April 8, 2019Rare Diseases
We are featuring the article below, in part, to applaud the cooperation of the NIH and our friends and colleagues at AstraZeneca.
Target Health will be meeting with FDA at the end of May and beginning of June for 2 very exciting programs in rare diseases; and more to follow.
Hypereosinophilic syndrome (HES) refers to a rare group of conditions that are associated with persistent eosinophilia with evidence of organ involvement. Signs and symptoms vary significantly based on which parts of the body are affected. Although any organ system can be involved in HES, the heart, central nervous system, skin, and respiratory tract are the most commonly affected. The condition was originally thought to be idiopathic or of unknown cause. However, recent advances in diagnostic testing have allowed a cause to be identified in approximately a quarter of cases. While most people have 0 to 500 eosinophils per microliter (uL) of blood, people with HES typically have more than 1,500 eosinophils/uL. The symptoms of HES vary widely from one patient to the next and can affect the heart, lungs, skin, gastrointestinal tract, central nervous system and other organ systems. Nearly all existing therapies for HES involve drugs that are not specifically approved for treating the syndromes, have significant side effects and sometimes become less effective over time.
The study reported below was only the second randomized, placebo-controlled trial to test the effectiveness of a drug specifically for treating HES. This finding comes from a small clinical trial led by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), and conducted through a partnership with the global biopharmaceutical company AstraZeneca. The results were published online in the New England Journal of Medicine (3 April 2019).
The medication tested in this Phase 2 clinical trial is benralizumab, also known by the brand name Fasenra. It consists of an antibody that binds to a protein, called IL-5 receptor a, found on the surface of eosinophils. It is hypothesized that once this binding takes place, immune cells called natural killer cells approach and destroy the eosinophils. In an earlier clinical trial, benralizumab safely improved the symptoms of people who have a form of asthma associated with an excess of eosinophils in the lungs. Subsequently, the FDA approved the drug for treating this condition, called severe eosinophilic asthma.
The NIAID trial involved 20 people with severe forms of HES who had at least 1,000 eosinophils/?L of blood when they enrolled in the study and whose condition had been stable on other HES therapies for at least a month before enrolling. These study participants all lacked a genetic marker associated with a type of HES that responds to treatment with a different drug. All study visits took place at the NIH Clinical Center in Bethesda, Maryland. The trial had three phases over a period of 48 weeks. At the start of the first phase, which lasted 12 weeks, study participants were assigned at random to receive either 30 mg of benralizumab or a placebo solution through an injection under the skin once every 4 weeks while continuing to take their current HES therapy. Neither the participants nor the investigators knew who was receiving the study drug or what the participants' eosinophil counts were during this first phase. In the second phase, which lasted from week 12 to week 24, all study participants were given 30 mg of benralizumab through an injection under the skin once every 4 weeks. Eosinophil counts were revealed beginning at week 13, and participants could taper their original HES therapy if doing so was tolerable. During the third phase, those participants whose symptoms or eosinophil counts had improved by week 24 could continue receiving benralizumab until week 48.
Results showed that at the end of the first phase, blood eosinophil levels were undetectable in nine of the 10 participants who received benralizumab and had declined by 50% or more in three of the 10 participants who received the placebo. While the use of an immunosuppressive drug explained why eosinophil counts declined in one of the placebo recipients, the reason for the decline in the other two placebo recipients is unknown. After at least 12 weeks of benralizumab therapy during the first phase, second phase or both, 17 of 19 participants had undetectable levels of eosinophils in the blood and a reduction in HES-related symptoms, with few or no side effects. (One person withdrew from the study at week 6 for logistical reasons.) These beneficial responses lasted through the end of the third phase in 14 of 19 participants, (74%). Nine of those 14 participants (64%) were able to taper off other HES therapies during the third phase. The 14 participants continued taking benralizumab for another year after completing the third phase. In addition, eosinophils were undetectable in the bone marrow of nine of the 10 participants in the treatment group in the first phase, and in the tissue of all eight participants whose tissue was tested at the end of the second phase.
A larger placebo-controlled trial of benralizumab for treating HES is needed to confirm these results, according to the study investigators.