery of RNAi therapy and reduction of its side effects
.

Alnylam's Enhanced Stable Chemistry (ESC) delivery technology platform not only improves the stability of RNAi therapy RNA fragments through GalNAc chemical modification, but also promotes the liver-targeted delivery of RNAi therapy
.
This technology was applied for the first time on Givlaari
.
However, this therapy is still possible to silence other non-target genes in the liver, leading to liver toxicity
.

The RNAi off-target effect is a major cause of toxic side effects.
In order to reduce this off-target effect, the researchers deliberately added a glycol nucleic acid (Glycol Nucleic Acid, GNA) to the RNA fragment
.
The addition of GNA can maintain the specificity of RNAi binding to the target while reducing its ability to bind to off-target sites, further improving the specificity and safety of RNAi therapy
.
Alnylam calls this technology ESC+ technology
.
This technology has been applied in many of Alnylam's research therapies and has obtained proof of concept
.

From rare disease to common disease

——Alnylam Company Demonstrates Broad Prospects for RNAi Therapy

As a leader in the development of RNAi drugs, Alnylam is currently vigorously developing innovative RNAi drugs in four disease areas: genetic diseases, cardiometabolic diseases, liver infectious diseases, and central nervous system (CNS) and eye diseases
.

Thanks to the unique delivery method, the positive success rate of Alnylam's R&D project from phase I clinical progress to phase III clinical trial results reached 59.
2%, which is much higher than the industry average
.

Alnylam has planned to expand the field of diseases treated by RNAi therapy from rare diseases to common diseases, such as hypertension, non-alcoholic steatohepatitis (NASH) and type 2 diabetes, to benefit more patients
.

Today, RNAi technology has begun to take off, and this is just the beginning
.

RNAi is still a very new treatment method.
With the new discovery of RNAi pathway functions and the continuous update of delivery methods, there will be more miracles.
Nucleic acid drugs are expected to become the third largest after small molecule chemical drugs and antibody drugs.
Type of drug
.

refer to:

1.
Alnylam nets FDA nod for Oxlumo, its 3rd rare disease drug, and plans unique value-based deals.

2.
https://
3.
Alnylam Presents Positive Results from HELIOS-A Phase 3 Study of Investigational Vutrisiran.
Retrieved April 19, 2021, from https://