AstraZeneca: Pipeline And Partnerships
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|Product||2014 Sales||2013 Sales|
All sales are in millions of dollars.
In millions of dollars, except EPS
For AstraZeneca, if 2014 can be considered a year of rebuilding, 2015 is the continuation of those efforts, with even more development deals being made to buff up the pipeline. With a slight increase in sales but declines in net income and earnings per share in 2014, the company is predicting a lower revenue decrease than previously expected for 2015 and a slight increase in core earnings per share because of increased investment in R&D. And according to CEO Pascal Soriot, AstraZeneca will be back to growth in a few years.
“We strengthened and accelerated our pipeline, and increased the momentum behind our growth platforms,” Soriot says about the company in 2014. “Our efforts are creating significant value for patients and shareholders.
“AstraZeneca has completed the first phase in its strategic journey. We have rebuilt strong foundations for sustainable delivery and are on track to return to growth by 2017.”
According to Soriot, the company’s growth strategy comprises maximizing the potential of existing medicines; leveraging its global scale; and investing in growth platforms and key geographies.
One of the company’s key moves so far in 2015 is clearly aimed at the continuing rejuvenation of AstraZeneca’s pipeline. In August, the company appointed Sean Bohen MD, PhD, as executive VP of Global Medicines Development and chief medical officer. He joined the company in September.
Executives say Dr. Bohen will be responsible for driving the progress of AstraZeneca’s portfolio of small molecules and biologics investigational medicines through late-stage development to regulatory approval. As chief medical officer, he will be responsible for patient safety across the entire AstraZeneca and MedImmune portfolio. Dr. Bohen joined AstraZeneca from Genentech where he was most recently senior VP of Early Development.
“I’m delighted to welcome Sean to AstraZeneca at a very exciting time for our company,” Soriot remarks. “Our continued strategic investment in science is driving momentum across all therapy areas. Sean is a tremendous scientist and an accomplished drug developer. His impressive expertise in key areas of our exciting pipeline, including oncology and immunology, will further strengthen and accelerate the delivery of new medicines for patients. His extensive diagnostics experience will also reinforce our efforts in precision medicine.”
Financial and product performance
More than two-thirds of the company’s $26.1 billion in sales in 2014 – 1.5 percent more than sales in 2013 – were driven by its marketed brands in its main therapy areas. And AstraZeneca’s five growth platforms – Brilinta/Brilique, diabetes, respiratory, Emerging Markets, and Japan — are sustaining near-term growth as the company makes progress toward its long-term ambitions.
“These platforms accounted for more than half our revenues in 2014,” Soriot says. “We will continue to focus on driving growth in these areas, with the addition of oncology as a growth platform in 2015 as we navigate a period that will see some of our established products losing their exclusivity.”
The company’s net income in 2014 was $1.24 billion, about 52 percent less than the previous year. Earnings per share came in at 98 cents versus $2.04 during 2013. R&D costs went up to $5.58 billion, 15.7 percent more than in 2013.
In the first half of 2015, sales were $12.36 billion, 6.5 percent less than in the same period of 2014 but up 1 percent under constant exchange rates. Reporting operating profit was $1.86 billion, 1 percent more under CER but 5 percent less than in first-half 2014. Earnings per share were 99 cents, an increase of 2 percent under CER but 4 percent less than in the same period last year.
“We made good progress in the period, delivering a robust underlying business performance. This represents six successive quarters of top-line growth,” Soriot says. “The initiatives introduced to increase efficiency are starting to reduce SG&A costs, supporting our continued strategic investment in science and the acceleration of our pipeline which has positive momentum across all key areas.”
The company spent $2.82 billion on R&D in the first half of 2015, with core R&D costs going up 24 percent to $2.64 billion as AstraZeneca continued its accelerated investment in the pipeline. The company anticipates a lower growth rate in the second half of the year.
AstraZeneca’s five growth platforms – the oral antiplatelet drug Brilinta/Brilique, diabetes, respiratory, emerging markets, and Japan – were up 15 percent in 2014, contributing 53 percent of total revenue. In the first half of 2015, these platforms grew 11 percent compared with the same period last year, and represented 56 percent of revenue.
The company’s top-selling products in 2014, each with sales of more than $500 million, were Crestor, Symbicort, Nexium, Seroquel XR, Pulmicort, Zoladex, Synagis, Onglyza, Toprol-XL/Seloken, and Faslodex.
The cholesterol reducer Crestor was AstraZeneca’s leading sales producer in 2014 at $5.51 billion, about 2 percent less than in 2013. In first-half 2015, sales were $2.48 billion, about 5 percent less than in the same period last year. The dip in sales reflected ongoing generic competition and price pressures, executives say.
The asthma medicine Symbicort was the company’s second best-selling product in 2014, achieving $3.8 billion, 9 percent more than in 2013. During the first half of 2015, Symbicort sales were $1.69 billion, about 9 percent less than in first-half 2014. According to executives, first-half 2015 sales in Europe declined by 8 percent to $582 million, reflecting increased competition from recently launched analogue medicines, but grew 28 percent in emerging markets to $187 million.
The proton-pump inhibitor Nexium was the third-best-selling product for the company in 2014, with sales of $3.66 billion, 5.6 percent less than in 2013. Sales were 12 percent lower in the United States because of decreased volume and 13 percent lower in the rest of the world because of generic competition in many markets, destocking in China, and a packaging-related recall in Japan. For the first half of 2015, Nexium sales were 27 percent lower than in first-half 2014, amounting to $1.29 billion. Executives say this was due to loss of exclusivity in the United States in February 2015, but sales in emerging markets represent a key opportunity for the brand.
Fourth in sales was the depression medicine Seroquel XR. Sales of the drug slipped 8.5 percent from 2013, to $1.22 billion, affected by generic availability. In the first half of 2015, sales were $526 million, 7 percent less than in the same period last year. The decline was again driven by generic competition.
The asthma drug Pulmicort had sales of $946 million in 2014, making it AstraZeneca’s fifth best-selling drug. Sales were driven by 35 percent growth in emerging markets. In first-half 2015, sales totaled $518 million, 10 percent more than in first-half 2014. Growth was driven primarily by the performance of Pulmicort Respules in emerging markets, which were up 37 percent to $303 million. China product sales increased by 43 percent to $240 million, reflecting sustained investment in supporting asthma and COPD patients for several years, both in hospitals and more recently in the home.
Sales of the prostate cancer drug Zoladex, AstraZeneca’s sixth best-selling drug, were $924 million in 2014, 7.2 percent less than in 2013. Sales in the 2015 first half were up 9 percent to $409 million, with notable performances including growth of 36 percent in China where sales reached $60 million.
The RSV drug Synagis was the company’s seventh top drug in sales in 2014, with $900 million, 15 percent less than in 2013. The decrease was driven by a 9 percent decline outside the United States and a 19 percent decline in the United States, where a 29 percent reduction in volume was offset by favorable price adjustments. In first-half 2015, sales fell 28 percent to $270 million, reflecting a 38 percent decline in the United States where the majority of sales are made. A significant factor was lower demand related to the American Academy of Pediatrics Committee on Infectious Disease guidelines issued in mid-2014. These guidelines further restricted patients eligible for preventative therapy with Synagis. The impact is anticipated to continue in the second half.
Sales of the diabetes drug Onglyza grew from $378 million in 2013 to $820 million in 2014, making the product the company’s eighth best-selling drug. The sales growth reflected AstraZeneca’s February 2014 acquisition of Bristol-Myers Squibb’s interests in the companies’ diabetes alliance. In the first half of 2015, Onglyza sales were $391 million, 2 percent less in the first half of 2014 but up 4 percent under CER. In the United States, first-half sales were down 16 percent to $211 million, driven primarily by destocking and competition in the DPP-4 class, as well as changes in promotional activities for Farxiga. Sales in the rest of the world were $180 million, with growth in all key markets, notably in Europe where sales were $71 million, up 23 percent. Sales during the first half in emerging markets grew by 56 percent to $77 million.
Toprol-XL/Seloken sales for 2014 were $758 million, about the same as in 2013. Global Seloken sales in 2014 (excluding the authorized generic) were up 7 percent at CER to $715 million. Sales in the United States declined 31 percent at CER to $91 million and by 4 percent at CER in Europe, to $124 million. In emerging markets, sales went up 17 percent at CER to $524 million. In the first half of 2015, Toprol-XL/Seloken sales were $378 million, up 7 percent at CER but down 2 percent at actual.
Sales of the breast cancer drug Faslodex were $720 million in 2014, an increase of 5.7 percent. In the first half of 2015, Faslodex sales were $333 million, up 5 percent at CER but down 5 percent at actual. A 1 percent rise in European sales to $101 million was complemented by 2 percent growth in the United States where product sales reached $165 million. In emerging markets, sales of $42 million represented a growth rate of 32 percent, which executives say is an encouraging result alongside the regulatory approval of 500mg Faslodex in China during May 2015.
“In parallel with the pipeline transformation, and leveraging our global scale and commercial expertise, our business shape is changing to become more sustainable, durable and profitable,” Soriot says. “Biologics now account for nearly half our pipeline. This increases the probability of success of our projects and potentially enhances the longevity of our assets. A greater focus on innovative delivery devices can offer choice to patients while also ensuring the durability of our products. Overall, we believe the growing proportion of specialty care products in our portfolio will boost profitability.”
Executives say oncology has become AstraZeneca’s sixth growth platform and will deliver long-term growth. Because of the changes made in the last two years that have transformed the company’s pipeline and accelerated clinical programs, the company has achieved its 2016 target for the number of potential medicines in Phase III — three years ahead of schedule. “The changes have also helped towards our goal of achieving scientific leadership in our three main therapy areas: respiratory, inflammation, and autoimmunity (RIA); cardiovascular and metabolic diseases (CVMD); and oncology,” Soriot notes.
AstraZeneca achieved 12 approvals in 2014. In addition to launching new medicines, such as the PARP inhibitor Lynparza for ovarian cancer and the opioid-induced constipation drug Movantik/Moventig, by the end of 2016 AstraZeneca anticipates 12 to 16 Phase II starts; 14 to 16 NME and major line extension regulatory submissions; and eight to 10 NME and major line extension approvals.
Lynparza was approved in December 2014 in the United States and the European Union as the first PARP inhibitor for the treatment of women with BRCA-mutated (BRCAm) ovarian cancer who have had very limited treatment options.
According to Soriot, “The story of Lynparza shows what AstraZeneca can achieve by following the science.” Lynparza development had been halted following Phase II trial results that indicated that the progression-free survival benefit seen in the overall ovarian cancer population was unlikely to translate into an overall survival benefit. Another challenge was identifying a suitable dose of the new tablet formulation. The team persisted, reanalyzing the Phase II data and obtaining the BRCAm status for almost all patients, and saw that the drug did significantly increase progression-free survival compared with placebo in patients with BRCAm ovarian cancer. Additionally, the team also identified a suitable dose and tablet formulation.
In September, AstraZeneca announced positive topline results from RECAPTURE 1 and RECAPTURE 2, the pivotal Phase III studies evaluating the antibiotic, CAZ-AVI (ceftazidime-avibactam), as a treatment for adult hospitalized patients with complicated urinary tract infections (cUTI), including pyelonephritis. CAZ-AVI consists of a cephalosporin (ceftazidime), an established treatment for serious bacterial infections, and a next generation non-beta lactam beta-lactamase inhibitor (avibactam). CAZ-AVI is being developed to treat a broad range of Gram-negative bacterial infections, which are becoming increasingly resistant to antibiotics and pose a threat to public health. In the United States, where AstraZeneca’s partner Allergan holds the commercialization rights, CAZ-AVI was approved as Avycaz by U.S. Food and Drug Administration in February 2015 for cUTI and complicated intra-abdominal Infections, AstraZeneca holds the commercialization rights to the compound in the European Union, where the regulatory submission seeking approval for a broad range of indications, was accepted and validated by the European Medicines Agency (EMA) in May 2015 and is under review.
Good news came for one of AstraZeneca’s growth platforms, Brilinta, also in September, when the FDA approved the product at a new 60mg dose to be used in patients with a history of heart attack beyond the first year. With this expanded indication, Brilinta is now approved to reduce the rate of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI.
During the first half of 2015, AstraZeneca submitted AZD9291 and cediranib for regulatory approval.
In June 2015, the company submitted the rolling new drug application (NDA) for AZD9291 as a potential medicine for the second-line treatment of patients with advanced or metastatic T790M-mutated non-small cell lung cancer. The EMA also accepted the regulatory submission for AZD9291.
CAURAL, a randomized Phase III trial in second-line metastatic EGFR T790M-mutation positive NSCLC testing AZD9291 plus durvalumab versus AZD9291 monotherapy, is being prepared for dosing. The trial has a primary endpoint of progression-free survival. At the ASCO meeting, preliminary efficacy and safety data for AZD9291 in the first-line treatment of EGFRm-positive advanced NSCLC were presented. Data showed that 81 percent (95 percent confidence interval (CI) 68 percent to 89 percent) of patients on a once-daily dose of AZD9291 were progression-free at nine months; the ORR was 73 percent (95 percent CI 60 percent to 84 percent). The longest duration of response was ongoing at 13.8 months at the time of data cut-off. These data support the ongoing development of AZD9291 in first-line lung cancer, including the Phase III FLAURA trial.
Cediranib’s marketing authorization application received acceptance from the European Union in July 2015 for an intended indication in platinum-sensitive relapsed ovarian cancer. The application was based on the ICON6 trial. ICON6 results showed that, compared to platinum chemotherapy alone, cediranib given with platinum-based chemotherapy and continued as maintenance, significantly improves PFS in women with recurrent ovarian cancer. Subsequent secondary-efficacy measures supported significant sustained efficacy, leading to a strong overall survival trend.
Earlier in July, AstraZeneca announced that the FDA had approved Iressa (gefitinib) tablets, a 250mg once-daily first-line treatment for patients with metastatic epidermal growth-factor receptor (EGFR) mutated non-small cell lung cancer. Iressa was granted orphan drug designation by the FDA in 2014.
Partnerships and collaborations
AstraZeneca has built, and will continue to build, its pipeline and portfolio through partnerships. “A focus on early-stage academic and biotech alliances supports our long-term pipeline aspirations,” Soriot says.
In September, MedImmune, the global biologics research and development arm of AstraZeneca, entered an agreement granting Daiichi Sankyo Co. Ltd. an exclusive license to develop and commercialize the intranasal flu vaccine FluMist Quadrivalent in Japan. Under the terms of the agreement, Daiichi Sankyo will pay AstraZeneca an upfront fee with subsequent development milestones and sales-related payments post launch. Daiichi Sankyo will take on the full responsibility for the future development and commercialization of FluMist Quadrivalent in Japan and will hold the marketing authorization; and AstraZeneca will supply FluMist Quadrivalent to Daiichi Sankyo.
Also in September, AstraZeneca entered into a collaboration agreement with Valeant Pharmaceuticals International Inc. under which it will grant an exclusive license for Valeant to develop and commercialize brodalumab. Brodalumab is an IL-17 receptor monoclonal antibody in development for patients with moderate-to-severe plaque psoriasis and psoriatic arthritis. Under the agreement, Valeant will hold the exclusive rights to develop and commercialize brodalumab globally, except in Japan and certain other Asian countries where rights are held by Kyowa Hakko Kirin Co. Ltd under a prior arrangement with Amgen Inc., the originator of brodalumab. Valeant will assume all development costs associated with the regulatory approval for brodalumab. Regulatory submission in the United States and the European Union for brodalumab in moderate-to-severe psoriasis is planned for the fourth quarter of 2015.
In May 2015 AstraZeneca entered an agreement with Abbott Laboratories Inc. to develop companion diagnostic tests to identify patients with severe asthma most likely to benefit from tralokinumab. No companion diagnostic blood tests have yet been approved for use in asthma. Under the terms of the agreement, Abbott will develop and commercialize diagnostic tests to measure serum levels of the proteins periostin and dipeptidyl peptidase-4 (DPP-4), identified as potential predictive biomarkers of up-regulated IL-13 in severe asthma. The tests will be developed in conjunction with the Phase III trials of tralokinumab as a potential treatment for patients with severe, inadequately controlled asthma.
Also in May 2015, AstraZeneca and Eli Lilly & Co. announced a clinical-trial collaboration to evaluate the safety and preliminary efficacy of durvalumab, in combination with ramucirumab, Lilly’s VEGF receptor-2 anti-angiogenic cancer medicine. The planned trial will assess the combination as a treatment for patients with advanced solid tumors.
A Phase I trial is expected to establish the safety and a recommended dosing regimen, with the potential to open expansion cohorts in various tumors of interest for the combination of durvalumab and ramucirumab. Under the terms of the agreement, the trial will be sponsored by Lilly.
In yet another agreement in September, AstraZeneca made a deal with the drug-delivery company Starpharma to license that company’s DEP drug delivery platform for use with its oncology medications. The deal could be worth up to $450 million.
Development partnerships in August included separate agreements between MedImmune with Inovio Pharmaceuticals and Mirati Therapeutics; and separate deals between AstraZeneca and Heptares Therapeutics, Peregrine Pharmaceuticals, as well as with Isis Pharmaceuticals.
Under the agreement with Inovio, MedImmune will acquire exclusive rights to Inovio’s INO-3112 immunotherapy, which targets cancers caused by human papillomavirus (HPV) types 16 and 18. INO-3112, which is in Phase I/II clinical trials for cervical and head and neck cancers, works by generating killer T-cell responses that are able to destroy HPV 16- and 18-driven tumors. These HPV types are responsible for more than 70 percent of cervical pre-cancers and cancers. MedImmune intends to study INO-3112 in combination with selected immunotherapy molecules within its pipeline in HPV-driven cancers.
Under the terms of the agreement, MedImmune owes an upfront payment of $27.5 million to Inovio as well as potential future payments upon reaching development and commercial milestones totaling up to $700 million. MedImmune will fund all development costs. Inovio is entitled to receive up to double-digit tiered royalties on INO-3112 product sales.
With Mirati Therapeutics, an oncology company focusing on genetic and epigenetic drivers of cancer, MedImmune will conduct a Phase I/II study to evaluate the safety and efficacy of MedImmune’s investigational anti-PDL1 immune checkpoint inhibitor durvalumab in combination with mocetinostat, Mirati’s investigational spectrum-selective histone deacetylase (HDAC) inhibitor. This novel combination will initially be evaluated in patients with non-small cell lung cancer, with the potential to explore additional indications in the future.
AstraZeneca and Peregrine will evaluate Peregrine’s investigational phosphatidylserine-signaling pathway inhibitor, bavituximab, in combination with durvalumab. The planned Phase I/Ib trial will evaluate the safety and efficacy of bavituximab in combination with durvalumab in multiple solid tumors. The companies will collaborate on a non-exclusive basis, to evaluate the combination of bavituximab and durvalumab with chemotherapy as a potential treatment in various solid tumors. The Phase I part of the trial is expected to establish a recommended dose regimen for the combination and the Phase Ib part of the trial will assess the safety and efficacy of the investigational combination. The initial trial will be conducted by Peregrine.
AstraZeneca and Heptares, the wholly owned subsidiary of Sosei Group Corp., entered into a licensing agreement under which AstraZeneca will acquire exclusive global rights to develop, manufacture, and commercialize the adenosine A2A receptor antagonist, HTL-1071, a small molecule immuno-oncology candidate, and potential additional A2A receptor-blocking compounds. AstraZeneca will explore the assets across a range of cancers, including in combination with its existing portfolio of immunotherapies. Under the terms of the agreement, Heptares will grant AstraZeneca an exclusive license to research, develop, manufacture, and commercialize HTL-1071. The companies will also collaborate to discover further A2A receptor-blocking compounds for development in cancer immunotherapy. Heptares will receive an upfront payment of $10 million and is eligible to receive additional, significant near term milestone payments based on agreed preclinical and/or clinical events.
With Isis Pharmaceuticals, Astra-Zeneca entered into a strategic collaboration to discover and develop antisense therapies for cardiovascular, metabolic and renal diseases. AstraZeneca will pay an upfront fee of $65 million to Isis Pharmaceuticals plus development and regulatory milestones for each program that AstraZeneca advances to clinical development. Isis Pharmaceuticals is additionally eligible to earn tiered double-digit royalties on annual net sales for each program.
In July 2015, AstraZeneca entered into an agreement with Fujifilm Kyowa Kirin Biologics Co. Ltd. to establish a joint venture for the development and commercialization of FKB238, a biosimilar version of bevacizumab, currently in Phase I development for the treatment of multiple solid tumors. AstraZeneca plans to use the biosimilar in combination with its portfolio of innovative oncology investigational and on-market medicines, across a range of cancers and at different stages of disease.
In April 2015, AstraZeneca announced an exclusive collaboration agreement with Celgene Corp. for the development and commercialization of durvalumab across a range of blood cancers including non-Hodgkin’s lymphoma, myelodysplastic syndrome and multiple myeloma. Under the terms of the agreement, Celgene made an upfront payment of $450 million in the second quarter to AstraZeneca. Celgene will lead on development across all clinical trials within the collaboration and will take on all research and development costs until the end of 2016, after which it will take on 75 percent of these costs. Celgene will also be responsible for global commercialization of approved treatments. AstraZeneca will continue to manufacture and book all sales of durvalumab and will pay a royalty to Celgene on worldwide sales in hematological indications. Within the collaboration, durvalumab will be assessed both as monotherapy and in combination with other AstraZeneca and Celgene potential and existing cancer medicines.
AstraZeneca entered into a collaboration in the second quarter with Innate Pharma SA to accelerate and broaden the development of Innate’s proprietary NKG2A antibody, IPH2201, including in combination with durvalumab. Currently in Phase II development, IPH2201 is a potential first-in-class humanized IgG4 antibody against NKG2A. NKG2A is a checkpoint receptor that inhibits the anti-cancer functions of Natural Killer and cytotoxic T-cells.
Under the terms of the agreement, AstraZeneca made an initial payment to Innate of $250 million, which included the consideration for exclusive global rights to co-develop and commercialize IPH2201 in combination with durvalumab, as well as access to IPH2201 in monotherapy and other combinations in certain treatment areas for which AstraZeneca has the option to pay a further $100 million prior to initiation of Phase III development. The agreement also includes additional regulatory and sales-related milestones.
Not all scientific collaborations are focused on compounds or products. In April, AstraZeneca and PatientsLikeMe signed a five-year agreement to provide access to PatientsLikeMe’s global network in support of AstraZeneca’s patient-driven research initiatives.
AstraZeneca will use patient-reported data from PatientsLikeMe to shape future medicine development and help improve outcomes across its main therapeutic areas, with an initial focus on respiratory disease, lupus, diabetes and oncology.
“Understanding what patients are experiencing every day and how they define the value of their treatments are fundamental to our ability to push the boundaries of science in developing the next-generation of medicines,” says Briggs Morrison, executive VP, Global Medicines Development, AstraZeneca.
Divestitures and acquisitions
In July, AstraZeneca sharpened its focus by agreeing to divest the thyroid cancer drug Caprelsa to Genzyme Corp. and global rights to the gastroenterology drug Entocort to Tillotts Pharma.
Genzyme will pay AstraZeneca up to $300 million, including an upfront payment of $165 million to acquire the global rights to sell and develop Caprelsa, and further development and sales milestone payments of up to $135 million. Tillotts will pay AstraZeneca $215 million to acquire the rights to sell and develop Entocort capsules and enema formulations outside the United States.
Other strategic transactions with companies such as Bristol-Myers Squibb and Almirall support the late-stage and marketed portfolio, executives say. On Oct. 31, 2014, AstraZeneca completed the agreement to transfer the rights to Almirall’s respiratory franchise to AstraZeneca. The transaction provides AstraZeneca with 100 percent of the rights for the development and commercialization of Almirall’s existing proprietary respiratory business, including rights to revenue from Almirall’s existing partnerships, as well as its pipeline of investigational novel therapies. The franchise includes Eklira (aclidinium); Duaklir Genuair, the combination of aclidinium with formoterol that has been approved in the EU and is being developed in the United States; LAS100977 (abediterol), a once-daily long-acting beta2-agonist (LABA) in Phase II; an M3 antagonist beta2-agonist (MABA) platform in preclinical development (LAS191351, LAS194871) and Phase I (LAS190792); and multiple preclinical programs. Almirall Sofotec, an Almirall subsidiary focused on the development of innovative proprietary devices, has also been transferred to AstraZeneca.
AstraZeneca paid $878 million upfront to Almirall, and further payments of up to $1.22 billion are to be paid for future development, launch, and sales-related milestones. AstraZeneca has also agreed to make various sales-related payments. Executives say the addition of aclidinium and the combination of aclidinium with formoterol, both in proprietary Genuair device, will allow AstraZeneca to offer patients a choice between dry powder inhaler and metered dose inhaler devices across a range of molecules and combinations.