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The Time Has Come

Inhaled drug delivery is emerging from its asthma and chronic obstructive pulmonary disease (COPD) niches into a greater number of indications, products and markets. Overall sales – which stood at $19.6 billion in 2012 – are forecast to more than double by 2016 to $44 billion (1), and will represent approximately 20% of the total drug delivery market by 2017 (2).

This growth is being driven by new product launches for unmet clinical needs, novel drug product combinations, and devices for improving patient compliance, with pressurised metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) being the major growth drivers (15.7% and 12.3% compound annual growth rate, respectively) (1). Inhalation is thus growing at a robust rate compared to other drug delivery routes, and is becoming not only a focus for sales, but an innovation driver for an industry that is constantly seeking new patenting opportunities.

This can already be seen from recent merger and acquisition (M&A) activities. In just over a year – starting with the acquisition of Pearl Therapeutics by AstraZeneca, and ending in November with the acquisition of Avanir by Otsuka – total transaction volume has exceeded $15 billion, clearly pointing towards a strategy that is increasingly focused on the respiratory drug market and, more specifically, on inhaled drug delivery.

Attracting Investment


Even if current M&A activity points to new potential for growth in inhaled products, the fact remains that this was already a sector of significant value for those few companies who were able to control the science and technology. Just four inhaled products (Advair, Symbicort, Spiriva and Flovent) had sales exceeding $1 billion in 2013.

Such high numbers attract interest from other sectors: from innovator competitors keen to make the most of market opportunities, to generic companies eager to challenge franchises that, in many cases, have lost patent protection. While the generics industry originally began to acquire its experience via capsules and tablets – where bio-equivalence was relatively straightforward to demonstrate – proving the equivalence of generic inhaled products to their innovator counterparts is difficult. Consequently, there has been more visible activity with new entrants in the innovator field, such as Novartis with Seebri (glycopyrrolate) for COPD and Tobi (inhaled tobramycin) for lung infection in cystic fibrosis (CF), as well as Bayer with ciprofloxacin for the same indication.

New Direction

It is expected that the new generation of inhalation drug products currently in development, or those that have recently been approved – comprising new chemical entities (NCEs) and repurposed drugs or products now delivered by inhalation – will be driving product sales for the coming years. The recent approval of Mannkind’s Afrezza (inhaled insulin in dry powder formulation) and the successful market introduction of the Tobi Podhaler (inhaled tobramycin dry powder formulation) are two such examples. Indeed, CF seems to be the favoured entry point into the lung infection market, with at least 10 companies developing treatments for infections in this area and with an intention – at a later stage – to apply for market licences to treat lung infections common among the general population.

Table 3 (see full PDF of article) shows the diversity of inhaled drugs in development, including pulmonary arterial hypertension, idiopathic pulmonary fibrosis, antiemetics and antivirals. In this latter category, special recognition should be given to Daiichi Sankyo’s inhaled Inavir (laninamivir): a long-acting neuraminidase inhibitor used for the treatment of influenza which, unlike its most direct competitor Tamiflu (Roche; oseltamivir), needs to be taken just once, and is now Japan’s leading flu product with sales of $120 million during 2013/2014.

Alternative Approach


Inhalation product sales are still concentrated on asthma/COPD medication and continue to provide their innovators with considerable profits – but how sustainable is this? Efforts to challenge Advair, Symbicort and other products – even though they are at or near the end of their patent life – appear to have encountered significant development and market hurdles, with few companies obtaining marketing authorisation approvals. In this regard, regulators have also played a role – as is often the case, the Atlantic Ocean continues to be an obstacle to a common view.

In the EU, the EMA has a defined, stepwise approach for developing a generic DPI product, involving in vitro comparison of impactor deposition profiles, pharmacokinetic studies to determine bioequivalence, and – only if the latter fails – pharmacodynamic studies. In contrast, in the US, therapeutic equivalence is determined by a weight of evidence approach, which includes necessary demonstration of bioequivalence in addition to in vitro and pharmacokinetic studies. Moreover, FDA criteria for device equivalence represent an obstacle, given that the generic device has to equate to the same operational steps as the reference device, among other matching requirements.

To date, the FDA has provided product-specific bioequivalence guidances for Budesonide, Albuterol and Fluticasone/Salmeterol, and more are expected to be released. The key question for generics developers is, therefore, one of regulatory strategy and, in the case of the US market, this means a choice between a 505(j) Abbreviated New Drug Application (ANDA) or a 505(b)(2) New Drug Application (NDA).

Generic Application

A 505(j) approval guarantees interchangeability between the reference and the generic product, whereas a 505(b)(2) grants approval solely for a new product that cannot be separated from its reference by a pharmacist. The interchangeability of the generic drug product in relation to the innovator – which may be simple for an oral dosage form, but is more challenging for a drug product that includes a device/user interface – is therefore a concern. This hurdle has been solved in the injectable, nasal inhalation and pMDI drug delivery fields, as technological standards have been defined and set as part of the drug product categories.

However, this is not the case in the DPI area, where inventing and patenting are very dynamic. The resulting diversity of devices and ingenious patent strategies protecting innovator devices – sometimes beyond the life of the active molecule itself – means that the device is occasionally the greatest obstacle to a successful 505(j) ANDA plan.

Opting for a 505(b)(2) NDA application, on the other hand, provides greater flexibility and innovation. It becomes possible to develop a DPI product that clinically demonstrates an equivalent therapeutic and safety profile to the reference innovator product, while using a different delivery device, a different formulation, or both – effectively making it a functional replacement by matching the target product profile. Notwithstanding the stronger intellectual property protection and the usual market premium, a branded product approved under a 505(b)(2) application carries substantially higher development and marketing costs than a generic.

Innovator Lifecycle Strategies


To fend off a generic market entry threat, innovator companies are introducing new products, but opting for non-superiority status in relation to their old products. A few examples illustrate this strategy: Boehringer Ingelheim has recently received FDA approval for Respimat Spiriva (a soft mist, non-superior version of its earlier capsule-based Spiriva Handihaler DPI), and GlaxoSmithKline (GSK) has followed the same route in relation to Breo (fluticasone furoate and vilanterol) to replace its extremely successful Advair, but also positioning it as non-superior.

Of greater interest is the current trend towards fixed drug combinations. This strategy has been successfully used by AstraZeneca in the Pulmicort/Symbicort transition (where formoterol was combined with budesonide in the same inhaler) and by GSK in the Flovent/Advair transition. It is presently being actively pursued by other companies, such as SkyePharma’s FlutiForm (fluticasone propionate and formoterol fumarate), Almirall’s Eklira (aclidinium bromide and formoterol fumarate) and Boehringer Ingelheim’s Combivent (ipratropium bromide and albuterol sulfate). This trend is likely to continue and may eventually intersect with small-molecule drug conjugate technology, where the two (or more) molecules are no longer combined via a pharmaceutical process such as blending, but will be chemically linked.

What Lies Ahead?


With the decreasing drug load (to the low microgram range) and concomitant complexity of formulation development activities for asthma and COPD, coupled with the increasing difficulties in manufacturing drug product combination formulations, significant effort needs to be made to form expert, well-designed particle engineering and formulation development strategies to encompass and address dose content uniformity obstacles.

The search for technological solutions that can produce products deliverable by inhalation – that is, manufacturing particles in the micron range that easily disperse during inhalation – has led the inhalation development world to spray drying. This unique technology was pioneered by Inhale/Nektar for the development of the Exubera inhaled insulin formulation and has, since then, become a fundamental tool in DPI formulation development.

Spray drying offers the flexibility in dry powder formulation to tune the particles to a defined size, with the potential to incorporate multiple actives in a single dry powder formulation, and even develop active ingredient-independent particles. These can be tailored to maximise aerodynamic performance and, hence, lung delivery, while enabling the necessary process scalability.

It is therefore no surprise that several inhalation drug development programmes and marketed products – for example, Bronchitol – use spray drying as their manufacturing process of choice. With companies such as Hovione and Bend adopting advanced science and technology in the field of spray-dried particle engineering, the technique looks likely to play an important part in the creation of new inhaled products.

References
1. Pulmonary drug delivery systems: Technologies and global markets, BCC Research Report, January 2012. Visit: www.bccresearch.com/market-research/healthcare/pulmonary-drugdelivery-systems-hlc094a.html
2. Global pulmonary drug delivery systems market 2012-2016, Research and Markets Report, July 2013. Visit: www.researchandmarkets.com/reports/2603870/global_pulmonary_drug_delivery_systems_market#pos-0
3. PharmaCircle database, accessed on 3 December 2014. Visit: www.pharmacircle.com

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Dr Gonçalo Andrade joined Hovione in 2013 as Business Development Manager, and has been working on promoting the company’s capabilities in particle design and formulation development for inhalation drug delivery. He is also responsible for the business development activities of Hovione’s proprietary inhalation devices. Gonçalo is a member of the Inhalation and Nasal Technology Focus Group of the American Association of Pharmaceutical Scientists, holds a PhD in Biochemistry from the Ludwig-Maximilian University, Germany, and is also a Lisbon MBA graduate.

Peter Villax is the Vice President of Innovation at Hovione. He graduated in Politics and Economics from the University of Aberdeen, Scotland, before starting his professional career as a trainee at International Rectifier, and later joining Hovione as a computer programmer. Peter joined the Hovione Board of Directors in 1991 and has devoted his career to R&D in pulmonary inhalation therapies, becoming an inventor and a patent holder. He is also President of the Portuguese Family Business Association, a member of the Board of Health Cluster Portugal, and President of the Intellectual Property Commission of the International Chamber of Commerce in Lisbon.

Carla Vozone
is Senior Director, Product Development and Licensing at Hovione. She has nearly 20 years of experience in the pharma industry with roles in regulatory affairs, active pharmaceutical ingredient sales in Europe and North America, and business development and licensing. Carla graduated in Pharmacy and holds an MSc in Pharmaceutical Technology from the College of Pharmacy, University of Lisbon, as well as an MBA with a specialisation in Pharmaceutical Management from Rutgers Business University, US. She also represents Hovione on the board of the International Pharmaceutical Aerosol Consortium on Regulation and Science.
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Dr Gonçalo Andrade
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Peter Villax
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Carla Vozone
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