Use of some CFTR modulators in the real world is not translating into the level of improvement in lung function seen in clinical trials, Australian research suggests.

A retrospective review of medical records at Monash CF in Melbourne evaluated the experience of 252 adults and children with CF from the introduction of CFTR modulators in May 2012 until September 2020.

About 55% of the adults and 46% of paediatric patients commenced on at least one CFTR modulator. Overall, 31 patients commenced on ivacaftor (IVA), 85 on lumacaftor/ivacaftor (LUM/IVA) and eight on tezacaftor/ivacaftor (TEZ/IVA). Four adults with severe CF lung disease commenced on elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) via compassionate access.

The study, published in Pulmonary Pharmacology & Therapeutics [link here], found that lung function significantly improved from baseline in adult patients started on IVA (Change in FEV1 = 1.85%; p=0.012) and TEZ/ELX/IVA (3.26%; p=0.001).

A significant increase in BMI was also seen in these groups (p <0.0001 and p= 0.005, respectively).

Patients started on LUM/IVA also showed significant improvement in BMI but no significant improvement in lung function or hospital admission days.

“Whilst it is encouraging that lung function was maintained and nutritional parameters improved, we did not demonstrate significant benefits as those seen in the initial trials,” it said.

“It is important to balance this small benefit with the potential adverse effects and added burden of treatment of these very expensive medications.”

The investigators, led by Dr Stephanie Kuek from Monash Children’s Hospital, said there were no significant improvements seen with TEZ/IVA.

“Overall, the changes in lung function and nutritional parameters were less convincing than seen in clinical trials, with no statistically significant improvement in any of these parameters.”

Regarding safety, they found 36.5% of patients ceased LUM/IVA, mostly due to adverse effects including respiratory symptoms such as wheeze, chest tightness, increased cough and drop in FEV1.

Most patients who ceased LUM/IVA due to adverse effects were changed to TEZ/IVA which was generally well tolerated.

No patients reported significant adverse effects whilst taking IVA or ELX/TEZ/IVA.

“These findings support ongoing use of IVA for individuals with gating mutations, and transition to ELX/TEZ/IVA once available for patients with at least one Phe508del mutation,” the study concluded.

“It will also be important to repeat real world studies for ELX/TEZ/IVA as it becomes more widely available in order to determine if benefit and adverse events are consistent with those in clinical trials.”