Orkambi’s Benefits in the Real World Go Beyond Lung Function: Study

Modulators may help 'every system in the body that involves CFTR function'

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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For a small group of people with cystic fibrosis (CF), one year of treatment with Orkambi (ivacaftor/lumacaftor) improved bone health and stabilized pancreatic function, nutritional status, reproductive hormone levels, and lung function.

These findings from a recent study in Israel demonstrate the use of Orkambi, which targets the faulty CFTR channels that drive CF, may have benefits for patients beyond lung function, which is the primary goal in most clinical trials.

“This is a new era for CF patients in which CFTR modulators, initiated at the earliest age possible, are about to completely change the course of the disease, not only in the respiratory aspect but possibly in every system in the body that involves CFTR function,” researchers wrote.

The study, “Real life evaluation of the multi-organ effects of Lumacaftor/Ivacaftor on F508del homozygous cystic fibrosis patients,” was published in the journal BMC Pharmacology and Toxicology.

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What is Orkambi?

Orkambi is a CFTR modulator, developed by Vertex Pharmaceuticals, that is currently approved in several countries, including the U.S., Europe, Canada, Australia, and Israel, for adults and children with two copies of F508del, the most common CF-causing mutation.

In clinical trials, Orkambi led to significant improvements in lung function and healthy weight gain, as well as fewer acute bouts of lung symptom worsening (pulmonary exacerbations) and hospitalizations.

However, the effects of Orkambi on other common disease symptoms, including CF-related diabetes (CFRD), bone disease, and changes in fertility hormones, are not as well-established.

In the new study, researchers conducted a clinical trial (NCT04623879) to examine the real-world effects of Orkambi on the lungs and other organs of 12 adults with CF who initiated treatment with Orkambi at their CF center in Haifa, Israel, between November 2016 and June 2019.

The mean age of the participants, which included eight men and four women, was 28.3 years. Patients had “long-standing lung disease and a relatively high degree of pulmonary compromise,” the researchers wrote, adding that “left untreated, such patients tend to deteriorate over time.”

This is a new era for CF patients in which CFTR modulators, initiated at the earliest age possible, are about to completely change the course of the disease, not only in the respiratory aspect but possibly in every system in the body that involves CFTR function

The patients started twice daily Orkambi treatment and were followed for one year, with clinic visits every three months.

The study’s main goal was to assess pancreatic function after a year of treatment. In many patients, the pancreas becomes damaged, leading to insufficient production of insulin, a hormone in the blood that helps cells take up blood sugar and use it as a source of energy. As a result of low insulin levels, CF patients may develop high blood sugar or CFRD.

To assess pancreatic function, blood sugar and insulin levels were evaluated. At the study’s start, all participants had pancreatic insufficiency, and four were diagnosed with CFRD.

Results showed that neither blood sugar nor insulin levels were significantly altered with a year of treatment with Orkambi among the eight patients who did not have CFRD. None of these patients developed CFRD over the course of the study.

Additional trial goals were to evaluate bone health, nutritional status, fertility, lung, and other organ function.

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How did Orkambi affect measures of other body functions?

Data indicated that Orkambi may have benefits for bone health, with no bone health parameters deteriorating over the course of treatment. Moreover, a significant decrease in blood levels of alkaline phosphatase, a potential marker of bone disorders, was observed after three months.

Trends toward beneficial changes in blood and urinary calcium, as well as bone density were also observed, but these findings failed to reach statistical significance.

Nutritional measures (body mass index, vitamin A and E levels), levels of reproductive hormones, and liver enzymes remained unchanged with treatment.

Consistent with data from previous studies, decreases in sweat chloride levels were observed and lung function decline was prevented with Orkambi.

Lung function was assessed with the percent predicted forced expiratory volume in one second (ppFEV1), a measure of how much air can be forcibly exhaled from the lungs in one second relative to what is expected for a person’s age and sex.

After three months, ppFEV1 values improved by 5.7% and remained stable after one year.

No significant differences in the number of pulmonary exacerbations or hospitalizations were observed. However, fewer exacerbations required the use of into-the-vein antibiotics during the year the patients were treated with Orkambi (28.6%) compared with the previous year (56.7%).

No adverse events were reported.

“Further larger studies with a heterogeneous patient population in terms of age and disease severity, should continue investigating the effect of CFTR modulators on extra-pulmonary manifestations,” the researchers wrote.

“This will have important implications on the need to continue other medications that now comprise the patients’ pharmacological regimen,” they added.