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Oh, what mRNA can do – is a common refrain this week. On Tuesday, Moderna and Merck announced that their investigational mRNA cancer vaccine improved outcomes in relapse-free survival in advanced melanoma.
More quietly on Monday, Vertex announced approval of a new drug application for VX-522, an mRNA therapy designed to treat the underlying cause of the lung disease cystic fibrosis.
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have changed the lives of many CF patients over the past few years.
For example, Vertex’s Trikafta, a triple-threat therapy that increases the amount and function of the F508del-CFTR protein on the cell surface, has turned the curve of this life-threatening lung disorder for scores of patients. First approved in October 2019, Trikafta is intended for CF patients who carry at least one copy of the F508del mutation in the CFTR gene.
Trikafta consists of new generation CFTR correctors elexacaftor, tezacaftor and ivacaftor. Vertex estimates that therapies like Trikafta have the potential to treat more than 90% of CF patients.
But Vertex is not satisfied with this number. And neither is SpliSense from Jerusalem. More on SpliSense soon.
Vertex is not satisfied with 90%
With IND approval, Vertex will begin a Phase I, single-dose escalation study to evaluate the safety and tolerability of VX-522 in adult patients with the CFTR genotype unresponsive to CFTR modulator therapy. The trial will begin “within a few weeks,” Vertex said in a press release.
VX-522 is delivered to the lungs by inhalation of CFTR mRNA encapsulated in a lipid nanoparticle. This is the result of a 6-year research collaboration with Moderna.
In a statement emailed to BioSpace On Wednesday, Ashley Mahoney, director of external communications at Vertex, explained the importance of inhalation delivery.
“We’ve known for some time that CFTR mRNA can produce functional CFTR protein in vitro, but the biggest challenge for us and for everyone working on mRNA has been delivering the mRNA to the target [human bronchial epithelial] cells in the lungs,” Mahoney said. “We have now successfully identified a lipid nanoparticle (LNP) to deliver CFTR mRNA to target cells at levels that result in levels of CFTR function associated with clinical benefit.”
The SpliSense ASO targets a specific CF mutation
In Israel, SpliSense announced the initiation of a Phase I/II trial to evaluate SPL84, the company’s lead antisense oligonucleotide (ASO). SPL84 is intended for the treatment of CF patients who carry a 3849+10 kilobase (Kb) C->T splicing mutation in the CFTR gene. Categorized as a class V mutation, the 3849+10 kilobase (Kb) C->T leads to a reduced amount of CFTR protein on the cell surface.
There is no specifically approved treatment for patients with this mutation.
SPL84 binds specifically to the mutated CFTR RNA in the target sequence with the intention of modulating the mutated region in the mRNA. This would allow the cell to produce fully functional CFTR proteins. ASO is also delivered directly to the lungs via inhalation.
In an interview with BioSpace, SpliSense CEO Gili Hart, Ph.D. explained the key differences between her company’s program and VX-522. First, while Vertex’s therapy is agonistic for the mutations, SPL84 specifically targets 3849+10 kilobases (Kb) C->T.
Second, SPL84 is “a very small, short, single-stranded RNA that can enter the cell very easily, very elegantly, without replication, without the need for a carrier, without the need for any lipid nanoparticles,” Hart said.
The small size of ASO allows efficient distribution through the mucosa.
“We were able to show that there is a very efficient, very precise distribution in the lungs of different animal models,” Hart said. This has been demonstrated in both non-human primates and muco-obstructive animal models, she added.
With the VX-522, the process is more cumbersome. Hart explained that the entire RNA sequence of the mutated CFTR gene must be packaged into LNP and inhaled through the lungs into the mucosa. Then the RNA needs to be released from the particles, get to the right area and then be translated into CFTR.
While CFTR modulators such as Trikafta only stabilize the mutated protein, thereby helping to manage CF symptoms, Hart believes that SPL84 may be curative because it creates fully functional CFTR.
CF is a life-shortening genetic disease with a total global patient population of about 100,000. Patients have mutations in the CFTR gene that lead to defective or missing CFTR protein. Sufferers will inherit two defective CFTR genes.
Before CFTR modulators like Trikafta, most patients succumbed to the disease in their early 30s. Today, patients with the F508del mutation can expect to live into their 50s, Hart said. SpliSense aims to improve the prospects for the remaining 20% who cannot benefit from modulators due to unresponsive mutations, side effects and lack of modulator efficacy.
The company’s platform, which develops RNA-based therapies for genetic and lung diseases, is based on the work of scientific founder and CSO prof. Ph.D. Batsheva Kerem, a renowned geneticist from the Hebrew University of Jerusalem, who was part of the research team that identified and cloned the CFTR gene.
SpliSense uses this platform to treat other pulmonary obstructive diseases such as asthma and COPD and the devastating lung disease idiopathic pulmonary fibrosis, which usually takes its toll within 3-5 years of diagnosis.
For all of these indications, “there is one well-characterized, published and clinically demonstrated gene that actually drives the obstruction,” Hart said.
SpliSense anticipates being in the clinic with an ASO targeting muco-obstructive disease in the fourth quarter of 2023.