Highlights
Trikafta (elexacaftor + tezacaftor + ivacaftor, ivacaftor) is a new drug that combines three medicines at once to treat cystic fibrosis.
Trikafta debuted in late October 2019, receiving approval from the U.S. Food and Drug Administration (FDA), which cleared it for use in patients 12 years and older with at least one F508del mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
- In December 2020, the FDA impressively expanded the list of CFTR mutations suitable for treatment with Trikafta, thereby making the drug applicable to patients with at least one F508del CFTR mutation as well as cystic fibrosis patients whose CFTR gene mutation would respond to prescription of this drug. A list of CFTR mutations that have responded in vitro to Trikafta administration is provided below.
- In June 2021, the FDA connected Trikafta to cystic fibrosis patients ages 6–11: the disease must carry either at least one F508del CFTR mutation or any of the mutations that responded in vitro to prescribing the drug. In parallel, a version of Trikafta with halved doses of its drug components was released.
In August 2020, the European Medicines Agency (EMA) approved Trikafta, though under a different brand name — Kaftrio (elexacaftor + tezacaftor + ivacaftor) — and without additional ivacaftor. The drug is approved in a combination regimen with ivacaftor for the treatment of patients aged 12 years and older with cystic fibrosis whose disease is characterized by certain mutational features of the CFTR gene: either one F508del mutation and one minimal function mutation (F/MF) or two F508del mutations (F/F).
- In April 2021, the EMA expanded the range of indications for Kaftrio: the drug can be used in combination with ivacaftor to treat patients aged 12 years and older with cystic fibrosis who have at least one CFTR mutation F508del. In other words, we are talking about all patients heterozygous for F508del.
Why Trikafta/Kaftrio Is the Best Cure for Cystic Fibrosis
Cystic fibrosis is rare, though most common, autosomal recessive disease of the Caucasian race that limits life expectancy. The genetic pathology is caused by mutations or variations in the CFTR gene, which encodes the chlorine ion transporter channel. Because the CFTR protein is localized in the apical part of the membrane of epithelial cells lining the excretory ducts of the secretory glands (sweat, saliva, bronchial, pancreatic, intestinal and urogenital tracts), multiorgan disorders associated with the secretion of dense secretions are observed in cystic fibrosis: sinusitis and chronic obstructive pulmonary disease (COPD), chronic lung infections, pancreatitis and pancreatic insufficiency, and male infertility.
Yes, Kalydeco (ivacaftor), Orkambi (lumacaftor + ivacaftor), and Symdeko/Symkevi (tezacaftor + ivacaftor, ivacaftor) — already commercialized by Vertex and the only specialized drugs for cystic fibrosis — cover a decent number of patients. However, approximately one-third of patients have been left out of therapy because of specific mutations insensitive to the drugs in question. The prescription of Trikafta/Kaftrio is designed for such a population.
Trikafta/Kaftrio is also suitable for use in cystic fibrosis patients who are already being treated with Kalydeco, Orkambi, or Symdeko/Symkevi. With Trikafta/Kaftrio, the therapeutic coverage of eligible patients has increased from 50% to 90%.
Trikafta/Kaftrio: List of CFTR Mutations Suitable for Treatment
Trikafta/Kaftrio will have a therapeutic effect in heterozygous or homozygous F508del mutation of CFTR gene, but the drug will also help in other mutations.
For this purpose, Vertex tested Trikafta/Kaftrio in vitro on rat thyroid cells of the Fisher line, which were transfected with certain CFTR mutations. The table lists those mutations in which the use of Trikafta/Kaftrio resulted in an increase in CFTR protein-mediated chlorine ion transport by at least 10% of normal (this threshold is considered to be clinically significant).
List of CFTR gene mutations susceptible to Trikafta/Kaftrio
| 3141del9 | E822K | G1069R | L967S | R117L | S912L |
|---|---|---|---|---|---|
| 546insCTA | FI 91V | G1244E | L997F | R117P | S945L |
| A46D | F311del | G1249R | L1077P | R170H | S977F |
| A120T | F311L | G1349D | L1324P | R258G | S1159F |
| A234D | F508C | H139R | L1335P | R334L | S1159P |
| A349V | F508C;S1251N^ | H199Y | L1480P | R334Q | S1251N |
| A455E | F508del* | H939R | M152V | R347H | S1255P |
| A554E | F575Y | H1054D | M265R | R347L | T338I |
| A1006E | F1016S | H1085P | M952I | R347P | T1036N |
| A1067T | F1052V | H1085R | M952T | R352Q | T10531 |
| D110E | F1074L | H1375P | M1101K | R352W | V201M |
| D110H | F1099L | I148T | P5L | R553Q | V232D |
| D192G | G27R | I175V | P67L | R668C | V456A |
| D443Y | G85E | I336K | P205S | R751L | V456F |
| D443Y;G576A;R668C^ | G126D | I502T | P574H | R792G | V5621 |
| D579G | G178E | I601F | Q98R | R933G | V754M |
| D614G | G178R | I618T | Q237E | R1066H | V1153E |
| D836Y | G194R | I807M | 0237H | R1070Q | V1240G |
| D924N | G194V | I980K | Q359R | R1070W | V1293G |
| D979V | G314E | I1027T | Q1291R | R1162L | W361R |
| D1152H | G463V | I1139V | R31L | R1283M | W1098C |
| D1270N | G480C | I1269N | R74Q | R1283S | W1282R |
| E56K | G551D | I1366N | R74W | S13F | Y109N |
| E60K | G551S | K1060T | R74W;D1270N^ | S341P | Y161D |
| E92K | G576A | L15P | R74W;V201M^ | S364P | Y161S |
| E116K | G576A;R668C^ | L165S | R74W;V201M;D1270N^ | S492F | Y563N |
| E193K | G622D | L206W | R75Q | S549N | Y1014C |
| E403D | G628R | L320V | R117C | S549R | Y1032C |
| E474K | G970D | L346P | R117G | S589N | |
| E588V | G1061R | L453S | R117H | S737F |
* — F508del is a responsive CFTR mutation, according to clinical and in vitro data.
Kalydeco, Orkambi, Symdeko/Symkevi: Why More Trikafta/Kaftrio Is Needed
In January 2012, Vertex offered Kalydeco (ivacaftor), the first specialized drug for cystic fibrosis.
Ivacaftor (VX-770) is a CFTR potentiator (stimulator) that increases the probability of opening the CFTR protein ion channel (by prolonging its opening time) so that chlorine ions can pass freely through it. Ivacaftor only works in certain CFTR mutations (4–5% of patients) and does not work in the case of F508del mutation of CFTR gene, homozygosity for which is responsible for at least two-thirds of the causes of cystic fibrosis. One has to understand that CFTR mutations are very diverse (there are already more than 2100 mutations), so it is difficult to help each patient with effective medication.
In July 2015, Vertex released Orkambi (lumacaftor + ivacaftor), which connects patients homozygous for the CFTR mutation F508del (approximately 50% of cystic fibrosis cases).
F508del, which leads to CFTR protein misfolding, results in abnormal intracellular processing and migration, which is reflected in the degradation and dramatic decrease of CFTR on the cell surface. The CFTR corrector (modulator) lumacaftor (VX-809) enhances the conformational stability of F508del-mutant CFTR by allowing more mature CFTR protein to process and migrate to the cell surface. For ivacaftor to work successfully, the CFTR protein needs to be located on the cell surface, which is exactly what lumacaftor promotes.
In February 2018, Vertex introduced Symdeko/Symkevi (tezacaftor + ivacaftor, ivacaftor), which, as an improved version of Orkambi, expanded the patient pool (by connecting additional CFTR mutations) and reduced adverse reactions.
The CFTR corrector tezacaftor (VX-661), further development of lumacaftor, similarly promotes the migration to the cell surface of normal and certain mutant forms of CFTR, including F508del.
Nevertheless, approximately 30% of cystic fibrosis patients remain outside the scope of the mentioned medications because their disease is characterized by mutant heterozygosity: one allele of the CFTR gene carries the F508del mutation, while the other carries a mutation with minimal functionality that results in the absence or synthesis of a defective protein insensitive to CFTR correctors — the so-called F508del–MF genotype. This is the population for which Trikafta/Kaftrio is designed: its CFTR corrector elexacaftor (VX-445) modulates CFTR differently and therefore its mechanism of action is synergistic with tezacaftor, providing an additional increase in F508del-mutant CFTR protein on the cell surface.
At one time, Vertex was faced with a difficult choice of which of the experimental CFTR-correctors, elexacaftor or bamocaftor (VX-659), to send for regulatory approval of triple therapy for cystic fibrosis, as their effectiveness proved to be equally effective.
Trikafta/Kaftrio: Efficacy and Safety of Cystic Fibrosis Treatment
- Due to the fact that the use of Trikafta/Kaftrio may worsen hepatic parameters, the drug is contraindicated in patients with severe hepatic impairment (e.g., cirrhosis, portal hypertension, ascites, hepatic encephalopathy). In the case of moderate hepatic impairment, it is recommended to assess whether the benefits outweigh the risks. ALT, AST, and bilirubin levels should be tested periodically.
The efficacy and safety of Trikafta/Kaftrio have been established in two phase 3 (randomized, double-blind, placebo-controlled or with an active drug comparison group, multicenter, international) clinical trials, AURORA F/MF (NCT03525444) and AURORA F/F (NCT03525548), among patients (n=510) aged 12 years and older with cystic fibrosis and at least one F508del mutation of the CFTR gene.
Exclusion criteria included a history of colonization with microorganisms associated with rapid pulmonary deterioration, such as Burkholderia cenocepacia, Burkholderia dolosa, Mycobacterium abscessus; impaired liver function (ALT, AST, alkaline phosphatase, or GGT ≥ triple the upper limit of normal or total bilirubin ≥ double the upper limit of normal).
The primary endpoint was stated to be the absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1).
The first clinical trial involved patients (n=403) with cystic fibrosis and a heterozygous mutation of the CFTR gene: one allele carrying the F508del mutation and the other carrying minimal function mutation (F/MF) resulting in either absence of CFTR protein or synthesis of a defective CFTR protein insensitive to Kalydeco or Symdeko/Symkevi.
After 4 weeks of treatment, the mean absolute change in ppFEV1 in the Trikafta/Kaftrio group compared to the placebo group was 13.8% (95% CI: 12.1–15.4; p<0.0001). Over the entire 24-week treatment period, this difference was 14.3% (95% CI: 12.7–15.8; p<0.0001).
The 24-week Trikafta/Kaftrio administration provided statistically and clinically significant exit to all secondary endpoints indicating reliable improvements in lung function as assessed by the following manifestations of cystic fibrosis:
- reduction in the incidence of pulmonary exacerbations per year by 63% compared with placebo (hereafter): rate ratio (RR) 0.37 (95% CI: 0.25–0.55; p<0.0001)
- reduction in the incidence of cystic fibrosis complications leading to hospitalization by 71%: RR 0.29 (95% CI: 0.14–0.61)
- reduction in the incidence of cystic fibrosis complications requiring intravenous antibiotics by 78%: RR 0.22 (95% CI: 0.14–0.43)
- decrease in sweat chloride: by 41.8 mmol/L (95% CI: −44.4 to −39.3; p<0.0001)
- improvement in respiratory symptomatology on the Cystic Fibrosis Questionnaire—Revised (CFQ-R): increase of 20.2 points (95% CI: 17.5–23.0; p<0.0001)
- improvement in body mass index (BMI): gain of 1.04 kg/m2 (95% CI: 0.85–1.23; p<0.0001).
The second clinical trial involved patients (n=107) with cystic fibrosis homozygous for the F508del mutation of the CFTR gene.
After 4 weeks of therapy, the Trikafta/Kaftrio group showed a mean absolute change in ppFEV1 of 10.0% (95% CI: 7.4–12.6) when compared to the control group receiving Symdeko/Symkevi (p<0.0001).
Administration of Trikafta/Kaftrio resulted in statistically and clinically significant improvements in secondary endpoints (relative to the comparison group) established by sweat chloride and CFQ-R respiratory domain: −45.1 mmol/L (95% CI: −50.1 to −40.1; p<0.0001) and +17.4 points (95% CI: 11.8–23.0; p<0.0001), respectively.
The NCT03691779 phase 3 (nonrandomized, open-label, multicenter, international) clinical trial tested Trikafta/Kaftrio in the treatment of cystic fibrosis among patients (n=66) aged 6–11 years homozygous or heterozygous for the CFTR mutation F508del (F/F or F/MF genotypes).
A 24-week administration of Trikafta/Kaftrio resulted in improvements in the following clinically important indices:
- absolute increase in ppFEV1 by 10.2% (95% CI: 7.9–12.6)
- decrease in sweat chloride by 60.9 mmol/L (95% CI: −63.7 to −58.2)
- improvement in CFQ-R respiratory domain by 7.0 points (95% CI: 4.7–9.2)
- improvement in BMI by 1.02 kg/m2 (95% CI: 0.76–1.28)
- improvement of Z value of BMI by 0.37 (95% CI: 0.26–0.48); this value assesses this anthropometric index of the patient, referring to the median of the standard population
- decreased lung clearance index (LCI2.5) by 1.71 units (95% CI: −2.11 to −1.30); this index is a measure of ventilation heterogeneity that may be more sensitive than spirometry in detecting changes in lung function in childhood.
Trikafta/Kaftrio: Question of Price
Vertex has priced Trikafta at $311 500 per year for American cystic fibrosis patients, which is 6% and 14% more expensive than Symdeko and Orkambi treatments. This is the wholesale acquisition cost (WAC), i.e. excluding discounts and rebates.
In Europe, a yearly treatment with Kaftrio costs about €194 000.
Such an exorbitant price does not allow any patient to get access to the long-awaited highly effective cystic fibrosis treatment. But it nevertheless generates a decent stream of money for Vertex: in 2019, earnings on the four cystic fibrosis drugs were $4.0 billion; in 2020, they rose to $6.2 billion. Vertex is set to close 2021 with an even better financial performance: revenue is projected to be $7.4 billion to $7.5 billion.
EvaluatePharma predicts that Trikafta/Kaftrio sales will reach as much as $4 billion by 2024, significantly outperforming and weaning demand for other Vertex’s drugs for cystic fibrosis.
According to calculations by the U.S. Institute of Clinical and Economic Review (ICER), the fair cost of Trikafta/Kaftrio should fall within the range of $67 900–79 900 per year, a reduction of 74–78%.
Of course, in a free market, no one has the right to tell Vertex what price tags it should charge for the cystic fibrosis drugs that are so necessary to mankind.
Moreover, it is categorically strange to perceive any pharmaceutical company as something abstract, virtual, and limited to the good and encouraging news coming from its PR department. We should never forget that behind any pharmaceutical company there are specific people, be they founders, investors or shareholders. And they want to make money, faster and more each time. The main concern and crown of the concept and essence of the pharmaceutical business is infinite profit growth and maximum expense reduction. Everything else tends asymptotically to zero.
Every business puts its own interests first. Altered by some severe or chronic illness, the value judgment of patients and their loved ones leads to the disappearance of critical thinking about pharmaceutical companies. Yes, they directly target and work with the most precious thing in everyone’s life — their health. But this treasure is extremely personalized, being important only to the individual. Businesses, on the other hand, have a bitter cold and undying peace of mind about it. Remember, health is nothing more than a point of application and the specificity of business practices in the pharmaceutical industry. And the key to understanding the situation is to acknowledge this without any circumlocutions.
Of course, this in no way implies that behind the mask of virtue of the pharmaceutical business lurks an indulgent monster. No, it is merely diligent in taking care of itself — read: the well-being of its owners. And it does so diligently, assiduously, and sometimes zealously.
Trikafta/Kaftrio: What’s Next
For the foreseeable future, Trikafta/Kaftrio patient coverage will expand by lowering the age bar for therapy-eligible patients. To this end, the NCT04537793 phase 3 clinical trial evaluating Trikafta/Kaftrio in cystic fibrosis children younger than 6 years (2 to 5 years) is underway.
Cystic Fibrosis: Hope for Complete Cure
It should be understood that Kalydeco, Orkambi, Symdeko/Symkevi, and even Trikafta/Kaftrio may not work in some cases, even if the patient should respond to the drug administration according to the available in vitro data. Moreover, the therapeutic response sometimes differs significantly among people with the same CFTR mutation. Such variability is thought to be related to genetic variants at and outside the CFTR locus.
And that’s why Vertex is making massive efforts to improve the effectiveness of cystic fibrosis treatment in one way or another.
Thus, Vertex is testing a new triple therapy regimen for cystic fibrosis that will be administered once a day — as opposed to Trikafta/Kaftrio, which is prescribed in the morning and evening. The regimen, which is expected to be more effective than Trikafta/Kaftrio, consists of three drugs, namely the CFTR potentiator VX-561 and two CFTR correctors, tezacaftor and VX-121.
VX-561, or deutivacaftor, is a deuterium chemically altered ivacaftor. The experimental drug compound, purchased from Concert Pharmaceuticals, is more stable in vitro and therefore has an extended half-life. Deuterium differs from hydrogen in having an additional neutron, which gives it the ability to form more stable chemical bonds with carbon, they are six to nine times stronger than those between hydrogen and carbon. Such a characteristic has a positive effect on the metabolism of the drug compound.
The clinical program for the new cystic fibrosis treatment regimen relies on two phase 3 trials, NCT05033080 and NCT05076149, among patients aged 12 years and older who are heterozygous or homozygous for the CFTR mutation F508del or characterized by the presence of a CFTR mutation that responds to Trikafta/Kaftrio.
Vertex also hopes to cure literally all patients with cystic fibrosis. To that end, CRISPR Therapeutics, Arbor Biotechnologies, and Affinia Therapeutics are partnering to test CRISPR-Cas9 genome editing technology that will cover the remaining 10% of patients who are not helped by Trikafta/Kaaftrio. And a friendship with Moderna is rolling out the VXc0522 mRNA approach, which involves inhaled delivery to the lungs of genetic instructions encoding normal CFTR protein synthesis.
Extras
Trikafta (elexacaftor + tezacaftor + ivacaftor, ivacaftor). Prescribing information. US. [PDF]
Kaftrio (elexacaftor + tezacaftor + ivacaftor). Prescribing information. Europe. [PDF]