The trial’s most recent finding were discussed at the 41st European Cystic Fibrosis Society (ECFS) Conference taking place in Belgrade, Serbia, through June 9. The oral presentation was titled “A phase 3, 2-part, single-arm study of ivacaftor treatment in patients < 2 years with a CFTR gating mutation: results from the ARRIVAL study in patients 1 to 2 years.”
These data were also recently published in the journal The Lancet Respiratory Medicine, in the study “Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study.”
The ARRIVAL trial (NCT02725567) is a two-part study that enrolled 25 children ages 12 to up to 24 months, with one of 10 so-called gating mutations — G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D, or R117H — that prevent the CFTR chloride channel from working properly.
In the study’s first part, seven children were treated with 50 mg or 75 mg of Kalydeco, developed by Vertex Pharmaceuticals, depending on weight every 12 hours for five days to assess safety. Next, the researchers treated 19 infants with 50 mg of the CFTR corrector for 24 weeks to evaluate its safety and efficacy in treating very young CF patients.
Treatment for 24 weeks of treatment showed about three times lower levels of the mean sweat chloride compared to mean levels at the trial’s start, dropping from 104.1 mmol/L to a mean value of 33.8 mmol/L. The post-treatment mean sweat chloride value is suggestive of improved CFTR activity, as values lower than 30 mmol/L are a diagnostic indicator that CF is unlikely.
Ten patients showed a decrease greater than 40 mmol/L in sweat chloride levels by week 24, with four of these patients achieving levels of less than 30 mmol/L.
Researchers also found that early treatment with Kalydeco improved the levels of several exocrine pancreatic biomarkers commonly used to determine CF-associated exocrine pancreatic dysfunction. Improvement in the levels of fecal elastase, serum immunoreactive trypsinogen, amylase and lipase enzymes were also reported, suggesting that Kalydeco could prevent this digestive complication from progressing at an early age.
The most common adverse effects reported in the trial were cough, fever, elevated liver enzymes, and a runny nose, and most were mild or moderate in severity. A serious increase of liver enzyme levels was reported in two patients, but they continued treatment after a dose interruption.
In general, the treatment was found to have an acceptable safety profile, consistent with the safety profile of Kalydeco seen in prior trials in older children and adults with CF.
“The data presented at ECFS are further evidence that treating the cause of CF may significantly slow the progression of this disease beginning early in life, underscoring the importance of starting treatment for eligible patients as early as possible,” Reshma Kewalramani, executive vice president and chief medical officer at Vertex, said in a press release.
The study’s researchers, however, stressed in their presentation the importance of noting the small number of patients, due to the rarity of this condition, and the lack of a comparator treatment. Although these points may limit the trial’s strength in assessing Kalydeco in this patient group, the company expects results will support the treatment’s label extension in the United States and Europe, so that Kalydeco can also be used to treat CF in toddlers ages 12 to 24 months.
In addition to ARRIVAL data, Vertex also presented recent results of real-world, long-term use of Kalydeco in two poster presentations. Data from a U.S. and a U.K. registry was collected for five and four years, respectively, after the treatment’s approval in each country.
Since Kalydeco is approved, no safety concerns were reported.
In the U.S., analysis of mortality rates showed that fewer patients being treated with Kalydeco died relative to those not on the treatment. A lower proportion of treated patients required transplants, hospitalization, or suffered pulmonary exacerbations. In the U.K., long-term outcomes were similar.
In both registries, the prevalence of many of CF-related complications, including bacterial lung infections and diabetes, tended to be lower in Kalydeco-treated patients. Treatment was also shown to improve patients’ nutritional status and slow lung function decline.
At ECSF 2018, Vertex will also present positive results from an ongoing multinational study (U.K., Italy, Netherlands) assessing the real-world effectiveness of Kalydeco in CF patients with a non-G551D gating mutation (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P or G1349D). This observational trial, called VOCAL (NCT02445053), shows that Kalydeco improves lung function, lessens the rate of pulmonary exacerbations, and raises body mass index (BMI) in patients over a 12-month period, compared to a 12-month pre-Kalydeco period.
The most recent clinical trial results of Symdeko (tezacaftor/ivacaftor and ivacaftor) in its 96-week EXTEND Phase 3 rollover study (NCT02565914) are also being presented. Results of an interim analysis at 48-weeks demonstrated consistent safety and sustained benefits in lung function, in line with results from previous trials.
Taken together, these data support the potential of Vertex’s pipeline to treat the underlying cause of CF and to expand treatment options to the vast majority of people with the disease.
“Over the past year, we’ve made rapid progress in developing multiple new medicines that treat the underlying cause of CF, and today, we are closer to our goal of developing medicines for all patients with CF than ever before,” Kewalramani said.