Will LNP delivery become the turning point after mRNA COVID-19 vaccine?

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Will LNP delivery become the turning point after mRNA COVID-19 vaccine?

Recently, the financial reports of multinational pharmaceutical companies have successively disclosed that the sales of mRNA COVID-19 vaccines based on LNP delivery have topped the list for two consecutive years. Pfizer/BioNTech Comirnaty hits new highs in 2022 with $37.8 billion in sales; $24.2 billion in 2021.

Another nucleic acid drug for rare diseases based on LNP – Alnylam’s world’s first RNAi drug Patisiran (trade name: Onpattro, approved in 2018), sales will reach US$850 million in 2022, an increase of 37% compared to the same period last year.

It is estimated that the revenue of mRNA COVID-19 vaccines may decline in the next few years, resulting in a shrinking LNP market size. But as the gene therapy pipeline matures and LNP technology iterates, the market will grow again. The market for LNP is estimated to rebound to $48 billion by 2036 [1].

LNP delivers RNA

LNPs typically consist of four components—ionizable lipids, phospholipids, cholesterol, and pegylated lipids. LNPs can encapsulate various drug payloads, including small molecules, peptides, DNA/RNA, etc., protect them from destructive enzymes, and enable transport across cell membranes.

At present, nucleic acid delivery represented by Pfizer/BioNTech mRNA COVID-19 vaccine is the most widely used direction of LNP so far .

Due to the instability of RNA itself, there have been a series of challenges in drug making in the past; today’s successful development has benefited from breakthroughs in delivery technology in recent years.

The emergence of LNP has overcome the easy degradation of RNA molecules and the relatively short half-life in vivo to a certain extent. Wait for the problem.

In addition to the outstanding market value of nucleic acid drugs, the reason why they are widely sought after is that compared with traditional drugs targeting proteins, RNA therapy has multiple advantages such as strong target specificity, rich targets, long-lasting drug effects, and high research and development efficiency. Technical advantages.

In terms of R&D efficiency, the “Big Ideas 2023” investment research report analyzes that the R&D cost of RNA drugs is relatively low and the R&D time is short. Compared with the development of small molecule drugs and antibody drugs, which takes an average of 10 years and costs 2 billion U.S. dollars, the development of RNA drugs takes an average of 5 years and costs 1.25 billion U.S. dollars.

LNP application trend

LNPs play a key role in the emerging field of in vivo gene therapy drugs. Compared with other delivery systems, such as GalNAc conjugates, AAV virus vectors, etc., LNP has the advantage of greater “load”.

Depending on the underlying mechanism of action, LNP enables four gene drug modalities:

Gene addition/replacement : for example, mRNA encoding genes are encapsulated in LNP;
Gene expression control : For example, the RNAi drug Patisiran uses LNP to encapsulate siRNA;
Gene editing : such as using LNP to deliver CRISPR/Cas9 gene editing system components;
DNA or RNA vaccines : For example, LNP-loaded S-protein mRNA COVID-19 vaccine.

In order to understand the penetration rate of LNP in gene therapy development, a report by Nature analyzed the global marketed and clinical stage in vivo gene therapy pipelines, and predicted the data from 2021 to 2036, with 538 assets from 273 companies (as of December 2021)[1].

Of the four segments, LNP currently has the highest penetration in RNA vaccines and gene editing at 20% and 29%, respectively. This is mainly attributed to the fact that RNA vaccines and gene editing need to deliver fragments that are usually too large for GalNAc conjugation.

Fig. Four applications of LNP in gene therapy . a, the overall percentage of in vivo gene therapy at each stage in the clinical pipeline; b, the penetration level of LNP drugs in in vivo gene drugs; c, the number of LNP assets at different development stages (Data 1)

LNP has lower penetration in two other applications – gene addition/replacement and gene expression control. In gene addition/replacement, AAV delivery has superior delivery efficiency, offering greater utility than current LNP. In terms of gene expression control, the main competitor of LNP is GalNAc.

However, as the revenue of mRNA COVID-19 vaccines declines in the next few years, the application of LNP may shift from vaccines to the development of the other three types of gene therapy in the future. Taking gene addition or replacement as an example, LNP has no clinical or marketed assets in this area in 2021 (vaccine accounts for 99%), and by 2036, the next generation of LNP innovation may make the application in this direction account for 27% ( Vaccines accounted for 46%).

Will LNP delivery become the turning point after mRNA COVID-19 vaccine?
Figure. LNP Market Forecast (Data 1)

Outlook

The safety of current LNPs has been extensively clinically validated in mRNA vaccines, but they still face limitations in delivery efficiency, immunogenicity, storage, and cost.

At the same time, there are extremely high barriers to challenge for patents related to the LNP delivery system.

Next-generation LNPs (e.g., utilizing novel non-lipid components, fusion proteins, and polymers) are expected to address these limitations and improve delivery efficiency, thereby reducing dosage and reducing immunogenicity.

These innovations are expected to be applied to all four gene therapy modalities, especially the breakthrough LNP application in gene addition/replacement.

References:

The landscape for lipid-nanoparticle-based genomic medicines. https://doi.org/10.1038/d41573-023-00002-2