Cystic fibrosis: is the next blockbuster a gene therapy?

For decades, cystic fibrosis has remained a relentless, life-limiting disease. But now, the future of cystic fibrosis care could be shifting from symptom management to something far more revolutionary. Gene therapy has emerged as a promising frontier in cystic fibrosis research, offering the potential to not just alleviate symptoms, but to address the genetic root of the disease itself.

In this article, we will explore how gene therapy works, the biotechs progressing their genetic drug candidates, and why it might just be the breakthrough that people with cystic fibrosis have been waiting for.

Cystic fibrosis: targeting the root of the disease

Around 1,000 new cases of cystic fibrosis are diagnosed in the U.S. each year. People with cystic fibrosis tend to have a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene codes for the CFTR protein, which is responsible for regulating the flow of salt in and out of the cells in the body. As a result of the mutation, salt becomes trapped in the cells. Without the flow of salt, cell surfaces become dehydrated. This leads to a thick, sticky mucus that gets coated on the lungs and other parts of the body, making it not only hard for people to breathe but also more prone to infections.

As a cure has not yet been found, standards of care for cystic fibrosis revolve around easing symptoms and improving the quality of life for patients. Medicines that target the CFTR gene are designed to improve the function of the protein and they are called CFTR modulators. But what if these genes could be replaced altogether?

Well, that’s what gene therapy strives to do. It corrects the faulty CFTR gene by delivering a proper copy of the gene to the cells affected by the disease. This enables the cells to make the CFTR proteins, mitigating the effects of cystic fibrosis.

There are a few gene therapy candidates in development at present, and just last month, a major breakthrough in the space has awed the patient and research community alike. 

Boehringer Ingelheim’s gene therapy candidate BI 3720931 hits clinic for cystic fibrosis

The first-ever inhaled lentiviral gene therapy hit the clinic in February, and it could be pivotal for those who don’t benefit from other cystic fibrosis therapies. The first-in-class therapy, BI 3720931, is a gene therapy that delivers a functional copy of the CFTR gene in the DNA of airway epithelial cells. Lentiviral vectors use modified lentiviruses – like those derived from the human immunodeficiency virus (HIV) – to carry the genes into cells. By sending the CFTR gene into cells, BI 3720931 aims to address the underlying genetic cause of cystic fibrosis. It is administered as a nebulizer solution, which means it is inhaled as a mist directly into the lungs with the help of a nebulizer. This way, the therapy reaches the cells in the lungs directly, potentially enhancing its effectiveness.

The treatment is being developed by German pharma giant Boehringer Ingelheim along with the UK Respiratory Gene Therapy Consortium (GTC) and OXB, a contract development and manufacturing organization (CDMO) in cell and gene therapy. The ongoing phase 1/2 trial will evaluate the safety, tolerability, and efficacy of BI 3720931 in adults with cystic fibrosis who are not eligible for CFTR modulator therapy.

The first part of the trial will examine different doses of the drug candidate in patients. In phase 2, two doses selected from phase 1 results will be given along with placebo in a randomized, double-blind, placebo-controlled trial to test the clinical efficacy and safety of BI 3720931. After 24 weeks, the participants will take part in a long-term follow-up trial.

“We are very excited about the start of the LENTICLAIR 1 first-in-human trial and how BI 3720931 could potentially improve the lives of people living with cystic fibrosis and who are unable to benefit from current CFTR modulators,” said Paola Casarosa, member of the Board of Managing Directors at Boehringer Ingelheim with responsibility for the Innovation Unit. “This is a crucial moment in the development of BI 3720931, which we have progressed together with our partners since 2018. The partnership with the GTC and OXB provides an excellent example of the progress that can be made when diverse organizations and people come together with a long-term, shared goal to create a new paradigm of care.”

Eric Alton of Imperial College London’s National Heart and Lung Institute, who coordinates the GTC, added that while the immediate patient group are those who are not eligible for CFTR modulators, this therapy “has the potential to achieve long-lasting CFTR function improvement and disease modification for people with cystic fibrosis irrespective of mutation type.”

AAV vectors to the rescue for cystic fibrosis

BI 3720931 may be the first inhaled therapy of its kind, but there are a few gene therapy candidates moving ahead in clinical trials currently. For instance, California-based 4D Molecular Therapeutics’ (4DMT’s) 4D-710 is in phase 1/2 studies to treat people with cystic fibrosis who don’t respond well to CFTR modulators. Similar to BI 3720931, 4D-710 delivers a functional copy of the CFTR gene to lung cells, but unlike the Boehringer candidate, it is transported via an adeno-associated virus (AAV) vector in a single-dose aerosol delivery.

The primary endpoints of the drug candidate in the ongoing phase 1/2 dose escalation and expansion trial are safety, tolerability, and identifying the maximum-tolerated dose in patients. Secondary endpoints include measuring clinical activity, quality of life, and lung function in patients. 4DMT expects to finish enrolling patients in the trial soon.

The biotech has all its eyes on 4D-710, especially as it ditched two of its rare eye disease programs in January to focus on 4D-710 and 4D-150 in wet age-related macular degeneration and diabetic macular edema, both of which are conditions that affect the eyes. So, now the biotech has $506 million in cash runway until 2028 to fund the development of its candidates, including 4D-710.

Besides 4D-710, Spirovant Sciences’ SP-101 is another AAV-based gene therapy in the making. The candidate is administered with doxorubicin, a chemotherapy that amplifies gene transfer. In preclinical studies conducted in ferrets with cystic fibrosis, the inhaled combination of SP-101 and doxorubicin led to the expression of the CFTR proteins in the lungs. Currently, Spirovant is the only company developing inhaled AAV gene therapy along with an augmenter – doxorubicin – and dosed its first patient in a phase 1/2 trial in November. Roland Kolbeck, Spirovant’s chief scientific officer (CSO), called it a “major milestone” for the cystic fibrosis patient community.

Krystal biotech: can KB407 piggyback on the success of Vyjuvek’s approval?

Meanwhile, Krystal Biotech’s KB407 is in the running to target cystic fibrosis too. The American biotech’s gene therapy is a modified HSV-1 vector carrying two copies of the CFTR gene to the lung cells. By inducing expression of full-length, normal CFTR protein, treatment with KB407 has the potential to restore ion and water flow into and out of lung cells to avoid mucus buildup in the lungs. The candidate is currently in phase 1/2 trials.

Krystal’s KB407 may be particularly promising since the startup has already seen success with one of its gene therapies. Its gene therapy Vyjuvek was greenlit by the U.S. Food and Drug Administration (FDA) in 2023, and is on the way to becoming a blockbuster drug. This is encouraging for KB407, which, like Vyjuvek, stems from the biotech’s engineered replication-deficient herpes simplex virus-1 (HSV-1) platform.

The HSV-1 platform enables the development of redosable gene therapies that can be administered non- or minimally‑invasively. Leveraging some of the properties of the virus, the platform is linked to episomal delivery – when genetic material is delivered to cells but doesn’t integrate with the host’s DNA – a high payload capacity, and the inherent evasion of the immune system, while being engineered to reduce cytotoxicity – the ability of a therapy to damage cells.

Non-traditional gene therapies: mRNA medicine RCT2100 in the clinic

Then, there is RCT2100. California-based ReCode Therapeutics’ RCT2100 is not the typical genetic medicine for cystic fibrosis, which involves the supply of the CFTR gene to lung cells. Instead, it is designed to deliver CFTR mRNA to target cells in the lungs and instruct them to generate a functional version of the CFTR protein that is missing in patients. 

The inhaled drug is chiefly for 10% to 13% of patients with cystic fibrosis who possess nonsense mutations. In cystic fibrosis, these mutations in the CFTR gene create instructions to stop the production of proteins early, as they contain a premature stop codon – a genetic sequence that signals a halt to protein production. This leaves cells with a shortage of CFTR proteins.

What RCT2100 does is it delivers a proper copy of the CFTR mRNA to cells with the correct instructions, thereby bypassing the effect of the premature stop codon. The therapy springs from the startup’s Selective Organ Targeting (SORT) lipid nanoparticle (LNP) delivery platform. LNPs are known to be effective carriers in delivering genetic material and improving drug stability. 

Recode is also developing a preclinical ‘gene correction’ candidate to treat the lung condition. Following its $15 million funding from the Cystic Fibrosis Foundation in November, the company disclosed that it had nabbed the FDA Orphan Drug Designation for RCT2100 two weeks ago, boosting the drug’s clinical development.

“While there have been tremendous advancements in the development of novel CF therapies in the past two decades, we are focused on the subset of CF patients who are not eligible for current treatments and who have been waiting for a treatment,” said Shehnaaz Suliman, chief executive officer (CEO) of ReCode Therapeutics. “We are currently enrolling patients in a phase 1b study evaluating RCT2100 in people with CF who do not respond to or are intolerant of current modulator therapies. We are grateful to the cystic fibrosis community and physicians for the continued support of the RCT2100 clinical program.”

Why have gene therapies for cystic fibrosis taken so long to come into the picture?

While research and development (R&D) in genetic medicine has expanded rapidly in recent years, it has been a long time coming. First and foremost, gene therapies are difficult to develop. Figuring out how to get the new copies of the CF gene into the correct cells has taken a while. Despite cystic fibrosis being one of the first diseases to be nominated to be treated with gene therapy after the CFTR gene was identified in 1989, initial outcomes were not fruitful.

“The long journey to pursue gene therapy as a cure for cystic fibrosis encountered more difficulties than originally anticipated,” explained a research paper published in the National Library of Medicine.

Over the years, geneticists have found over 2,000 different variations of the CFTR mutation. While delivering the CFTR gene to lung cells seemed like a straightforward idea in theory, it turned out that it was harder to deliver it compared to small molecules.

Now that scientists are testing various delivery systems for these medicines, there is a renewed interest in gene therapy. In fact, as 10% of patients currently have no treatment prospects – those with nonsense mutations – there is a necessity for gene therapies to hit endpoints and, in turn, potentially the market.