Results announced this week of a clinical trial testing the drug dupilumab, made by the biotechnology company Regeneron Pharmaceuticals (REGN) and global pharmaceutical company Sanofi (SNY) gave hope to asthma sufferers and got the attention of industry analysts. "This could be a true blockbuster that really provides a game-changing therapy for a lot of patients with a lot of need," George Yancopoulos, Regeneron's CEO, told the online newsletter Fierce Biotech, While the findings are medically and financially promising, the science behind the study suggests some limitations, yet also other opportunities for the drug.
The clinical trial tested dupilumab on adult patients with moderate and severe asthma against a placebo. The trial was an intermediate-stage study that tested the drug for effectiveness and safety on a relatively small sample, in this case 104 patients who were not able to control their asthma with conventional treatments. The sample was divided evenly and randomly between those receiving the drug or a placebo, injected in doses of 300 milligrams once a week for 12 weeks.
The findings, published in the New England Journal of Medicine and presented at the annual meeting of the American Thoracic Society, showed a sharp difference between the drug and placebo groups in controlling asthma attacks, known as exacerbations. While only 3 of the 52 patients receiving dupilumab experienced exacerbations, 23 of the 52 placebo patients had asthma attacks, nearly 8 times the rate of the patients receiving the drug. The study also reported statistically significant improvements between dupilumab and placebo recipients in other indicators of lung function and asthma symptoms.
Asthma is a widespread chronic disease that has so far frustrated scientists in finding a cure. The disease is believed to be caused by a combination of inherited and environmental conditions, such as allergens (e.g., pollen, mold) and tobacco smoke, that cause the airways in the lungs to become inflamed and contract, reducing the amount of air entering or leaving the lungs. This inflammation results in recurring periods of wheezing, shortness of breath, tightness in the chest, and coughing.
World Health Organization estimates some 235 million people suffer from asthma, and while it has a relatively low fatality rate compared to other chronic diseases, more than 8 in 10 asthma deaths occur in lower income countries. In the U.S., the Centers for Disease Control and Prevention estimates nearly 26 million people have asthma, divided between 19 million adults and 7 million children. African-American children are twice as likely to have asthma as white children.
Blocking the chain reaction
Dupilumab, developed initially by Regeneron and licensed to Sanofi for clinical testing and commercialization, addresses immune system features of asthma. One of Regeneron's markets is diseases related to inflammation, one of the ways the immune system reacts to infection. In the case of asthma, the inflammation occurs in the airways, and believed to result from a series of reactions causing an overproduction of a type of white blood cell, known as type 2 helper T-cells. This chain reaction triggers an out-of-control proliferation of inflammatory responses.
The drug dupilumab blocks the actions of immune system cells believed to start this chain reaction. Dupilumab is an antibody that activates areas on cells known as receptors for the gene interleukin 4 and a close relative interleukin 13 that sends signals to temper or alter type 2 helper T cells, the cells that trigger inflammation. The inflammation in the case of asthma in the airways, but the same biological pathway in the body also controls some skin inflammations, such as those resulting in eczema.
The clinical trial results suggest dupilumab can be an effective tool for controlling -- but not curing or preventing -- asthma by reducing the occurrence of exacerbations suffered by people with the condition. Not as widely reported, however, was the high occurrence of side effects in clinical trial participants. Large majorities of both the dupilumab (81%) and placebo (77%) patients experienced adverse reactions.
While the events were characterized as moderate to mild, they included injection site reactions, inflammation of nose and throat passages, upper respiratory tract infections, headache, and nausea. The high incidence of side effects would need to be addressed in later trials and possibly changes in the drug's formulation requiring less-frequent injections.
In addition, the trial's results, while encouraging, were limited to adults with moderate to severe forms of the disease who were not responding well to other control strategies. While that makes the findings no less meaningful for these asthma sufferers, dupilumab still needs to be formulated and tested with children, who represent more than 1 in 4 asthma sufferers in the U.S., as well as adults with milder forms of the disease.
More than just asthma
At the same time, the underlying biology of dupilumab suggests it could be a treatment for atopic dermatitis, a condition popularly known as eczema, an itchy skin inflammation that sometimes accompanies asthma. Like asthma, the cause of atopic dermatitis is unknown and symptoms of the disease flare-up periodically. A 2007 study found between 6 and 11 percent of the U.S. population suffers from atopic dermatitis, and about two-thirds of people with the disease experience moderate to severe symptoms.
Sanofi and Regeneron are recruiting participants for a clinical trial of dupilumab to treat atopic dermatitis. The trial is an intermediate-stage study of 240 patients with moderate to severe forms of the disorder at 74 sites in the U.S., Canada, Europe, and Japan. The study will test dupilumab against a placebo, but also at five dosing levels.
The companies plan as well further tests of dupilumab as a treatment for controlling asthma. A new clinical trial will enroll some 600 patients, although the locations have not yet been disclosed. The new trial will test the drug with adults against a placebo, as well as in different combinations with conventional control treatments.
The collaboration between Sanofi and Regeneron began in 2003 to develop Zaltrap, a drug given intravenously for metastatic colorectal cancer, approved by FDA in August 2012 for sale in the U.S. The companies expanded their partnership to antibodies in 2007, where Sanofi licenses the output of Regeneron's antibody discovery technology. In the first three years of the partnership, the companies took five antibodies to clinical trials.
In 2009, Sanofi and Regeneron further expanded the collaboration to advance as many as 30 new antibodies to clinical testing by 2017, for which Sanofi is paying $160 million. Under the agreement, say the partners, the two companies share expenses, with Sanofi funding development costs up front and Regeneron reimbursing half of the development costs from its share of future profits. The companies will share profits from the U.S. equally, while profits from outside the U.S. will be divided on a sliding scale.