New Drug
Cara Aldridge Young
In late October 2019, FDA approved elexacaftor/tezacaftor/ivacaftor and ivacaftor (Trikafta—Vertex Pharmaceuticals), the first triple-combination therapy to treat patients ages 12 years and older with at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis (CF) population. In two clinical trials, the drug substantially improved patients’ lung function—13.8% from baseline compared with placebo in the first trial and 10% from baseline compared with tezacaftor/ivacaftor in the second trial.
“Trikafta has opened up modulator therapy to so many patients who didn’t qualify before,” said Cameron McKinzie, PharmD, BCPPS, BCPS, CPP, who is residency program director of PGY2 pediatrics and clinical pharmacist in the outpatient pediatric pulmonary clinic at the University of North Carolina (UNC) Children’s Hospital in Chapel Hill.
UNC’s CF center, one of the largest in the country, provides care—including pharmacist services—to about 650 pediatric and adult patients. With several hundred of these patients qualifying for the drug, “we are talking a lot about Trikafta in both the pediatric and adult CF clinics,” said McKinzie, who has a pharmacist counterpart in the adult clinic. “It has generated a lot of excitement for our patients and providers.”
McKinzie shared her excitement and expertise about the new drug in an interview with Pharmacy Today.
PT: How and why is this drug a breakthrough therapy? What makes it unique?
McKinzie: A couple of things make this therapy different. Most important, the previous modulator therapies have only been available for about 50% of CF patients. It’s all based on patient genotype. With this new therapy, Trikafta, that has been expanded to almost 90% of patients 12 and older. So just in the number of patients who qualify, that is a significant difference.
In terms of effectiveness, for some of these patients who would’ve qualified for previous modulator therapies, like Orkambi and Symdeko, the difference in efficacy—improvement in lung function, weight gain, prevention of pulmonary exacerbations—is drastically different. We haven’t seen effectiveness like this since the first modulator that came out, Kalydeco, which was only indicated for patients with gating mutations at the time. So this is a huge change in efficacy for these patients.
PT: The drug was initially approved for patients 12 years and older but may eventually be approved for younger children and babies. How would this change the outlook and prognosis for patients with CF?
McKinzie: I believe it is currently in clinical trials for patients aged 6 to 11. We would expect that if it is approved, that eventually we would be looking at even younger ages. The hope, of course, is that in starting modulator therapy at younger ages, we can prevent disease progression, reduce CF-related complications like diabetes or liver disease, and ultimately, extend patients’ life span.
And another thing in terms of outlook and prognosis, the question has always been, will these modulator therapies allow patients to come off other therapies? The treatment burden for CF patients is pretty high in number of medications and the time required, especially for a lot of their inhaled therapies.
The CF Foundation, in a study called SIMPLIFY, will start to systematically look at whether we can, after patients are stable on modulator therapy, withdraw some of their other medications, like hypertonic saline, or Pulmozyme. I think it’s exciting in general to think about whether we can not just give patients another therapy, but start to reduce their treatment burden.
PT: What are some things pharmacists should be prepared to explain to caregivers and patients about how the drug is administered?
McKinzie: There are some unique things about this. Trikafta comes as two different pills that make up the medication. The pills in the morning are orange, and they contain all three drugs—elexacaftor, tezacaftor, and ivacaftor. The evening pills are blue and only contain ivacaftor. There aren’t many drugs for which you have two different types of pills that patients need to be able to remember to take—once in the morning and once in the evening.
The drug is packaged to help reinforce that, but I think it’s certainly something that pharmacists should make sure patients and their caregivers understand, because they wouldn’t want someone to take all of the orange pills and then all of the blue pills. [See graphic.]
All of the modulators, including Trikafta, should be taken with fatty foods to improve absorption. There’s no minimum amount of fat required with each dose, so we educate patients to do their best.
The other thing that’s worth noting is that the missed-dose instructions are a little unique. Because the morning pills and the evening pills are different, the instructions depend on which dose you missed and how long it’s been.
There are great resources for patients on the manufacturer’s website, trikaftahcp.com, with graphics to help them figure it out. Pharmacists should know that those are available. There are also pictures of what the drug looks like, what the packaging looks like, etc.
PT: What are possible adverse effects pharmacists should tell patients and caregivers to look out for?
McKinzie: Trikafta has some significant drug–drug interactions. It’s a CYP3A4 substrate, so it’s contraindicated with CYP3A4 inducers like rifampin, and in combination with CYP3A4 inhibitors, dose adjustments are recommended. It has a few other drug–drug interactions, including with warfarin and statin therapy.
From a monitoring standpoint, it’s important to monitor liver function—bilirubin, AST, and ALT every 3 months for the first year that the patient’s on therapy.
When the drug was in development, there were some concerns about development of cataracts in pediatric patients. Pediatric patients need comprehensive eye exams to assess for cataracts prior to starting any modulator therapy and then routine eye exams after that while they’re on the drug.
The more common side effects are GI symptoms like diarrhea and abdominal discomfort. Many patients have also noted an increase in their sputum production pretty soon after starting the medication. This has not necessarily happened for every patient, but some patients have certainly noted it. And in the trials, there was an incidence of rash that was higher in the Trikafta group than the placebo group.
PT: With concerns about the high cost of the drug, how can pharmacists help ensure access to patients who need it?
McKinzie: The manufacturer, Vertex, has financial assistance that’s available to patients with commercial insurance through their GPS [Guidance & Patient Support] program. There are other patient assistance programs available to CF patients—programs like the HealthWell Foundation grant that would help cover costs, as well. Providers and pharmacists can help by making sure patients are enrolled in all the programs they’re eligible for.
I do think there will continue to be concerns about the cost, especially as the CF population is aging. That’s increasing our number of patients who are on Medicare, and I think those traditionally are our patients who struggle the most with the cost of medication since they don’t qualify for a lot of the assistance programs. So it is trickiest to make sure Medicare patients can afford the medications. They do qualify for some things, like the HealthWell grant.
PT: Is there anything else you would like our readers to know about the new drug?
McKinzie: There are still a number of CF patients who don’t have modulator therapy currently. The CF Foundation has launched an initiative called Path to a Cure. They have designated $500 million dollars to go toward CF drug discovery and development. They’re looking at gene therapy and how to ensure that all CF patients have therapy directed at the underlying genetic cause of CF and ultimately the path to the cure.
So I think it’s important for folks who aren’t as familiar with the CF world to know that there are still patients who don’t qualify, but there is a big emphasis being placed on that by the CF Foundation nationwide.
For those who wouldn’t quality for Trikafta—if you are still waiting—I think it’s important just to know that there’s still a lot of work being done.
Elexacaftor/tezacaftor/ivacaftor and ivacaftor (Trikafta)
Manufacturer: Vertex
Drug class: CFTR correctors and potentiator
Indication: Treatment of patients ages 12 years and older with at least one F508del mutation in CFTR gene as confirmed by FDA genotyping assay
Recommended dosage: Morning dose, two elexacaftor 100-mg, tezacaftor 50-mg, and ivacaftor 75-mg tablets; evening dose, one ivacaftor 150-mg tablet (take doses 12 h apart with fat-containing food)
CF treatment resources