Takhzyro (lanadelumab) is an injectable therapy that’s approved for preventing swelling attacks in children and adults with hereditary angioedema (HAE).
The therapy, which is administered via a subcutaneous or under-the-skin injection, was originally developed by Dyax and later acquired by Shire, now a part of Takeda.
Prevention of swelling attacks in HAE
How does Takhzyro work?
In HAE, swelling attacks are caused by the overproduction of a molecule called bradykinin that promotes blood vessel dilation and increases blood vessel permeability.
Takhzyro is a monoclonal antibody designed to bind to and block kallikrein, an enzyme that’s needed to produce bradykinin from its precursor molecules. Specifically, kallikrein works to cleave, or split, a molecule called high-molecular-weight-kininogen (HMWK) into two pieces: cleaved HMWK and bradykinin.
By inhibiting kallikrein, Takhzyro prevents this cleavage from occurring, causing less bradykinin to be produced, and thereby reducing the frequency of swelling attacks.
Who can take Takhzyro?
Takhzyro was first approved by the U.S. Food and Drug Administration (FDA) in August 2018 for the treatment of adults and adolescents, ages 12 and older, with HAE. With that decision, it became the first monoclonal antibody to be approved for this indication in the country. The FDA expanded that indication in February 2023 to extend the use of Takhzyro to children as young as age 2.
In the European Union, Takhzyro also has been approved as a routine preventive HAE treatment for adults and adolescents, ages 12 and older, since November 2018. In November 2023, its indication also was expanded in the EU to include children as young as age 2.
Takhzyro also is approved for similar indications in a number of other countries, including Australia, Canada, China, and Japan.
Takhzyro comes as a slightly opaque, colorless to slightly yellow solution without visible particles that is administered as a subcutaneous injection at an age-based dose:
Individuals ages 12 and older should receive 300 mg once every two weeks, administered by the patient or caregiver.
Patients ages 6-11 are to be given 150 mg every two weeks, administered by a healthcare provider or caregiver.
Children ages 2-5 with HAE should receive 150 mg every four weeks, or roughly once per month, administered by a healthcare provider or caregiver.
For patients ages 6 and older, dosing once every four weeks may also be considered if swelling attacks are well-controlled for more than six months with biweekly dosing.
The 150 mg dose comes in pre-filled, single-dose syringes containing 150 mg of Takhzyro in 1 mL of liquid. The 300 mg dose comes in either pre-filled syringes or single-use vials, each containing 300 mg of medication in 2 mL of liquid.
In either form, the medication should be stored in the refrigerator and protected from light, then taken out 15 minutes before use. Pre-filled syringes can be directly injected into a clean site on the abdomen, thigh, or upper arm.
If using the single-use vial, Takhzyro will be withdrawn from the vial using a needle suitable for subcutaneous injection. This prepared syringe should then be injected within two hours if stored at room temperature, or within eight hours if refrigerated.
Patients and caregivers who will administer Takhzyro should always first be properly trained.
Takhzyro in clinical trials
Takhzyro’s approval for adult and adolescent patients was mainly supported by findings from the Phase 3 HELP trial (NCT02586805), which tested the therapy’s safety and efficacy for HAE attack prevention in 125 patients, ages 12 and older.
Participants in HELP were randomly assigned to receive one of two Takhzyro doses or a placebo for about six months. The Takhzyro doses were 300 mg, given every two or four weeks, or 150 mg every four weeks.
All doses of Takhzyro were found to reduce HAE attack rates relative to the placebo, with the greatest reductions observed at the 300 mg dose taken every two weeks. That dose led to an 87% reduction in attacks relative to the placebo. Every patient treated at that dose experienced at least a 50% reduction in HAE attack rates, while 67% achieved at least a 90% reduction compared with the start of the trial. Moreover, 44% remained attack-free, compared with 2% of those given the placebo.
Additional analyses indicated the effects of Takhzyro were observed as soon as two weeks after patients started treatment, and were sustained throughout the trial. Takhzyro-treated patients also experienced significant and clinically meaningful improvements in life quality.
Most participants then joined an open-label extension study (NCT02741596), in which all could receive Takhzyro at a dose of 300 mg for up to 33 months, or just short of three years. Another 103 people not involved in the previous trial also were enrolled. Takhzyro again was associated with a mean 87% reduction in HAE attacks compared with pre-trial attack rates and life quality improvements.
The open-label Phase 3 SPRING trial (NCT04070326) evaluated Takhzyro in pediatric HAE patients, ages 2-11. Its findings backed the expansion of Takhzyro’s label to include children as young as age 2.
In the trial, 21 participants received 150 mg Takhzyro once every two weeks (ages 6-11) or every four weeks (ages 2-5) for one year. The patients receiving biweekly Takhzyro could switch to monthly dosing if they remained attack-free after six months.
The treatment was well tolerated and effective in younger patients, similarly to adults. The mean attack rate during treatment decreased by 94.8% from pre-trial values, with 76.2% of the participants remaining attack-free. Among the seven patients who switched from every-other-week dosing to monthly dosing, attacks remained well-controlled after the switch. Use of the therapy also was associated with improvements in life quality for patients and reductions in caregivers’ burden.
A Phase 3 trial (NCT04180163) tested Takhzyro’s safety and efficacy among 12 Japanese HAE patients, ages 12 and older. Takhzyro was similarly effective in these patients as in those participating in the HELP study, with the mean monthly attack rate dropping by 74% after one year.
The EMPOWER (NCT03845400) observational study evaluated Takhzyro’s real-world effectiveness among 102 HAE patients in the U.S. and Canada. Its findings indicated that as in the interventional trials, Takhzyro was associated with HAE attack rate reductions, improved life quality, and a favorable tolerability profile.
Designed similarly to EMPOWER, the ENABLE trial (NCT04130191) is looking at the real-world effectiveness of Takhzyro among 140 HAE patients in Austria, Germany, Switzerland, and other countries. The study is set to finish in September 2024.
An ongoing Phase 3 clinical trial (NCT05460325) is evaluating the effects of Takhzyro among HAE patients in China. An estimated 2o participants, ages 12 and older, will receive 300 mg Takhzyro every two weeks for about six months while being monitored for safety and HAE attacks. The trial is set to finish in June 2024.
Common side effects of Takhzyro
The most common side effects associated with Takhzyro include:
injection site reactions
upper respiratory infections
muscle pain, known as myalgia.
Allergic reactions to Takhzyro have been observed. If a severe reaction occurs, Takhzyro should be discontinued and appropriate treatment administered. Symptoms of an allergic reaction may include wheezing, difficulty breathing, chest tightness, fast heartbeat, faintness, rash, or hives.
Use in pregnancy and breastfeeding
There are no available data on the use of Takhzyro during pregnancy. Monoclonal antibodies such as Takhzyro can be transported across the placenta during the third trimester, and thus, risks to the unborn child may be greatest during that time. Patients should speak with their healthcare team if they are pregnant or may become pregnant while using Takhzyro.
Takhzyro has been detected in the milk of lactating monkeys, but there are no data on its presence in human breast milk or its effects on a breastfed infant. Patients and their doctors should weigh the potential benefits of the therapy and the risks to the child when making a decision on whether or not to breastfeed while taking Takhzyro.
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