Berotralstat - Indications, Uses, Warnings, and Drug Interactions

Overview:

Berotralstat is a oral medication prescribed to prevent recurrent attacks of hereditary angioedema (HAE) in children 12 years and older. Berotralstat, developed by Biocryst pharmaceuticals, is the first oral drug that is a non-steroidal option that has been made available for HAE patients. Initially, prevention of episodes of HAE was possible only by taking medications in the form of injections or infusions. Therefore, the introduction of oral therapy has been a boon for patients in helping them lead independent and active lives.

The United States Food and Drug Administration (FDA) has approved the use of Berotralstat in HAE patients. The approval came after a positive outlook of the drug in helping patients overcome the symptoms. Phase 3 APeX-2 trial (NCT03485911) and Phase 2/3APeX-S trial (NCT03472040) evaluated the drug's safety in subjects older than 12 years of age. APeX 2 trial tested two doses of Berotralstat versus a placebo in 121 HAE patients who had at least two attacks of HAE eight weeks before the start of the trial. Both doses of Berotralstat were proven to work effectively, with the 150 mg dose significantly reducing the attack rate from 2.35 to 1.51 per month. These reduced attacks were sustained for 48 weeks, which reduced the frequency from 2.9 episodes to one episode per month.

Patients reported improved quality of life and satisfaction in receiving an oral dose of the medicine compared to regular shots of injections. In addition, studies suggested an enhanced tolerance to the therapy, with the most common side-effect being gastrointestinal effects, which were observed to get better with time and typically resolved by themselves.

How Does Berotralstat Work?

Berotralstat is a molecule that blocks the action of plasma kallikrein, which is a precursor for an inflammatory molecule called bradykinin. Excess production of bradykinin in patients with HAE leads to sudden and recurrent episodes of swelling. By suppressing the effects of plasma kallikrein, the medicine reduces the effects of bradykinin, thereby treating and preventing the symptoms of HAE.

What Are the Indications and Uses of Berotralstat?

Berotralstat is an oral prescription medicine that prevents recurrent swelling attacks in patients of HAE older than 12 years. There is not much information available about the use of the drug in children less than 12 years. Also, Berotralstat is not recommended in treating acute attacks of HAE. Extra capsule doses are non indicated as they can trigger potential problems in heart rhythm due to QT prolongation.

Dosage and Administration:

The recommended dosage of Berotralstat varies among different conditions. Below are the recommended dosages of the drug.

1. Recommended Dosage: The recommended dosage of Berotralstat is a 150 mg capsule to be taken orally once daily with food.

2. Recommended Dosage in Patients With Hepatic Impairment: No adjustment of the dosage is required in patients with mild hepatic impairment. However, in patients with moderate to severe hepatic impairment, one capsule of 110 mg must be taken daily with food.

3. Recommended Dosage With Concomitant Use With P-gp or BCRP Inhibitors: In patients with long-term administration of P-gp or BCRP inhibitors like Cyclosporine, the recommended dosage of Berotralstat is a 110 mg capsule that is to be taken orally once daily with food.

4. Dose Adjustment in Patients With Persistent Gastrointestinal (GI) Reactions:

GI reactions can occur as adverse effects of the intake of Berotralstat. A reduced dosage of 110 mg once daily with food is recommended in such patients.

Dosage Forms and Strengths:

The medicine is available in the form of capsules. There is a slight variation in the color of the capsules of different dosages.

• 150 mg capsule has an opaque white body with a black imprint of "150" and a light blue opaque cap with a black imprint of "BCX."

• 110 mg capsule has a light blue opaque body and cap, with a white imprint of "110" on the body and a white imprint of "BCX" on the cap.

Contraindications:

There are no contraindications for the use of Berotralstat.

What Are the Warnings and Precautions for Berotralstat Use?

Berotralstat is not recommended for use in cases of acute HAE. Additional doses, or doses higher than the recommended 150 mg capsule once daily, are not advised. An increase in QT interval was observed in patients taking higher doses, and the irregularity of the heart rhythm was concentration-dependent.

Adverse Effects:

The adverse effect noted with the use of Berotralstat is a prolongation of the QT interval. The adverse effects reported in clinical trials cannot be directly compared to data observed in clinical practice, as results can vary. However, based on age, sex, and location, the safety of the drug has been proven to be similar among all subgroups of patients.

Side effects of the gastrointestinal system, like abdominal pain, vomiting, and diarrhea, were observed more commonly in patients receiving 150 mg of Berotralstat when compared to those receiving 110 mg or placebo. The reactions started early after the initiation of treatment, became less severe with time, and typically resolved on their own. Zero patients in the Berotralstat 150 mg dosage group and one in the 110 mg dosage group discontinued treatment midway due to severe GI reactions.

Less Common Adverse Effects:

Less adverse side effects that were noted in patients treated with high doses of Berotralstat included headache (9%), fatigue (6%), and flatulence (6%). The occurrence of the above adverse effects was on a slightly higher end when compared to the placebo group.

Laboratory Anomalies:

Clinical trials showed an elevation of the transaminase levels, with ALT levels eight times higher than the standard upper limit and AST levels three times higher than the normal upper limit. However, no patient reported any severe adverse reactions due to an elevation of transaminases.

For Patients:

What Do You Need to Know About Hereditary Angioedema (HAE)?

Hereditary angioedema is a rare genetic condition that causes recurrent and severe skin and mucous membrane swelling. Swelling can occur in different body parts during different attacks. Also, more than one body part may be affected during an attack. HAE is believed to affect one in 10,000 to one in 50,000 people. There is no cure for the condition, and the only way to prevent recurrent symptoms is by taking oral Berotralstat capsules, thereby decreasing the frequency of symptoms.

What Are the Causes of Hereditary Angioedema?

The most important cause of the occurrence of HAE is due to a defect in the gene C1 inhibitor that codes for plasma kallikrein, a precursor for bradykinin. Elevated levels of bradykinin trigger swelling in body parts due to the seepage of fluid from the blood vessels into the tissue spaces. Eighty percent of cases have been reported due to the inheritance of defective genes, whereas 20 percent of cases have occurred due to spontaneous mutations. In addition, however, research has suggested a type of HAE that occurs due to an increase in estrogen levels during pregnancy and the use of birth control pills.

What Are the Treatment Options for Hereditary Angioedema?

There is no cure for the condition. Treatment focuses on reducing the recurrence of frequent attacks and treating the symptoms. Medications like Epinephrine, antihistamines, and corticosteroids that are usually used for treating allergic conditions like swelling and itching do not work for HAE. Berotralstat is the only medication to be taken once daily, which helps prevent recurrent bouts of swelling. The drugs currently being used to treat HAE include Berinert, Cinryze, Haegarda, Ruconest, Firazyr, Kalbitor, and Takhzyro.

What Information Should Be Conveyed to the Health Care Provider Before Starting Berotralstat?

The health care provider must be kept informed about all the medical conditions, which include information like:

• Liver disorders.

• Undergoing dialysis treatment.

• Pregnant, or plan to get pregnant.

• Breastfeeding, or plan to breastfeed.

Also, patients must inform the health care providers about all the medications that they take, which can include prescriptions for HAE, OTC (over-the-counter) medicines, vitamins, or herbal supplements. Sharing this information is essential as Berotralstat may affect how certain medicines work, and other drugs may interfere with the actions of Berotralstat. Therefore, a list of medications to be shown to the doctor or pharmacist is recommended.

For Doctors:

Drug Interactions:

This part explains clinically relevant interactions that occur between Berotralstat and other medications.

1. Potential for Berotralstat to Affect Other Medications:

Berotralstat can influence the actions of other drugs that include:

P-gp Substrates: Berotralstat at a dosage of 300 mg inhibits the actions of P-gp substrates like Digoxin. Hence, appropriate dosage and dose titer monitoring is recommended while prescribing P-gp inhibitors along with Berotralstat.

CYP2D6 and CYP3A4 Substrates: Berotralstat at a dosage of 150 mg moderately inhibits CYP2D6 and CYP3A4. During prescribing associated medications in which slight variations in the dosage can lead to significant adverse effects (narrow therapeutic index), which are metabolized by CYP2D6 (like Thioridazine and Pimozide) or CYP3A4 (like Cyclosporine and Fentanyl), appropriate monitoring and dose titration is required.

2. Potential for Other Medications to Affect Berotralstat:

P-gp or BCRP Inhibitors: Berotralstat is a P-gp and BCRP substrate. In patients with a long-term administration of P-gp and BCRP inhibitors like Cyclosporine, a dosage of 110 mg of Berotralstat is recommended.

P-gp Inducers: Concomitant use of P-gp inducers like Rifampin, St. John's wort, and Berotralstat is not recommended, as P-gp inducers decrease the plasma concentration of the drug, thereby affecting its efficacy.

Use of Berotralstat in Specific Populations:

A) Use in Pregnancy: There is no sufficient data available on the drug-related effects that occur if used during pregnancy. However, animal studies had shown no structural alterations when Berotralstat was administered orally to pregnant rats and rabbits, at dosages ten and two times more, respectively, than the maximum recommended daily dose for humans. In addition, studies suggested that there has not been a significant impact on the organogenesis of the fetus. The levels of Berotralstat in the fetal blood were 5 to 11 percent compared to the maternal blood levels. The estimated risk for significant congenital disabilities and miscarriages in the pregnant population of the United States has been 2 to 4 percent and 15 to 20 percent, respectively.

B) Use in Lactation: There is no evidence available on the presence of Berotralstat in human milk, nor its effect on milk production by the mother. Also, no effects have been noted in the breastfed infant. However, when the drug is present in animal milk, there are chances of its occurrence in human milk. Very low levels of Berotralstat were detected in the plasma of rat pups, the concentration being approximately two percent of maternal plasma. Therefore, multiple health and developmental advantages in the baby fed with breast milk must be weighed with the mother's clinical need for Berotralstat. Also, potential side effects in the infant due to the drug in the mother's milk or an underlying medical condition in the mother must be identified. Animal studies had shown no significant effects when Berotralstat was administered in doses equal to the maximum recommended daily dose for humans. Both rats and pups showed a statistically significant decrease in body weight gain.

C) Use in Pediatric Patients: The safe and effective use of Berotralstat has been established in pediatric patients of age 12 years and above. Prophylactic use of the drug in preventing recurrent episodes of attack in HAE patients has been proven effective. In addition, the safety and reduction of attack rates have been studied in the clinical trials conducted on adults and teens between the ages of 12 and under 18 years. However, the safe use of Berotralstat in children younger than 12 years of age has not been established.

D) Use in Geriatric Patients: The safe use and effectiveness of Berotralstat were assessed in a group of elderly patients aged equal to or more than 65 years as a part of clinical trial 1. The results of the study were found to be consistent with overall study results. In addition, the safety profile of the drug, when evaluated during trial 2 for five additional patients aged 65 years and above, also showed consistent results that matched with those of trial 1.

E) Use in Patients With Renal Impairment: A dosage requirement of Berotralstat is not required in patients with mild, moderate, or severe renal impairment. However, the effects of Berotralstat have not been studied in end-stage renal disease with CL-CR<15 ml or eGFR <15 mL/min/1.73 m2 or in patients on hemodialysis. Therefore, the use of the drug has not been recommended in such patients.

F) Use in Patients With Hepatic Impairment: According to studies, a dosage change is not recommended in patients with mild hepatic impairment. However, the dose has to be adjusted to 110 mg capsule once daily to be taken with food in patients with moderate to severe hepatic impairment.

Description:

Berotralstat capsule is a plasma kallikrein inhibitor that is represented as a dihydrochloride salt. The chemical name of Berotralstat is 1-[3-(aminomethyl)phenyl]-N-(5-{(R)-(3-cyanophenyl)[(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide dihydrochloride.

Berotralstat hydrochloride is a white to off-white powder having a molecular weight of 635.49. The molecular formula of the drug is C30H26F4N6O.2HCl. The powder is soluble in water at a pH of less than or equal to 4. Berotralstat is available as 150 mg, and 110 mg hard gelatin capsules recommended for oral use. The capsule consists of active and inactive ingredients that include:

Active Ingredient: Berotralstat dihydrochloride.

Inactive Ingredients: Colloidal silicon dioxide, Crospovidone, magnesium stearate, and pregelatinized starch.

Clinical Pharmacology:

Mechanism of Action:

Plasma kallikrein is a protease that binds to high-molecular-weight-kininogen (HMWK) and breaks it down to cleaved high-molecular-weight-kininogen (cHMWK) and bradykinin. Bradykinin is an effective vasodilator that increases the blood vessels' vascular permeability, leading to pain and swelling, a common symptom of HAE patients. A deficiency or dysfunction of C1-inhibitor (C1-INH) leads to improper regulation of plasma kallikrein, leading to its elevated blood levels. An uncontrolled increase in the plasma kallikrein activity causes high levels of bradykinin that lead to recurrent bouts of angioedema. Berotralstat is a plasma kallikrein inhibitor that binds to plasma kallikrein, inhibiting its proteolytic activity. Thereby, it controls the excess bradykinin that is produced, leading to an improvement in the symptoms.

Pharmacodynamics:

Oral administration of Berotralstat once daily in HAE patients has shown inhibition of plasma kallikrein, which was concentration-dependent. In addition, there was a reduction from the baseline level of specific enzyme activity.

Electrophysiology of the Heart: There is no noted prolongation of the QT interval to a clinically noticeable extent when there is an administration of the recommended dosage of 150 mg. However, at three times the recommended dosage, the mean increase in QTcF (Fridericia's Correction Formula) showed 15.9 msec (23.5 msec). Also, the increase observed in QTcF was dependent on the drug concentration.

Pharmacokinetics:

Exposure to Berotralstat is found to increase to a greater level than proportionally with the dose, and also, a steady state of the drug is reached in the body within six to 12 days. Post-once-daily dose administration noted that exposure to the drug was five times that of a single dose.

The pharmacokinetics of the drug were similar when clinical studies were conducted on both healthy adult subjects as well as HAE patients.

Absorption: The time taken to reach a maximum plasma concentration after taking the Berotralstat capsule was observed to be five hours, ranging from one to eight hours. Administration of Berotralstat with a high-fat meal did not show any significant differences in the time period of Cmax (maximum serum concentration of the drug) and AUC (area under the curve) of the drug.

Distribution: Binding to the plasma proteins has been noted to be 99 percent. Also, the blood-to-plasma ratio after administering a single dose of radiolabeled Berotralstat 300 mg was around 0.92.

Metabolism: The enzymes CYP2D6 and CYP3A4 are responsible for the metabolism of Berotralstat. Studies have shown that after the administration of a single dose of radiolabeled Berotralstat releases eight metabolites that have total plasma radioactivity of 34 percent, with each metabolite accounting for between 1.8 and 7.8 percent of the total plasma radioactivity.

Elimination: The biological half-life of Berotralstat was studied to be approximately 93 hours, ranging from 39 hours to 152 hours.

Excretion: After administration of a single radiolabeled dose of Berotralstat 300 mg, the excretion of the drug was found to be 79 percent in the feces, and approximately 9 percent in the urine, out of which 3.4 percent has remained unchanged.

Pharmacokinetics in Specific Populations:

A patient's age, gender, race, and body weight significantly influence the drug's systemic distribution.

In Geriatric Patients: Pharmacokinetic analytic studies conducted in an elderly population in the age groups of 65 years to 74 years have not shown a significant clinical impact due to systemic exposure to the drug.

In Pediatric Patients: Population-based pharmacokinetic analytic studies in which pediatric patients in the age groups of 12 to less than 18 years of age, who were administered a daily dose of 150 mg Berotratstat, showed an exposure at a steady rate which was about 20 percent higher than in that of adults. A steady-state concentration is when the amount of drug absorbed by the body is the same amount that gets cleared from the body on continuous administration. The high exposure in children, compared to adults, is, however, not clinically meaningful (improvements that are noticeable to the patient).

In Patients With Renal Impairment: Pharmacokinetics of a single dose of 200 mg Berotralstat given orally were documented in patients with severe renal impairment compared with concurrent cohorts; no clinically significant differences were noted. In addition, the maximum plasma concentration (Cmax) was increased up to 47 percent, and the area under the curve (AUC) was increased by 14 percent. However, the drug's pharmacokinetics has not been studied in subjects with end-stage renal disease.

In Patients With Hepatic Impairment: Studies have been conducted to assess the pharmacokinetics of a single oral dose of 150 mg Berotralstat in patients with mild, moderate, and severe hepatic impairment. Compared to people with normal hepatic function, the pharmacokinetics were found to have remained unaltered in patients with mild hepatic impairment. In patients with moderate liver dysfunction, the Cmax levels were increased by 77 percent, and AUC levels were increased by 78 percent. In severe hepatic impairment patients, Cmax levels were increased by 27 percent, and AUC was decreased by 5 percent. Compared to healthy HAE subjects, the median half-life, or the time required for a substance to reduce to half, was increased in both moderate and severe hepatic impairment patients by 37 and 22 percent, respectively. In addition, the percentage of free (unbound) Berotralstat has been found to have increased from 1.2 percent in healthy subjects to 2.4 percent in subjects with severe hepatic impairment.

Drug Interaction Studies:

Effects of Berotralstat on the Pharmacokinetics of Other Drugs:

A once-daily dose of 150 mg Berotralstat is a weak inhibitor of CYP2C9 (substrate Tolbutamide) and CYP2C19 (substrate Omeprazole) and a moderate inhibitor of CYP2D6 (substrates Dextromethorphan and Desipramide) and CYP3A4 (substrates Danazol, Midazolam, and Amlodipine).

Berotralstat, when administered at a dosage of 300 mg, is an inhibitor of P-gp (substrate Digoxin) and is not an inhibitor of BCRP (substrate Rosuvastatin).

Effects of Other Drugs on the Pharmacokinetics of Berotralstat:

Betrotralstat is a BCRP transporter and P-gp substrate. When administered with P-gp and BCRP inhibitors like Cyclosporine, it increased the Cmax of Berotralstat by 25 percent and AUC by 55 percent.

Non-Clinical Toxicology:

Carcinogenesis: A two-year study on Wistar rats and a 26-week study on Tg.rasH2 transgenic mice was conducted to determine the carcinogenic effects of the drug Berotralstat. Dosages of 20 mg/kg/day and 50 mg/kg/day were approximately administered to the rats and mice. There was no reported evidence of tumorigenicity in either of the species.

Mutagenesis: There has been no incidence of genetic mutations upon using Berotralstat, which was confirmed in the in vitro chromosomal aberration assay done in human peripheral lymphocytes, Ames test (in-vitro bacterial reverse mutation assay, in vivo micronucleus assay in rats.

Fertility Impairment: Fertility studies have been conducted on rats to determine the effects of Berotralstat. The rats were administered oral doses of the drug up to 45 mg/kg/day, approximately two times the maximum recommended human daily dose, on an mg/m2 basis during the study. It was concluded that there were no effects on the fertility of male and female rats.

Clinical Studies:

A clinical study was conducted on 120 adult and teen subjects above 12 years of age to determine the efficacy of Berotralstat in preventing attacks of hereditary angioedema. The study was used to assess the drug's actions in both Type 1 and 2 HAE patients and was a randomized, multicenter, placebo-controlled, double-blind, parallel-group study. Subjects were divided into three random groups in a ratio of 1:1:1 and administered Berotralstat 110 mg, Berotralstat 150 mg, and placebo administered orally, once daily with food for 24 weeks.

The subjects were asked to discontinue the use of prophylactic HAE medications before the start of the study. However, they were allowed to use emergency medications for the treatment of untoward episodes of HAE. 75 percent of the enrolled subjects reported using long-term prophylactic medications before the start of the study. Also, 74 percent of patients reported a history of attacks causing laryngeal angioedema. About 70 percent of the enrolled subjects confirmed baseline attacks of two or more per month.

The use of Berotralstat 150 mg and 110 mg has shown a significant reduction in the frequency of attacks compared to the placebo group. In addition, regardless of the frequency of episodes before the start of the clinical study, there was a significant decrease in the attack rates in subjects who were administered 150 mg and 110 mg single-dose oral Berotralstat compared to subjects of the placebo group.

About 58 percent of patients who were administered 150 mg and 51 percent who were administered 110 mg of the drug showed a reduction of equal to or greater than 50 percent of HAE attacks compared to the baseline attack rate. Post-study, 50 and 23 percent of subjects who received 150 mg dosage and 27 and 10 percent of subjects who received 110 mg dosage of the drug showed a 70 to 90 percent reduction in the attack rate compared to the baseline. In addition, attacks rated as moderate and severe were reported to have reduced to 40 and 10 percent in patients who received 150 mg and 110 mg, respectively.

Storage and Handling:

The supply and storage of Berotralstat capsules are as follows:

• 150 mg capsule of Berotralstat with an opaque white body with a black imprint that reads "150" and a light blue cap with a black imprint that reads "BCX."

• 110 mg capsule of Berotralstat with a light blue opaque body and cap, having "110" in a white imprint on the body and a "BCX" white imprint on the cap.

• Each carton contains four child-resistant shell packs containing a 28-day supply of the drug.

• Each shell pack contains a 7-capsule blister card.

• There is a tamper-evident seal on each carton. The carton should not be used if the tamper-evident seal is missing or broken.

• The drug must be stored at 20 degrees Celsius to 25 degrees Celsius (68 degrees Fahrenheit to 77 degrees Fahrenheit). Excursions are permitted between 15 degrees Celsius and 30 degrees Celsius.

Patient Counseling Information:

Healthcare providers must inform patients about the benefits and risks of Berotralstat before prescribing or starting to administer the drug. Also, patients must be advised to read the FDA-approved patient labeling before beginning the medication.

1. Drug Interactions: Patients must be informed about drug interactions that occur when Berotralstat is taken along with certain other drugs. Therefore, they must notify their healthcare providers about the other prescription, non-prescription, or herbal medications that they are using.

2. Contraindicated for Acute HAE Treatment: Patients must be explained not to take the medication for acute HAE attacks and continue using the same rescue medicines they have been using for such attacks. Also, they have to be informed that the safety of using Berotralstat is yet to be established in treating acute attacks. Also, patients must be advised not to take additional doses or doses higher than 150 mg for treating severe HAE, as it can lead to disturbances in heart rhythms (prolongation of QT interval).