Opportunity costs of gene therapies. Where do we go from here?

Over 30 gene therapies have received regulatory approval. However, there is still considerable room for the industry to improve the safety, efficacy, and affordability of these life-saving treatments. Dr Cheryl Barton discusses some novel approaches the industry is adopting to develop sustainable, cost-effective, and life-saving gene therapies.

There are 32 approved in vivo and ex vivo products that alter gene expression. During the first half of 2024, two gene therapies were approved: Pfizer’s Beqvez (fidanacogene elaparvovec) in Canada for haemophilia B and CT-053 (CARsgen). Seven more products are expected to be approved by the end of the year. According to Citeline, as of April 2024, 2,093 therapies (including genetically modified cell therapies, such as CAR-T cell therapies) are in development, and 30 products were being evaluated in phase 3 clinical trials.

All the major pharma companies, including AstraZeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Otsuka Pharmaceuticals, Roche, and Sanofi, have invested in this area. According to Citeline, between January 2023 and March 2024, pharma signed 202 partnerships, acquired 40 companies, and raised over $3.2 billion from private equity investors in gene, cell, and RNA therapies.

Efficacy and commercialisation

Gene therapies have yielded mixed results in the clinic, though. In some rare diseases, companies have made headway in the treatment of Duchenne muscular dystrophy (DMD), haemophilia A and B, sickle cell anaemia, and spinal muscular dystrophy. However, many gene therapy programmes have faltered either due to lack of efficacy, such as Novartis’ OTQ923, or due to unexpectable side effects; for example, Pfizer’s fordadistrogene movaparvovec andBioMarin’s BMN307.

Even when companies have reached the finishing line, the commercialisation of gene therapies has proved challenging. UniQuire’s Glybera (alipogene tiparvovec) was withdrawn from the European market five years after it was approved to treat familial lipoprotein lipase deficiency (LPLD). More recently, Bluebird Bio’s Zynteglo (betibeglogene autotemcel), a cell-based gene therapy to treat transfusion-dependent beta-thalassemia (TDT), has been slow to gain traction in the market.

Manufacturers are working hard to improve gene therapy delivery to optimise safety, efficacy, and predictability, in order to ensure patients have widespread access to affordable, sustainable, life-changing therapies.

CRISPR Cas9 and next-generation gene therapies

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)-mediated technology has rapidly replaced transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs) as the leading gene-editing tool, as it provides an efficient, simple, versatile, and cost-effective method for genetic engineering of cells and organisms.

In late 2023, the first ex vivo CRISPR-based therapeutic was approved by the FDA: Vertex Pharma/CRISPR Therapeutics’ Casgevy (exagamglogene autotemcel, exa-cel) as a treatment for sickle cell disease and beta-thalassemia. This represents a turning point in gene therapy and in-vivo CRISPR-based therapies are in the pipeline; for example, Intellia Therapeutics phase I LNP-delivered CRISPR drug NTLA-2002 for the treatment of hereditary angioedema (HAE).

According to Dr Erik Wiklund, CEO of Circio, Norway: “Gene therapies have been available for more than 30 years, and there are now AAV-based and HSV-based approaches available. However, these therapies are technologically suboptimal, and we need to move away from viral delivery systems towards nucleic acid (NA) systems to enable repeat dosing. Next-generation gene therapies, such as prime editing, will offer a more efficient strategy for many monogenic disorders. However, it will take several years before these new technologies are clinically validated.”

New gene transcriptional regulation tools are under development, including CRISPR interference (CRISPRi), and CRISPR activation (CRISPRa), as well as novel Base Editor (BE), Prime Editor (PE), Programmable Addition via Site-specific Targeting Elements (PASTE), and CRISPR-associated transposase (CAST) technologies, and ‘bridgeRNA’.

Interest in Bes and Pes-editing is growing, as these tools circumvent some of the limitations of CRISPR; namely, they have the potential to correct large genes (>4 kb) without creating a double-strand break (DSB) in the DNA, reducing unwanted DNA modification and off-target effects.

In April 2024, Prime Medicine received the go-ahead from the FDA to initiate a phase I/2 trial with PE-based PM359, an ex vivo gene therapy to treat CGD (chronic granulomatous disease). Prime Medicine’s PE technology enables it to replace the faulty NADPH oxidase gene without making DSBs in DNA. PM359 has received rare paediatric drug designation and orphan drug designation from the FDA.

Exsilio Therapeutics, SaliGen Therapeutics, and Tome Biosciences are developing programmable genomic elements that can precisely insert whole genes into cells. In May 2024, SalioGen Therapeutics teamed up with Nanite to leverage its Gene Coding technology, based on mammalian transposons, to deliver cystic fibrosis transmembrane conductance regulator (CFTR) gene directly into the lungs using polymer nanoparticle (PNP).

Advances in viral and non-viral delivery

Meanwhile, advances in non-viral (e.g., conjugate-based platforms, exosomes, lipid nanoparticle/LNPs, and non-lipid hydrophilic nanoparticles/HNPs) and viral (e.g., adeno-associated virus/AAV, capsids, herpes simplex virus/HSV, and virus-like particles/VLPs) delivery has played a major role in the targeted delivery of genetically engineered therapeutics.

A new generation of targeted therapies is starting to emerge. In January 2024, GenEdit partnered with Roche’s Genentech to utilise its non-lipid hydrophilic nanoparticle (HNP) NanoGalaxy platform for the targeted delivery of NA-based medicines to treat autoimmunity and has previously partnered with Sarepta Therapeutics, focusing on neuromuscular diseases, respectively.

According to Romain de Rauville, CBO of EXO Biologics: “Cell therapy (or ex-vivo gene therapy) is now a well-accepted technology with life-changing impact. On the other hand, gene therapy still faces numerous challenges and is reliant on safe and efficient drug-delivery systems. AAVs are costly to manufacture and treatment price can be significant; for example, Luxturna is priced at $850,000. Consequently, gene therapy players are looking for more affordable and safer drug delivery systems.”

In May 2024, Regeneron demonstrated that DB-OTO can restore hearing in patients born with mutations in the gene otoferlin whereby the otoferlin gene is split in two and delivered in a dual adeno-associated virus (AAV) modality. However, functional viruses are challenging to manufacture and viral-delivered gene therapies need to be given at high doses/high viral titres, and may only be administered once due to immunogenic responses. New delivery modalities for genome editors may provide a cost-effective solution to these problems.

Dr Wiklund further notes: “The ultimate goal is to develop a delivery chemistry that allows tissue and cell type targeting and there are many technologies currently being tested. To overcome the constraints of vector technology, we need to move away from AAVs and LNP delivery technologies and use other viral and DNA formats that enable repeat dosing.”

Indeed, Circio has engineered a genetic cassette that forms a circular mRNA, which accumulates in the target cell to increase protein output by between 10 and 100 fold, depending on vector and cell type. While Circio is deploying this technology in AAVs, it could nonetheless be used more broadly in other vectors to enhance any system where high and durable protein expression is required. For example, Excellio Labs, EV Therapeutics, Exo Biologics, and ReNeuron are developing exosome-based therapies to provide a biocompatible, cost-effective alternative to viral vectors.

According to Kasia Maj, co-founder and CEO, of Excellio Labs: “Exosomes offer several compelling advantages over traditional and other novel delivery systems. Exosomes are naturally occurring biocompatible, low immunogenic nanovesicles that can deliver genetic material with high specificity to target tissues. In addition, exosomes can be seamlessly integrated into the cellular machinery, to offer precise and efficient delivery of therapeutic genes.”

The versatility of Exosome-based delivery systems offers the potential to significantly enhance the therapeutic efficacy of RNA treatments and enable the precise delivery of CRISPR/Cas9 components for gene editing. As Maj also commented: “Exosome production is generally more straightforward and less expensive compared to viral vector manufacturing, which makes them an economically and technically attractive option for gene delivery.”

In June 2024, Belgium-based EXO Biologics completed dosing the first cohort of its phase 1/2 EVENEW study to assess the safety and efficacy of intratracheal administered therapeutic EXOB-001 an exosome-based therapy for the prevention of bronchopulmonary dysplasia (BPD), in pre-term babies. According to Romain de Rauville: “EVs are inherently safe and, unlike AAVs, there is no need to remove toxic empty capsids.”

In other words, a new era of gene therapies is dawning. The biopharma industry is keen to embrace novel gene editing tools and delivery technologies and is on its way to developing a new generation of affordable and redosable gene therapies. Time will tell if this technology can be applied beyond the rare disease space to tackle more common and complex diseases.