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ystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to missing or defective CFTR proteins. These mutations must be inherited from both parents, which makes the condition quite rare, affecting around 100,000 people globally.

As the genetic basis of the condition has become better understood, pharma has focused on developing drugs that target the underlying cause of the CF, rather than simply helping patients manage their symptoms; Boston-headquartered Vertex Pharmaceuticals has led the way in this genetic-focused approach.

Vertex began working on CF in the late 1990s, but only initiated its first CF-related clinical trial in 2006. Just five years later the company received fast track designation from the US Food and Drug Administration (FDA) for its first drug, Kalydeco (ivacaftor), with approvals promptly following around the world.

The company then began to focus on developing combination therapies to support ivacaftor’s mechanism of action, and thus improve its efficacy and expand the number of patients who can benefit from the treatments. These efforts led to the approvals of innovative drugs Orkambi (lumacaftor/ivacaftor) and Symdeko (tezacaftor/ivacaftor + ivacaftor) in 2015 and 2018 respectively in the US.

In October 2019, Vertex demonstrated the success of this additive model when its triple combination therapy Trikafta (elexacaftor/ivacaftor/tezacaftor + ivacaftor) was approved by the FDA. The drug is indicated to treat all patients aged 12 years or older with at least one F508del mutation in the CFTR gene, meaning this drug is able to treat 90% of the CF patient population, which represents around 27,000 people in the US.

In a statement, acting FDA Commissioner Ned Sharpless commented: “[This] landmark approval [makes]…a novel treatment available to most cystic fibrosis patients, including adolescents, who previously had no options and giving others in the cystic fibrosis community access to an additional effective therapy.

“We used all available programs, including priority review, fast track, breakthrough therapy, and orphan drug designation, to help advance today’s approval in the most efficient manner possible.”

GlobalData cardiovascular and metabolic disorders senior analyst Kelly Lambrinos also noted the speed of approval, saying: “While the approval was widely expected, the FDA’s decision came just three months after the company’s announcement of a completed regulatory submission.

“Despite the therapy’s strong efficacy, the approval timeline still came surprisingly faster than investors and clinicians anticipated, reflecting its importance and the significant unmet need for CF patients.”

Vertex has submitted a marketing authorisation application (MAA) for Trikafta to the European Medicines Agency and is planning to submit approval applications in other countries this year.

However, the company is already beginning to agree reimbursement deals with certain European Union countries, such as the Republic of Ireland, in advance of the approval.

NHS England had expressed significant interest in the promise of Trikafta during its contentious negotiation process with Vertex for its other CF medicines, which came to a positive conclusion in October 2019; Vertex will be engaging with NICE “in due course” regarding the reimbursement of Trikafta, the company’s spokesperson Heather Nichols emphasises.

“More than 20 years ago, Vertex scientists set out to crack the code of CF. Trikafta is the fourth breakthrough CF medicine we’ve brought to patients in just seven years,” explains Nichols.

“This is the first time that thousands of people with CF have a breakthrough medicine to treat the underlying cause of their disease. This approval is monumental in our efforts to change the course of this disease for thousands of CF patients.”

Nichols explains Trikafta is designed to “increase the quantity and function of the F508del CFTR protein at the cell surface”.

Elexacaftor and tezacaftor are both CFTR correctors, which means they fix the defective proteins, allowing more of the proteins to move to their proper place on the cell surface.

Ivacaftor, which is known as a potentiator, then allows CFTR proteins on the surface to stay open longer, and therefore keep chloride channels open. Disruption to chloride ion channels’ function leads to a dysregulation of epithelial fluid in various organs throughout the body, which characterises CF.

Trikafta’s success in treating the underlying cause of CF was clear from data collected during two Phase III trials. Nichols notes that “Trikafta was generally well tolerated and demonstrated improvements in multiple outcome measures in CF, including improvement in FEV1 [forced expiration volume in one second].”

In a 24-week Phase III study, Trikafta demonstrated its efficacy and tolerability in patients with one F508del mutation and a mutation in the second allele, which resulted in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor or tezacaftor/ivacaftor alone.

This means Vertex’s newest drug is effective in the patients who are ineligible for and would receive little benefit from Symdeko, Kalydeco and Orkambi; the latter is only indicated for patients with two copies of the F508del mutation.

The second, four-week study investigated Trikafta in 107 CF patients who are homozygous for the F508del mutation, compared to Symdeko. In this trial, the drug was able to increase the mean percent predicted FEV1 from baseline by 10%, demonstrating the efficacy of Trikafta in yet another CF patient group.

“For the first time, approximately 6,000 people with CF aged 12 years and older who have one F508del mutation and one minimal function mutation (F/MF) have a medicine that targets the underlying cause of their CF,” notes Nichols.

“Additionally, approximately 12,000 people with one or two F508del mutations who are currently eligible for one of Vertex’s three other FDA-approved CF medicines are now also eligible for Trikafta.”

Lambrinos notes: “The most rapid switch is expected in homozygous F508del patients, particularly those receiving Orkambi, based on the strength of the Trikafta data in this patient population and Orkambi's weaker tolerability profile.”

Although the US-based CF Foundation notes Trikafta’s “potential to be significantly more effective than current modulators at treating the underlying cause of CF”, the charity was keen to ensure the 10% who are not eligible for this ground-breaking therapy are not left behind.

The foundation’s spokesperson Jessica Rowlands notes: “Despite extraordinary progress in helping people with CF live longer and healthier lives, there is still critical work to be done to help all people living with this disease.

“The CF Foundation is steadfast in our commitment to finding treatments for the underlying cause of disease for all people with CF, including those with…rare mutations.”

Vertex has also committed itself to treating 100% of CF patients, no matter the hurdles.

“That means working to get Trikafta to younger children and continuing to work on genetic approaches to help those who need something other than a small molecule to treat their disease,” says Nichols.

Vertex’s study of Trikafta in patients aged six to 11 is ongoing – for the time being, these patients are unable to replace Orkambi, Symdeko or Kalydeco even if they have at least one F508del mutation in the CFTR gene.

Nichols also notes Vertex is investigating gene therapy as an option to treat the last 10% of patients; she picks out the company’s ongoing partnerships with CRISPR, Arbor, and Moderna to “develop other approaches to treat…people that may not respond to our CFTR modulator medicines.”

She concludes: “Given the scientific and other challenges of addressing the last 10%, it will take commitment, new scientific advances, time and resources to bring effective treatments to all patients.

“However long it takes, we will be relentless in our efforts to complete the journey together. We won’t stop until we have developed breakthrough medicines for all people with CF.”