Breathing New Life into Existing Drugs

Finding new uses for old drugs is now a significant trend in the pharma industry. There can be some inconsistency about terminology, but generally speaking, a repurposing project will take a drug already approved for one indication and seek approval for another or, alternatively, a new formulation may be created to allow administration via a different route for the same indication. A repositioning project, meanwhile, tends to take an existing drug and give it an improved or altered product profile, while keeping the same administration route. Either way, as well as providing advantages for patients, repurposing or repositioning can also be used to extend intellectual property (IP) coverage and drive additional revenue for innovators. Drug repositioning now accounts for almost a third of all new drug products, generating half a trillion dollars in annual sales across all dosage forms (1).

Inhaled administration offers significant repurposing opportunities; only a relatively small number of medicines made their first appearance on the market in inhaled form. A number of drugs that are today very familiar in inhalers started life in another delivery format, including beta-2 agonists, anticholinergics, and corticosteroids, as well as antibiotics, such as tobramycin and aztreonam. Though most are locally effective products – notably those designed to treat respiratory disease – some are systemically targeted, such as drugs to treat diabetes, migraine, or Parkinson’s disease.

Repositioning is more likely to reflect lifecycle management strategies, whether by providing a new improved inhaled delivery mechanism, or offering patients improved dosing regimens. It is also possible to use the inhaled route to dose more than one drug at the same time, opening up opportunities for new combination products. Alongside the actual drug and its formulation, an improved delivery device can also encourage enhanced patient adherence.

Faster and cheaper

Repurposing or repositioning a drug is often a faster and more affordable way to develop new products than de novo drug discovery and development. Attrition rates are lower, as the active will already have passed safety trials, and less preclinical testing is required, with inhaled toxicology the main tests potentially needed. The reduced timescales needed for the project also translate to lower costs.  

Inhaled products can offer therapeutic advantages over oral or injected dosage forms, even if they are not used to treat diseases of the lung. One of the most important benefits that the inhaled route offers is fast onset of action. If the molecule is inhaled sufficiently deeply into the lungs, the speed with which it is taken up by the bloodstream is almost as fast as administration by injection. This rapid uptake has been exploited with orally inhaled insulin products, such as Affrezza (MannKind) and Pfizer’s now-withdrawn Exubera, as well as with products aimed at treating pulmonary arterial hypertension, such as Bayer’s Breelib (iloprost). Other conditions where speed could be a distinct advantage include pain relief, particularly migraine, and in Schizophrenia, bi-polar disorders, and Parkinson’s disease, where rapid onset would be desirable to treat acute symptoms. Inhaling a drug also avoids first-pass metabolism of the liver that occurs with oral dosing, which can enhance the activity of a drug that may be broken down quickly through hepatic metabolism or by the digestive system. Avoiding this metabolism may also make beneficial changes to the metabolite profile, which is particularly important if a drug has known metabolite-related adverse events.

On the life-cycle management front, a drug approved for an adult might undergo repositioning for the pediatric market, and this may or may not include changing the delivery mechanism; for example, from a pressurized metered dose inhaler (pMDI) to a smart nebulizer or a dry powder inhaler (DPI) to suit the expanded patient population. Children may find it particularly difficult to synchronize inhalation with a pMDI and may have less user errors with a DPI or nebulizer presentation.

Of course, there also has to be a therapeutic rationale for the change. The starting point should, therefore, be to determine an unmet therapeutic need, and how market share and commercial value might be derived from meeting it. For innovators, improving patient compliance is important because if patients take a drug correctly and therapeutic benefits are established, it will likely result in more prescriptions being filled. In inhalation, there is ample opportunity to improve upon the delivery method. For example, metered dose inhalers can be difficult for patients to use correctly because of the requirement to time the dose with breathing in, so advanced devices that improve patient use and compliance are important. An innovative delivery device can also provide an additional layer of market protection from competition.

Identifying the right niche

Looking more closely at clinical need, the global respiratory market obviously continues to be the most attractive. Significant unmet patient needs remain in asthma and chronic obstructive pulmonary disease (COPD), as well as more niche diseases, such as cystic fibrosis, pulmonary hypertension, and idiopathic pulmonary fibrosis, as shown in Figure 1, with some low volume but high value opportunities. Increasingly, the strongest growth potential lies in rarer diseases and systemic indications. The general market is growing at a rate of about 6 percent. But with cystic fibrosis, for example, the market is growing more quickly at >10 percent (see Figure 2). Drug designation for rare diseases can also come with other advantages, such as potential fast track designation, abbreviated approval processes, accelerated review, tax credits, fee waivers, and extended exclusivity – depending on the market region and regulator.

Systemic diseases, where delivery via the lung can benefit or enable targeting, offer substantial opportunities for drug repurposing. Drugs can be given a faster onset of action, while conserving potency, safety and tolerability. It can also be possible to dose within tight therapeutic windows, or to mimic the pharmacokinetic profiles that are achieved with the injectable drug delivery route. Inhaled administration can also be potentially used to effect mucosal vaccination.

A formalized and rational process should be used to identify the repurposing or repositioning projects most likely to succeed. The process should evaluate a product’s potential against key criteria, to filter opportunities and short-list product concepts. The evaluation should consider business strategy, clinical needs, commercial opportunity, technical aspects, and overall feasibility (see Figure 3). As an example, there are an estimated 300 projects within development databases that could benefit from an inhaled dosing strategy. The first step should be a quick triage of potential projects’ alignment to corporate vision and R&D investment strategy. This should still leave a considerable number of projects – perhaps around 100. The next stage of the filter is to consider clinical needs and market potential. An unmet medical need provides a compelling value proposition. Even if the condition is already covered by other products, the size of the patient population and the prevalence of the disease may still make the project viable. However, there should be a sound scientific rationale alongside the efficacy, safety and mechanism precedent.

The next consideration is commercial potential. It is important to judge how crowded the existing marketplace is, and whether a new product is sufficiently differentiated against the competition to offer both clinical and commercial value. Without these, it is unlikely that the drug will gain sufficient market share and meet reimbursement targets. Assessments also need to be made as to whether the desired value inflexion could be achieved within a reasonable timeframe, and whether the predicted return on investment is sufficiently attractive.

A commercially viable project will also need technical advantages. In-house proprietary technology, intellectual property, and improved functionality can all drive meaningful market differentiation. These aspects are also likely to provide product protection to deter direct competition.

The final filter is a project’s feasibility. Successful inhaled delivery is notoriously complex to achieve, and there are barriers to entry from a practical perspective; can the drug be formulated and delivered as an inhalable aerosol, and can it be dosed consistently in sufficient amounts at the target site of deposition within the lung to be efficacious and safe? Research and detailed diligence should be undertaken to assess whether a project leverages a company’s specific technical know-how, as well as the disease area and geographic focus. This final filter should leave just a handful of potential projects that meet all criteria.

De novo drug development is expensive and time consuming, so repurposing and repositioning existing drugs for new applications is extremely appealing from a commercial perspective. However, it’s crucial that the evaluation process also considers the scientific rationale and how patients will benefit. There is particularly unmet medical need in lung diseases, both common and rare, and the opportunity to improve on drug delivery methods through more advanced devices for both asthma and COPD, but the opportunities don’t stop with respiratory diseases – there is plenty of potential in the systemic delivery space too.