Clinical Bulletin October 2020

Potential New Oral Therapy for Hereditary Angioedema

Berotralstat (BCX7353), is an oral inhibitor of plasma kallikrein in development for the prevention and treatment of hereditary angioedema (HAE). The manufacturer, BioCryst Pharmaceuticals, recently announced new data from the APeX-2 and APeX-S clinical trials, which showed that HAE patients taking oral, once-daily berotralstat experienced sustained decreases in their attack frequency and improvements in quality of life scores over 48 weeks. Berotralstat was also safe and generally well-tolerated over 48 weeks in both APeX-2 and APeX-S.

Highlights from the trials include:

• In the APeX-2 study, 31 patients who were randomized to 150 mg of oral, once-daily berotralstat at the beginning of the study and completed 48 weeks of therapy had a mean baseline attack rate of 2.9 attacks per month, which declined to 1.5 attacks per month after one month and to 1.0 attack per month at 12 months. • In the APeX-S study, patients completing 48 weeks of treatment on 150 mg of berotralstat (n=73) had a median attack rate of zero attacks per month in six of the 12 months, including month 12 (week 48). • The low attack rate experienced by HAE patients on 150 mg of oral, once-daily berotralstat reduced the burden of disease and translated into improvements in patient’s quality of life as measured by the mean angioedema questionnaire (AE-QoL). This effect was seen through the 48 weeks in the APeX-S trial.

An integrated 48-week analysis across both APeX-2 and APeX-S showed berotralstat to be safe and generally well tolerated in a total of 342 patients with a total of 232 patient-years of daily oral dosing. The most common adverse event was the common cold, which occurred with similar frequency in berotralstat and placebo patients. Gastrointestinal events led to discontinuation of berotralstat in 3.2 percent of patients. Drug-related serious adverse events occurred in less than 1% of the patient in the studies and resolved after stopping or interrupting the berotralstat therapy.

There are currently 7 products approved by the FDA for preventing and treating HAE attacks. A summary of these therapies is listed alphabetically below: Mechanism of HAE Route of Est. Annual Cost Brand Name Age Indication Action Treatment Admin of Therapy Berinert® C1 inhibitor Acute Adults & pediatric IV $352,000 C1 esterase Adults, adolescents & Cinryze® Prophylaxis IV $350,000 inhibitor pediatric B2 bradykinin Firazyr® Acute Adult SQ $355,000 receptor antagonist C1 esterase Haegarda® Prophylaxis Adults & adolescents SQ $273,000 inhibitor Kalbitor® Kallikrein inhibitor Acute ≥ 12 years SQ $506,000 Ruconest® C1 inhibitor Acute Adults & adolescents IV $310,000 Takhzyro® Kallikrein inhibitor Prophylaxis ≥ 12 years SQ $591,000

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Berotralstat may provide the first oral option for patients with HAE that could allow them to prevent HAE attacks and potentially reduce their overall burden of therapy. If approved, this may provide a non-injectable treatment option for patients and physicians. The FDA is expected to review berotralstat’s new drug application by December 3, 2020 and if approved, is expected to be immediately available in the U.S.

References:

1. https://www.globenewswire.com/news-release/2020/06/06/2044593/0/en/Long-term-48-week-Data-Show-Treatment- with-Berotralstat-Provides-Robust-and-Durable-Reductions-in-HAE-Attacks-and-Improvements-in-Quality-of-Life- Scores.html 2. https://ir.biocryst.com/news-releases/news-release-details/journal-allergy-and-clinical-immunology-publishes-results 3. https://www.haea.org/pages/p/ApprovedTreatments

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New Treatment Approved for the

Inmazeb® (atoltivimab, , and -ebgn) is the first treatment to be approved by the FDA on October 14, 2020 for (Ebola virus). The antibody cocktail is indicated for the treatment of adults and pediatric patients, including newborns of mothers who have contracted the viral . Inmazeb is administered as a single, weight-based intravenous infusion (50 mg atoltivimab, 50 mg maftivimab and 50 mg odesivimab per kg) over 2-4 hours.

Inmazeb was created using Regeneron’s VelocImmune® platform and associated VelociSuite® technologies. The treatment consists of three monoclonal antibodies of similar structure, atoltivimab, maftivimab and odesivimab, which bind to epitopes on the Zaire ebolavirus glycoprotein. The three antibody combination neutralizes the Ebola virus by blocking the virus from entering into host cells via the glycoprotein and/or enables antibody-dependent effector function by bringing in other immune cells to target infected cells, which is a way for an antibody to get extra help from the immune system in order to clear infected cells from the body.

The Ebola virus was first described in 1976 near the Ebola River in what is now the Democratic Republic of Congo. Since then, the virus has emerged periodically and infected people in several African countries. It is a rare and deadly disease in people and nonhuman primates. The virus replicates rapidly in humans and debilitates them quickly. It causes symptoms such as fever, hemorrhage, and difficulty breathing preventing the body from effectively producing an immune response that will slow or stop Ebola. Consequently, there is a race between the body's response and virus replication that Ebola wins in about 60% of infected patients. People can get Ebola through direct contact with an infected animal (bat or nonhuman primate) or a sick or dead person infected with Ebola virus.

The safety and efficacy of Inmazeb was established through the 681-patient PALM Trial, a randomized, multicenter, controlled trial initiated in 2018 in the Democratic Republic of the Congo (DRC). The WHO, the National Institutes of Health (NIH) and the Institut National de Recherche Biomédicale (INRB) in the DRC jointly sponsored and served as co-principal investigators of the trial. In 2019, as reported in the New England Journal of Medicine, the PALM Trial was stopped early following a pre- specified interim analysis that showed superiority of Inmazeb to ZMapp (anti-Ebola cocktail that is made up of three-part mouse and part human antibodies) and remdesivir with respect to mortality. Specifically, 34% of Inmazeb-treated patients had died by day 28, whereas 51% of control patients had died.

Adverse events that occurred in at least 10% of Inmazeb patients were chills, elevation in fever (pyrexia), rapid heartbeat (tachycardia), rapid breathing (tachypnea), vomiting, low blood pressure (hypotension), diarrhea and inadequate oxygen supply to the tissue (hypoxia); of these, only chills occurred more frequently with Inmazeb than ZMapp. The evaluation of adverse events in Inmazeb® patients may have been confounded by the signs and symptoms of the underlying Zaire ebolavirus infection.

1055 Westlakes Dr. Suite 175 Berwyn, PA 19312 | AscellaHealth.com | 877-389- 9040 Clinical Bulletin October 2020

Inmazeb is the first FDA approved treatment for the Ebola virus and represents an advancement as compared to prior used therapies. The FDA also approved Merck’s Ervebo, the first vaccine for the prevention of Ebola virus disease, in December 2019. Inmazeb and Ervebo illustrate two significant advancements for treatment and prevention that should reduce mortality in several African countries most susceptible to Ebola outbreaks.

Access to this therapy should assist in treating any outbreaks that may occur and Regeneron is providing the product under established protocols to lower income countries. It is interesting to note the study for Inmazeb was compared to therapy containing remdesivir, (Veklury®), recently approved by the FDA for the treatment of COVID-19 patients.

References: 1. Inmazeb Package Insert: https://www.regeneron.com/sites/default/files/Inmazeb_FPI.pdf 2. https://investor.regeneron.com/news-releases/news-release-details/regenerons-antibody-cocktail-regn-eb3- inmazebr-first-fda 3. https://www.pharmaceutical-business-review.com/news/regeneron-inmazeb-fda-approval-ebola/ 4. https://www.firstwordpharma.com/node/1765401?al=150d51- 665e38b7757949ea664cc843b57da27a%5E%7C%5EMTExMDAyOA%3D%3D%5E%7C%5ENQ%3D%3D&cp1=bmV 3c2xldHRlcl9yZWdpb25faWQ9bGVhZF9hcnRpY2xl

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