Can you summarize briefly what the Catalent Applied Drug Delivery Institute’s non-invasive macromolecule delivery consortium (NMDC) has achieved since it was established two years ago?
The first goal was to get industry and academia talking about the topic in a coordinated way. An initial meeting of the consortium led to separate workstream meetings being convened to cover the different potential routes of administration – oral, ophthalmic, respiratory and transdermal delivery. Each of these delivery routes is at a different stage of technology maturity, and therefore it made sense to work on them separately as they have differing scientific and technical support needs, as well as regulatory requirements. Most of the focus has, therefore, been within these individual workstreams, rather than more wide-ranging work across the whole field of potential non-invasive macromolecule delivery (NMD) routes.
After that initial meeting, we realized that an assessment of the current state of play across NMD science would be very beneficial. A group of Catalent people and industry partners worked on this, with contributions from several universities in the U.S. and Europe. The result was a comprehensive guide to NMD, which was made freely available to both industry and academia, and can be downloaded from the Catalent Institute’s website [drugdeliveryinstitute.com]. I understand it is even being used for some university course work, which I’m very pleased about.
Early on, we presented the consortium at the Milken Institute’s Partnering for Cures conference. It was selected as an award winner as an innovative partnership at the annual conference that year; we were delighted that the project was recognized as novel, and that if it succeeds in meeting its goals, it could have a material impact on patient outcomes.
Since then, the different workstreams have focused on discussing the challenges they are facing. A common theme this brought to light was certain areas where regulatory guidance is needed, across the different routes of administration. We have therefore begun engaging with the FDA through its Critical Path Initiative, and also through the emerging technologies group at the Center for Drug Evaluation and Research (CDER). This is still in the early stages.
We have also been raising industry visibility and awareness of the need for NMD at numerous scientific conferences in the U.S. and Europe, as well as holding Catalent Institute symposia, including most recently, one solely focused on biologics, held at the University of California in San Francisco. We ran a debate session at November’s AAPS annual meeting in Denver, with the consortium chair and one of its lead scientists in an active dialogue session with attendees on the purpose and role of NMD for biologics.
How has the industry landscape changed in the two years since the consortium was set up?
Well, the prevalence of biologics in pharma pipelines has continued to grow, as we had expected. The launch of the consortium coincided with the submission and approval of Mannkind’s inhaled insulin product, and there was a degree of momentum around non-invasive delivery at that time. Since then, there have been multiple new start-up companies and active patenting in the area, and some very early discovery stage partnerships for various technology platforms with industry.
However, the Mannkind product has not performed as well as initial expectations suggested it might, and Novo Nordisk also recently discontinued its long-standing program to develop oral insulin formulations. Novo’s statements seemed to suggest that NMD will only be successful when it not only solves a problem that patients actually view as a problem (which, with hindsight, does not seem to be the case with insulin), and with a solution that payers are willing to pay for. The scientific success of investigational NMD technologies has been mixed, with several reaching Phase III clinical trials. There is a belief in industry that NMD will be possible, but it is also clear that traditional delivery technologies that were well established will only offer limited utility for NMD, and it is going to require more innovation.
I would add that managed care providers and payers, whether singlepayer or private, will continue to play significant roles in healthcare. The pricing pressures that bodies such as the National Institute for Health and Care Excellence (NICE) in the U.K. have brought to bear in single-payer systems are increasingly being applied by private payers in the U.S. as well. So, although the NMD dosages might be expensive to produce, if they could reduce the medical costs of administration, it would certainly help payers become more comfortable with adopting cutting-edge delivery routes. This would have to be done carefully, as current outpatient-based, patient-self-administered approaches with treatments in therapeutic areas such as oncology and antithrombotics have introduced patient adherence challenges that will have to be addressed.
What are the biggest drug delivery challenges that remain for macromolecule drugs?
The biggest challenge is to reach therapeutic levels in the body, and in the right place in the body, for different types of treatments. There are numerous factors that affect almost any kind of formulation, both oral and non-oral, including solubility, permeability and stability. Reaching specific targeted sites can be difficult; for example, accessing the back of the eye with ophthalmic formulations remains a significant challenge, as is penetrating the blood–brain barrier for brain-related treatments.
There is now a greater understanding of how to deal with solubility challenges with small molecules, and some of these principles may also apply to certain larger molecules. Some types of larger molecules, like peptides, may lend themselves more to traditional techniques, whereas antibodies are far more complex from a delivery standpoint.
Most investigational NMD delivery platforms have only achieved very low bioavailability percentages, increasing the amount of active ingredient that will be required, and as a result, driving up costs. Numerous start-ups and established companies are working on solutions designed to improve bioavailability and targeted delivery. Not all will succeed – the complexity of some technologies may make them too difficult to scale-up and manufacture. Designing for future scalability should not be forgotten.
Many platform technologies have been developed using a model compound, chosen because it has optimal characteristics for that specific delivery system. It may not indicate how broad the platform’s applicability is, which is important to know for its future uptake. Not knowing the boundaries in terms of effectiveness is a recipe for losing credibility very quickly.
Which industrial and academic partners are currently involved in the NMDC?
Right now, the formal partners on the industry side who have provided funding or share one of the routes of administration workstreams, are 3M, Takeda, Allergan, Novartis and Genentech. On the academic side, we have Brown, Johns Hopkins and Rutgers Universities in the U.S., and Saarland University in Germany. In addition, several other companies are involved as participants in workstreams and conferences. Many more academic and corporate institutions will be represented by speakers at our upcoming, groundbreaking NMD scientific conference as well.
Has open innovation proved possible with these partners, and what might be done differently in future?
Open innovation is a concept that gets a lot of press, and we are trying to apply it in a pre-competitive way. However, open innovation and the pharmaceutical industry’s ‘for-profit’ model do not necessarily co-exist very well. Networked innovation and pre-competitive innovation may represent models that work a little better.
We have had to be very cautious in some of our discussions. This is difficult – when there is a group of scientists brainstorming around how to solve a problem, if it is done well it may generate intellectual property (IP), and in a room with people from five companies and four universities, this creates some interesting challenges in first-to-file patent regimes like in the U.S.
I passionately believe, however, that there are physical formulations and experiments that these workstreams can, and should, be creating and doing today. Right now, we are focused more on trying to fill in gaps in the science and the regulatory side, and a little less on things that might create IP risk or complexity. This is a challenge that I’m confident we will find a way to deal with appropriately.
As an example, one idea we have considered is comparative evaluation of a number of commercially available (but not necessarily clinically proven) technology platforms for the oral delivery of peptides and proteins. We could pick an appropriate model compound, and ask the providers of those technology platforms to provide a formulated version of that molecule in a dosage form. Then, the universities involved in that workstream could provide comparative analytical testing and stability experiments, and perhaps in silico modeling or cell-based testing, across all of the submitted technologies. This could be used to provide a comparative, unbiased evaluation of the technologies, at least for that model compound, and give an insight into the strengths, weaknesses and current state of development of each of these commercially available platforms.
What’s on NMDC’s agenda for the next year?
As well as continuing with the workstream focused efforts, we have some big conferences coming up. We’re taking part in the Drug Delivery Partnerships conference in February, and we are also organizing a groundbreaking conference focused on all routes of non-invasive macromolecule delivery on February 21–24 in San Diego. The aim is for it to be a collaborative forum for both industry and academic scientists to discuss all the aspects of NMD. We are extending our focus at this meeting to include delivery of macromolecules across the blood-brain barrier as well. We believe this conference will be an important step forward in progressing NMD to patient value.