Top 10 Cystic Fibrosis Stories of 2021
Cystic Fibrosis News Today brought you daily coverage of the latest scientific findings, treatment developments, and clinical trials related to cystic fibrosis (CF) throughout 2021, a year still marked by the COVID-19 pandemic.
We look forward to reporting more news to patients, family members, and caregivers dealing with CF during 2022.
Here are the top 10 most-read articles of 2021, with a brief description of what made them relevant for the CF community.
In June, Health Canada approved Trikafta as a triple-combination therapy for CF patients, ages 12 and up, who have at least one F508del mutation. The therapy, developed by Vertex Pharmaceuticals, is a combination of three CFTR modulators (elexacaftor, tezacaftor, and ivacaftor) and works enhances the function of the CFTR protein.
F508del is the most common CF-causing mutation, with one copy found in about 90% of all those with CF.
The decision gives access to about 1,100 people for a first time to a therapy that directly addresses the underlying cause of their disease, according to Vertex.
Trikafta was also approved for the same CF patient group — those ages 12 and older with at least one copy of the F508del mutation — in March by health regulators in Australia. The triple-combination therapy was approved in 2019 in the U.S. and in 2020 in the European Union, where it is marketed under the brand name Kaftrio.
Elexacaftor and tezacaftor, two CFTR correctors, work by binding to the faulty CFTR protein and help it fold correctly. This allows cells to shuttle more of the protein to the cell’s membrane, where it works as a gate. Ivacaftor, also marketed separately as Kalydeco, is a potentiator, meaning its binding to the CFTR protein holds the channel open.
Results from a small study using MRI brain scans suggest that people with CF may carry subtle changes in areas of the brain involved in mood and cognition.
Mood disorders like symptoms of anxiety and depression, as well as cognitive difficulties, are reported to trouble CF patients more than those without this disease. In this study of five CF patients, all with higher measures of anxiety and depression relative to a group of 15 healthy adults, low oxygen levels in brain tissues — a condition known as hypoxia — were identified as a potential cause.
Study researchers recommended that mental health evaluations be integrated into CF care, and efforts made to identify early changes in the brain that can affect mood and cognition for better disease management and treatment.
Two experimental RNA-based therapies for CF, developed by ReCode Therapeutics and named RCT223 and RTX0001, restored the function of the CFTR protein in patient-derived lung cells.
Both therapies are designed to treat the 10% to 13% of CF patients with nonsense mutations in the CFTR gene who have limited therapeutic options. These mutations introduce a premature stop signal in the gene’s DNA sequence, leading to the production of a shorter, non-functional CFTR protein.
RCT223 uses a transfer RNA (tRNA) molecule — which plays a role in the process of protein production — to replace the premature stop signal, allowing the production of the full CFTR protein. RTX0001 is designed to deliver to cells a working version of CFTR’s messenger RNA (mRNA), the molecule generated from DNA that serves as a template for protein production, to promote increased production of a working CFTR protein.
ReCode announced plans to apply to the U.S. Food and Drug Administration in 2022 for clearance to start clinical trials of these RNA-based therapies in the U.S.
In April, Krystal Biotech announced plans to launch a Phase 1 clinical trial of KB407, its investigational inhaled gene therapy for CF. The announcement followed the therapy’s positive results in nonhuman primates, where KB407 was administered three times weekly at a high or low dose.
The repeated doses of KB407 were well-tolerated, with no adverse effects observed at the highest tested dose. The therapy’s use also led to a sustained CFTR gene activity, detected at least until 28 days after the last dose.
KB407 is designed to deliver two healthy copies of the CFTR gene directly to patients’ lung tissues using a modified version of the herpes simplex virus type 1 (HSV-1). The modified virus is safe for human use.
Results from a Phase 3 clinical study (NCT03691779) showed that Trikafta was safe and effective in children with CF ages 6 to 11 who have two F508del mutations or one F508del and one minimal function mutation.
The findings came in support of a supplemental new drug application filed by Vertex to the FDA requesting the approval of Trikafta for children, ages 6 to 11, with relevant mutations. Of note, the agency approved the expansion of Trikafta’s use to eligible children in this age group in June.
Trial results showed that Trikafta led to improvements in lung function, and lessened the disease’s impact on patient’s overall health and daily life. Trikafta also reduced the levels of chloride in sweat, the gold standard in diagnosing CF, and led to significant improvements in patient’s nutritional status. A better nutritional status in CF patients is associated with better lung health and survival.
In July, Vertex announced plans to launch two Phase 3 clinical trials assessing the safety and efficacy of a potentially new, next-generation triple combination therapy for CF — VX-121 plus tezacaftor and VX-561 (deutivacaftor).
Both VX-121 and tezacaftor are designed to enhance the amount of mature CFTR protein at the cell surface, while VX-561 aims to boost CFTR function at the cell surface.
The trial will compare this once-daily therapy with Trikafta.
Researchers in Italy found that the risk of developing a severe COVID-19 infection, one with a greater need for ventilation and a greater risk of death, is higher among CF carriers, especially men with mutations in one copy of the CFTR gene.
CF carriers have disease-associated mutations in only one of their two CFTR gene copies. Despite not developing the full-blown disease, they have lower levels of CFTR protein or working protein levels and can experience lung inflammation more often than is common. Carriers are also more susceptible to CF-related conditions, such as lung infections, including pneumonia.
These findings highlight the need to check carrier status in hospitalized COVID-19 patients to identify those at risk of severe disease. According to the study’s researchers, these patients would benefit from closer surveillance or more aggressive treatment.
Researchers in Singapore developed a precise gene-editing tool that may offer a new avenue for developing genetic therapies for people with CF.
The new gene-editing therapy, called CGBE (CG base editor), showed an ability to reverse single DNA mutations, as those that occur in CF.
DNA has four building blocks: guanine (G), cytosine (C), adenine (A), and thymine (T). A change from G to C underlies many genetic diseases, including CF. As such, a technology able to reverse this change — C back to G — could lead to a new treatment for the disease.
Our most-read article of 2021 concerned a report that CF patients may experience vitamin D intoxication due to accidental errors made by pharmacists in preparing prescriptions.
Many CF patients have exocrine pancreatic insufficiency, a condition in which the pancreas is unable to release digestive enzymes to break down food in the intestines. This often results in low levels of nutrients, including vitamin D. As such, patients are often prescribed the vitamin as a supplement, but problems can arise if they take too much of it.
Researchers in Belgium reviewed the medical histories of 244 CF patients and found that 13 (5%) had abnormally high levels of 25-hydroxyvitamin D (25(OH)D), the major form of vitamin D in the blood — a median of 185.5 nanograms per milliliter (ng/mL); toxicity is defined by levels exceeding 150 ng/mL.
These patients were taking a dose that was a median 69 times higher than the prescribed one, the researchers found, and the main cause of these excessive 25(OH)D levels was an error in preparing the compounded multivitamin pills. Identified errors were in the processes of trituration or grinding, and dose calculation.
Clinical complications in patients are rare, the team added.
At Cystic Fibrosis News Today, we hope these stories and our reporting throughout 2022 contribute to informing and improving the lives of everyone affected by CF.
We wish all our readers a happy 2022.