While another storm that hit the East Coast of the U.S. served to delay the scheduled FDA Pulmonary-Allergy Drugs Advisory Committee (PADAC) meeting last week, South San Francisco-based Theravance Inc. and its partner GlaxoSmithKline plc, of London, shouldn't have too much longer to wait for what is predicted to be a positive review from the PADAC for their once-daily inhaled corticosteroid.

Certainly, Theravance seems to think so. In January the company completed a $287.5 million debt financing in preparation to make milestone payments to its partner GSK upon launch of their combination products developed under the two companies' 2002 collaboration around long-acting beta 2 agonists (LABAs) and bifunctional muscarinic antagonist-beta2 agonists (MABAs). (See BioWorld Today, Jan. 18, 2013.)

Theravance may also be receiving positive vibes from a January PADAC recommendation that clinical data included in a new drug application from Boehringer Ingelheim GmbH, of Ingelheim, Germany, provided substantial and convincing evidence to support the approval of olodaterol as a once-daily maintenance bronchodilator treatment for airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. (See BioWorld Today, Jan. 31, 2013.)

The Theravance/GSK COPD drug, previously called Relovair, which contains fluticasone furoate (FF)/vilanterol (VI) and has been tentatively branded as Breo in the U.S. and Relvar in Europe, has a PDUFA date of May 12. If approved, Breo will become GSK's extension for its blockbuster respiratory drug Advair (fluticasone/salmeterol).

Howard Liang, an analyst with Leerink Swann also had positive things to say, writing in a research note that "with risks already mitigated to some extent with its established mechanisms of action, Breo/Relvar has demonstrated the feasibility of once-a-day dosing."

FF/VI is an investigational once-daily inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) combination treatment that works by relaxing the muscles in the walls of the airways, allowing the airways to expand and lead to improved lung function in COPD and asthma patients.

Driving Market Growth

New long-acting beta agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are going to drive market growth in the respiratory area through the next decade, according to research by Decision Resources. They report that the market for COPD will gradually build to more than $13.4 billion in 2020 in the U.S., France, Germany, Italy, Spain, the UK and Japan.

While these emerging combination therapies and less frequent dosing regimens are significant developments in this disease area there is certainly room for other treatment strategies.

Patients with severe asthma have persistent symptoms despite treatment with high-dose steroid and other therapies.

With a large and growing patient population, the asthma market is one of the most lucrative drug markets in the pharmaceutical industry. Asthma affects more than 8 percent of the U.S. population causing significant societal and economic burden. It is a figure that is set to grow with lung diseases such as asthma and COPD on the rise, according to the American Lung Association and the National Institutes of Health.

Tough Time for Asthmatics

Spring is a particularly challenging time for asthmatics with its increasing pollen counts. With frequent use of corticosteroids patients run the risk of developing steroid-related side effects.

A variety of new treatment options are being investigated to help improve overall asthma control in patients with severe refractory asthma. As a result new potential therapies are beginning to emerge. Bispecific antibodies, which simultaneously recognize two different antigens, could hold significant therapeutic potential in respiratory diseases.

BioLineRx Ltd., of Jerusalem, for example, is developing BL-9010, a bispecific antibody treatment for severe and persistent asthma, that targets and links together two immunological modulators – IgE and CD300a. Allergen-bound IgE activates cells involved in allergic responses, such as mast cells, while CD300a inhibits immune responses. In research to date the company has found that BL-9010 significantly blocked allergic responses. Importantly, this could be reproduced in human mast cells, where BL-9010 was shown to inhibit the allergic reaction of these cells in-vitro. The human mast cells were activated by IgE molecules from allergic patients and by specific allergens, mimicking the human disease, while BL-9010 prevented the release of allergy-mediating substances by the cells.

KaloBios Pharmaceuticals Inc., of South San Francisco, said data from its Phase I/II study of KB002 (precursor chimeric anti-GM-CSF monoclonal antibody to KB003) in persistent asthma demonstrated preliminary safety, tolerability and signs of activity and support continued development of humaneered antibody KB003, which is in Phase II testing in severe asthma patients inadequately controlled by corticosteroids. (See BioWorld Today, Feb. 28, 2013.)

The KB002 study, which screened more than 50 patients to enroll both atopic (eosinophilic) and non-atopic (neutrophilic) asthma subjects, randomized 24 subjects (2:1, active treatment versus placebo). The objectives of the study primarily were to evaluate safety and tolerability, effects on sputum inflammatory markers, and lung function after a single dose of KB002. Mean FEV1 value for the active treatment group increased 120ml from baseline to day 42 and decreased 40ml for the placebo group.

KB002 and KB003 are recombinant monoclonal antibodies designed to target and neutralize human granulocyte macrophage colony-stimulating factor (GM-CSF), with potential for use in inflammatory and autoimmune indications.

Asthma Research

In the research arena studies of the immune system's role in the development of asthma will also lead to new therapies. A team from Brigham and Women's Hospital and Harvard Medical School has implicated activated innate lymphoid cells in the damage caused by asthma, and identified the molecule lipoxin A as a signal that naturally dampens the activity of those cells and so might be a therapeutic target in asthma.

Innate lymphoid cells are important for the rapid defense against bacteria and viruses, but like all components of the innate immune system, they need to be actively modulated over time to avoid chronic inflammation. The researchers found that this process apparently fails for several types of innate lymphoid cells, which continued to produce cytokines in the absence of any antigen that would warrant such production.

They also found that while some types of innate lymphoid cells are present at lower levels in asthmatic subjects compared to healthy controls, the cells that were present were more likely to be activated. In culture experiments, however, their activity could be reduced by treatment with lipoxin A4. (See BioWorld Today, March 4, 2013.)