Rising costs for r&d, tighter regulations and price pressures make the task of translating the ‘eureka’ moments of medical science into safe, effective and cheaper medicines an increasingly difficult task. Susan Birks reports.
A report published recently by the UK research and consulting organisation Office of Health Economics (OHE) highlighted the escalating costs of R&D for new medicines. The costs have risen from £125m (US$199m) per new medicine in the 1970s to £1.2bn ($1.9bn) in the 2000s (2011 prices). While such estimates are controversial and vary around the world, four factors have been identified in raising R&D costs:
- Higher ‘out-of-pocket’ costs, up nearly 600% from the 1970s
- Lower success rates as tougher therapeutic areas are tackled, e.g. neurology (Alzheimer’s), autoimmune diseases (arthritis) and oncology
- Increased R&D timescales – from six years in the 1970s to 13.5 years in the 2000s – as both regulation and science have become more complex
- Increased cost of capital, i.e. providing returns to funders that reflect the high risks of R&D – from 8% in the 1970s to 11% in the 2000s
But as the costs of R&D rise, the price of medicines is being pushed down. To mitigate the rising costs, pharmaceutical companies have been forced to adopt new R&D models, make decisions earlier in the development process about whether a treatment is viable or not, foster more open innovation and partner more to share the risk while bringing down the cost.
Companies big and small have realised there is potential in more flexible collaborative models involving academia. One newly launched scheme is the European Lead Factory. Initiated and co-ordinated by Bayer HealthCare and run by an international consortium of 30 partners, this €196m, 5-year project sets out to provide an ‘industry-like’ discovery platform to translate cutting-edge academic research into high-quality drug lead molecules.
Part of the project is to create an exceptional collection of small molecules. Bayer HealthCare and six other members of the EFPIA will collectively contribute at least 300,000 substances; Bayer alone will provide about 50,000 compounds and its expertise in early drug discovery. Academia and Small and Medium Enterprises (SMEs) will also jointly develop a library of around 200,000 compounds .
An equally important part of the European Lead Factory will be setting up a European Screening Centre with compound logistics and High Throughput Screening (HTS) facilities, which will be located in Scotland and The Netherlands respectively. The highly automated process will allow researchers to screen the Joint European Compound Collection for molecules that could be a promising starting point in developing new drugs.
Technology has largely been keeping pace with the ever-increasing requirements of the drug discovery world. Several new enabling technologies have been introduced over recent decades to aid the discovery process, including: RNAi screening, combination high-throughput screening, 3D cell-based assays, DNA-encoded library technology, next-generation sequencing, translational assays and hit to lead optimisation.
New computer-based technologies will create a greater understanding of the biology of disease and the evolution of ‘Virtual man’ to enable researchers to predict the effects of new drug candidates
But according to PricewaterhousCooper, pharmaceutical companies could dramatically improve the R&D productivity in many ways. In its second paper in the PwC Pharma 2020 series the firm contends that by 2020 the R&D process could be shortened by two-thirds, success rates may dramatically increase and clinical trial costs could be cut substantially. New computer based technologies, it says, will create a greater understanding of the biology of disease and the evolution of ‘Virtual man’ to enable researchers to predict the effects of new drug candidates before they enter human beings.
Such approaches – grouped loosely under the umbrella of Virtual R&D – include: computer-aided and structure-based drug design, molecular dynamics simulation, fragment-based approaches and predicting anti-target effects.
One aspect receiving much acclaim in particular is fragment-based lead discovery (FBLD), also known as fragment-based drug discovery (FBDD). Based on identifying small, low molecular weight chemical fragments that may bind only weakly to the biological target, but which can then be built into a clinical candidate with a higher affinity, it is showing signs of success. Compared with high-throughput screening (HTS), where libraries with millions of compounds with molecular weights of around 500 Da are screened and nanomolar binding affinities are sought, in the early phase of FBLD libraries with only a few thousand compounds having molecular weights of around 200 Da may be screened, and millimolar affinities can be considered useful.
The advantages of this latter approach using small fragments include more hydrophilic hits and fragments that are less likely to contain sterically blocking groups that interfere with an otherwise favourable ligand-protein interaction, whereas the larger molecules can have interfering functionalities that make near-perfect fits invisible during HTS.
The hits may be easier to find but the process requires specialised biophysical methods such as NMR, surface plasmon resonance, calorimetry and X-ray crystallography and, once found, the work then begins in building the molecule into the desired candidate. Many companies are now working using a combination of screening approaches and integrating knowledge from all methods.
Another technology area creating excitement in drug discovery is macrocycles and constrained peptides. Based around their potential to disrupt intracellular protein-protein interactions, their application is also interesting to Big Pharma.
Macrocycles epitomise the concept of a small molecule biologic, as they present the most attractive aspects of both conventional small molecules and biologics
Because protein-protein interactions with large surface areas are very difficult to address with small molecules, macrocycles are an effective way of getting to a size that allows enough interaction with the protein. A similar approach is to create constrained peptides by artificially linking linear peptides into specific structures possessing favourable drug-like properties, such as cell permeability. At least a dozen biotechs are busy developing platforms for synthesising or screening macrocycles and constrained peptides and Big Pharma has been quick to set up partnerships with them.
According to Nick Terrett, Chief Science Officer of Cambridge, MA-based Ensemble Therapeutic, ‘macrocycles epitomise the concept of a small molecule biologic, as they present the most attractive aspects of both conventional small molecules and biologics’. He believes they have ‘proven affinity for difficult-to-target protein-protein interactions and yet retain attractive drug-like small molecule properties including the ability to get inside cells, and be taken as oral pills’. The real test is still to come, however – when they prove their worth in late-stage clinical trials.
Researcher picking colonies of cultured human embryonic stem cells.
Source: Wellcome Library
Regenerative medicine is set to be one of the biggest and most exciting growth areas in the next few years. In 2012 the Wellcome Trust and the Medical Research Council (MRC), two of the UK’s largest funders of medical research, announced an investment of £8m in a new stem cell research centre. Based at Cambridge University, the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute will build on existing investment by the MRC and the Wellcome Trust, uniting 30 leading research teams with expertise across the three main types of stem cell: embryonic, adult and induced pluripotent cells. Research scientists will work alongside technology specialists and doctors to develop new therapeutic approaches and this will be underpinned by stem cell biology.
And here is the rub for drug discovery. The investment in time, new technologies and testing and risk of failure needs to be recouped through high prices and long patent lives. One of the biggest threats, however, is the fast rise of generics and biosimilars. Healthcare authorities faced with ageing populations and shrinking budgets will continue to push for lower cost drugs, and demand for generics and biosimilars will increase. As a result the current mantra of drug discovery industry is: work faster, cheaper and smarter.
In 2012, the US FDA approved 39 new drugs, a dramatic rise from the average of 23 per year in the previous 15-year period, according to Bloomberg. Hopefully this trend suggests that some new R&D models are having an effect.
