The biologics market treats and manages many chronic diseases including diabetes, multiple sclerosis and rheumatoid arthritis. Most biologics need to be delivered via injection, which involves a more complex development pathway to bring such drug-device combinations to market and compliance issues arising from patients being unwilling or unable to administer their drugs.

Crucially, biologics represents over $120 billion in annual revenues, and this will grow by around 50% by 2015. But for established players, competitive threats – such as the arrival of biosimilars (lower-cost copies of off-patent innovator drugs) and an increasing resistance from payers to reimburse new drugs that are not considered to provide cost benefits – are holding back future therapeutic advances.

For many drug providers, this doesn’t just relate to the challenges faced during the introduction of a novel drug therapy, it also focuses on product lifecycle management and therapeutic product evolution; for example, the drug involved may be an injectable reformulation of an existing therapy to enable patient-managed administration. Going further, the drug formulation itself may remain unchanged, but the delivery device is where new patient benefits are achieved.

Putting administration in patients’ hands

The protein-based nature of biologics means that they cannot normally be delivered orally due primarily to gastric degradation, and so require another delivery route. Typically, this is a subcutaneous injection or intravenous infusion, although nasal, pulmonary or other transmucosal routes are also potential options. These routes usually require a delivery device of some form: be that a simple syringe or a more complex appliance, such as an inhaler or an advanced injection device.

"Crucially, biologics represents over $120 billion in annual revenues, and this will grow by around 50% by 2015."

Efficacy remains an important factor in selecting the delivery route and device; however, while people can resign themselves to various forms of delivery as long as they manage their condition better, their reluctance to do so may affect compliance and hence clinical outcomes, and the ultimate overall cost of treating an improperly managed disease. The device has increasingly become a popular route to differentiation in the marketplace against competitor drugs that may provide relatively similar patient outcomes under ideal clinical conditions.

The ability to self-administer drugs and self-manage these chronic diseases brings benefits to patients and payers. For the former, the disease can be managed more conveniently at home. For the latter, there are potential time savings for those administering the drug and, if better adherence is achieved, the costs of treating complications that arise from failure to comply with the optimal treatment regimen are avoided.

Different diseases entail varying user needs when it comes to delivery devices. Some are practical issues, such as:

  • the ability of users to operate the device correctly, even when their cognitive and dexterity capabilities are limited by disease state or age
  • the level of feedback when in use
  • fill and delivery variability for different dosing
  • variable flow rates; robustness of design; memory and diary features
  • portability.

Others are more subjective, such as how intuitive it is to use, the design and ergonomic appeal, connectivity and anticipated and/or real levels of pain during use.

Issues surrounding the market-facing aspects are crucial, and include:

  • how well developed the device is and its potential time to market
  • the track record and credibility of the device developer
  • IP protection
  • overall cost.

In the area of diabetes, pens are an established means of delivery. Pen designs have evolved over the past 30 years to address usability issues (such as the ability to set the correct the dose dialled right up to the point of administration), ease of use (such as the ability to use the device quickly on the go) and improve the overall desirability of the devices.

Pen designs are relatively mature with limited scope to dramatically improve usability or product appeal; however, it is only in the past six years that prefilled autoinjectors have become the preferred format for the delivery of drugs for autoimmune diseases such as rheumatoid arthritis. The usability of these could be augmented through further design iteration – an area of intense focus for device manufacturers.

Once suitability issues have been addressed, there is an opportunity to develop devices that improve the total user experience and fit better with the user lifestyle. The resultant devices will then take on a consumer product feel, appealing to the user at a more emotive level. To achieve this, the need to segment the market in line with the needs of patient subgroups arises. Commonly a consumer market strategy, the pharmaceutical market has only just begun to use this approach; insulin, the human growth hormone and erythropoietin are now provided in a range of delivery formats by the same biopharma company.

The challenges of injectable drug delivery

Biologics are also placing new demands on drug delivery technology. Their large molecule nature tends to make many drugs, such as monoclonal antibodies, more viscous than insulin or non-biologics, and so the physical force required by the patient/device to inject the drug can become a challenge. Increasing the drug volume can reduce viscosity, but this limited by the subcutaneous layer’s inability to absorb more than around 2ml of drug in an injection lasting a few seconds. IV infusion delivers higher volumes, but is not amenable for home use.

"The ability to self-administer drugs and self-manage these chronic diseases brings benefits to patients and payers."

Reformulation is one solution; for example, Halozyme has a human synthetic version of hyaluronidase. This enzyme temporarily degrades hyaluronan (a structural component of the subcutaneous), allowing a single injection to deliver much larger volumes. The technology is being used both to develop new drugs and as a lifecycle means of enabling the subcutaneous delivery of existing ones, such as Roche’s Herceptin.

Developing devices that allow subcutaneous infusion of a drug over longer periods of time – from several minutes to over an hour – is another approach. In the US, electronic pumps are an increasingly common means of accurately treating type 1 diabetes; however, these pumps are too complex and expensive for biologics delivery, where the infusion rate is not critical. Wearable, mechanical patch pump alternatives are being developed by a number of companies, such as Valeritas.

Needle-free devices transport drugs through the skin using pressure generated by a spring or the release of a gas. These devices offer the potential to rapidly deliver high-viscosity drugs to needle-phobic patients.

Another challenge for some biologics is the rapid removal of the drug from systemic circulation, which means they must be delivered more regularly, reducing adherence. Formulation technologies are in development to address this; for example, MedinCell has a biodegradable polymer depot for the subcutaneous delivery of peptides, small molecules and biologics that extends the effect of drugs post-injection while minimising manufacturing costs.

While evidence suggests that less frequent dosage regimens can improve adherence, obtaining the scientifically rigorous data that will convince payers to adopt these innovations is not easy.

New routes of administration

Other routes of administration for biologics, such as pulmonary delivery, have faced difficulties. Pfizer withdrew its approved inhaled insulin Exubera from the market 18 months after registration for commercial reasons – a setback for the inhaled biologics route. The potential 2013 approval of Mannkind’s similar inhaled insulin product Afrezza, and the recent review panel backing for Alexza’s inhaled schizophrenia and bipolar mania treatment Adasuve, however, are promising.

Oral delivery remains the holy – if somewhat elusive – grail of biologics, but there are companies chasing this difficult goal. Merrion Pharmaceuticals’ gastrointestinal permeation enhancement technology, for instance, allows oral delivery of large molecules such as proteins, and Entrega, formed by Enlight Biosciences in partnership with major pharma firms, is using its spatially directed proprietary drug delivery platform to create orally bioavailable formulations of many biologic drugs.

Biopharma: responding to changing needs

Many companies do not have the internal capabilities – or inclination -to develop a specific device. In these cases, they look externally for an existing device that, with some modification, would create the desired marketplace differentiation, but this is a complex process.

"Once suitability issues have been addressed, there is an opportunity to develop devices that fit better with the user lifestyle."

A growing number of device manufacturers offer biopharma companies access to ‘platform technology’ with the benefits of proven device development and manufacturing experience, and established IP. These outsourced technologies potentially allow adoption of the to-be-marketed device later in the clinical development process, or enable a relatively straightforward lifecycle switch for an already marketed drug. Other biopharma companies are strengthening their in-house device development capabilities. In either case, it is key that market and user needs are understood, and that the biopharma company is capable of orchestrating the overall drug-device combination development.

To be successful, companies need to recognise where different delivery systems can play a role in improving the patient experience and ensuring competitiveness. As is already the case for some drugs, it will be the drug-device combination – not the drug alone – that will increasingly define the attractiveness of the product both to users and payers.