Focus turns to pre-empting disease causes and ageing


Drug discovery is brimming with innovation and technology but success is still seldom and slow. Susan Birks reports on the changing discovery landscape and how the odds can be improved

According to the US Food and Drug Administration’s Center for Drug Evaluation and Research (CDER), in 2014, the US approved 41 new molecular entities (NMEs) and new therapeutic biological products. About 30% of these were new biologics. This growth in biologicals is highlighted in Visiongain’s market report,1 which predicts that the overall world market for biosimilar mAbs will exceed US$4bn by 2020, multiplying in value many times from 2015 to 2025. Fifteen of the NMEs targeted rare or orphan diseases, which suggests recent FDA efforts to accelerate orphan drug development is taking effect. Furthermore, according to the US Personalised Medicine Coalition (PMC) more than 20% of the 2014 approvals were personalised medicines.

In addition to the continued move towards precision drugs, there has been a further refocusing of discovery away from alleviating symptoms towards pre-emptive disease treatment. For example, Janssen R&D, part of Johnson & Johnson, has launched three research platforms focused on disease prevention, disease interception, and the microbiome – areas, it says, ‘of transformational medical innovation that are expected to change the healthcare landscape’.

There has been a further refocusing of discovery away from alleviating symptoms towards pre-emptive disease treatment

‘The future of healthcare will increasingly depend on identifying and correctly interpreting the earliest signals of disease susceptibility, preventing or intercepting disease before it even begins, and using the latest scientific insights from promising, emerging fields like the microbiome, to transform medicine,’ said William Hait, Global Head of Janssen R&D.

As a result, the Netherlands-based Janssen Prevention Center (JPC) will focus on the prevention of chronic, non-communicable diseases such as Alzheimer's, heart disease, cancer and autoimmune diseases, which increasingly impact ageing populations and burden healthcare systems globally. The Disease Interception Accelerator (DIA) is a new, incubator-like group based in the US (Raritan, NJ) that addresses the root causes of disease.

‘Disease interception will intervene earlier than today’s clinically accepted point of diagnosis and seek solutions that stop, reverse or inhibit progression to that disease, for instance Type 1 diabetes or various forms of cancer,’ said Benjamin Wiegand, Global Head, DIA. The DIA will work to understand disease susceptibility, risk assessment and tackle the origins of disease such as genetic predisposition, environmental exposure and phenotypic alterations.

The Janssen Human Microbiome Institute (JHMI), meanwhile, will focus on the human microbiome. ‘By better understanding the microbiome – the diverse population of bacteria living in and on the human body – we hope to gain a deeper understanding of its role in disease and find new therapies to address major autoimmune diseases and other conditions for which no sufficient treatment options exist today,’ said Dirk Gevers, Global Head, JHMI.

Cross-sector collaboration

As people are living longer than ever before, there is a greater socioeconomic need for strategies to prevent illnesses associated with ageing or lifestyle. Ageing diseases such as Alzheimer’s remain high on the discovery agenda and the dementia field will benefit from a new £50m initiative within Europe to improve drugs that could prevent the condition. Scientists from across Europe will collaborate to identify people at high risk of developing Alzheimer’s disease and invite them to participate in trials of new drugs that could slow its onset. The European Prevention of Alzheimer’s Dementia Initiative (EPAD) will involve 35 partners from the academic and private sectors and will initially run for five years.

As people are living longer than ever before, there is a greater socioeconomic need for strategies to prevent illnesses associated with ageing or lifestyle

In the UK, it also involves partners from the Universities of Cambridge, Oxford and Cardiff. It will establish a European-wide register of 24,000 people deemed at high risk of developing dementia. Scientists hope that by identifying relevant biomarkers, they will detect people with early stage dementia even if they have no noticeable symptoms.

With such a complex slow-acting disease, collaboration on finding new Alzheimer’s treatments is essential. For this reason, the Alzheimer’s Drug Discovery Foundation (ADDF) and Pfizer’s Centers for Therapeutic Innovation (CTI) will work together on finding small-molecule drugs for Alzheimer’s disease and related dementias. ‘By leveraging our combined resources and proficiency, we believe we can speed up the discovery and development of new drugs for Alzheimer’s disease and potentially benefit tens of millions of people,’ says Howard Fillit, MD, Founding Executive Director and CSO at ADDF.

Longer-term relationships

Another discovery trend is that outsourced collaborations are becoming more long-term. For example, Evotec and Sanofi have entered into negotiations for a major multi-component strategic collaboration expected to be signed in 2015. As part of the deal Evotec will acquire Sanofi’s scientific operations in Toulouse where Evotec will create a European compound management facility and service. The deal also covers an open innovation programme with Sanofi and Evotec offering their combined approximately 1.7 million small molecule libraries to biotech and other pharma players. It also nets Evotec a €250m minimum guaranteed commitment from Sanofi over the next five years, including an undisclosed upfront cash payment.

For contract research organisations generally, accelerating research is a major consideration

For contract research organisations generally, accelerating research is a major consideration. Under the new banner of Covance Early Phase Development Solutions, drug development company Covance has introduced what it calls a multi-disciplined approach to early drug development that aims to help companies accelerate delivery timelines.

‘Our market research showed that the two greatest challenges our biopharma clients face today are continuity of a drug development programme – both scientific and operational – and the need for stronger outsourcing partnerships,’ said Steve Street, VP & Global General Manager, Covance Early Development. ‘We created Early Phase Development Solutions to help our clients overcome those challenges.’

The company says that having a dedicated team provides the ongoing continuity essential for faster and more successful early drug development. These teams stay with a client’s programme throughout the development journey, ‘minimising cumbersome hand-offs’ and delivering guidance at every step. The same team that delivers the first-in-human ready molecule is available to partner with the sponsor as the programme advances through Phase I and Phase II trials to proof-of-concept and full-development ready.

Synthetic biology

An area of innovation likely to benefit the drug discovery sector is synthetic biology – the design of biological organisms with new or improved functions. This is an area that many governments are keen to fund and develop. Scientists in Edinburgh, Scotland, for example, have been promised £11.4m over five years for a new centre to advance research in synthetic biology. Researchers will explore how stem cells can be reprogrammed for use in personalised medicines, help to create improved safety tests for new treatment, and build tools to help identify new types of drugs.

Researchers will explore how stem cells can be reprogrammed for use in personalised medicines

As part of the investment, there will also be two collaborative projects to help create the fragments of DNA needed to create useful biological components. These projects include a £2.4m plan by the Universities of Edinburgh and Liverpool to study the rapid design and synthesis of DNA circuits. An additional £2m project involving the University of Cambridge and the Genome Analysis Centre will seek to enhance the national capacity of synthetic DNA design and manufacture. Synthetic biology research centres are also to be created at the Universities of Manchester and Warwick.

Gene-editing tools

Genome-editing tools are also becoming more important in drug discovery. This year AstraZeneca (AZ) announced its new programme to develop new medicines using CRISPR (clustered regularly interspaced short palindromic repeats). CRISPR enables researchers to make changes to specific genes in a faster and much more precise way than current methods. AZ will share cell lines and compounds with its partners, complementing the company’s in-house CRISPR programme and building on its ‘open innovation’ approach to R&D.

Meanwhile, one of AZ’s recent collaborations in the G protein–coupled receptors (GPCR) field appears to be bearing fruit. Heptares Therapeutics, a ‘clinical-stage GPCR structure-guided drug discovery and development company, says that using its proprietary StaR technology, the first stable version of Protease-Activated Receptor-2 (PAR2) in a therapeutically relevant form has been generated, from which its X-ray structure has been solved. PAR2 appears to play a key role in neurogenic inflammation and pain in particular associated with cancer, osteoarthritis and gastrointestinal pain.

Because of the unusual mechanism of activation, which leaves part of the receptor to act as its own ligand, it has proved extremely difficult to identify small molecule antagonists which could be used as a treatment for such pain conditions.

Figure 1: Global new active substances: first launches by region 2001-2013<br>Source: Scrip Magazine (2001–2006), Pharmaprojects/Citeline Pharma R&D Annual Review (2007–2014)

Figure 1: Global new active substances: first launches by region 2001-2013
Source: Scrip Magazine (2001–2006), Pharmaprojects/Citeline Pharma R&D Annual Review (2007–2014)

Sigma-Aldrich is also collaborating in the CRISPR field with the Institute of Molecular Genetics, Czech Center for Phenogenomics, to establish CRISPR Core Lab. ‘With the availability of our CRISPR Technology, scientists will be able to more consistently and confidently modify genes of interest leading to more reproducible outcomes in their research,’ says Sean Muthian, Director of Strategic Marketing and Collaborations at Sigma-Aldrich.

‘Employing new technologies based on custom programmable nucleases, such as the CRISPR/Cas technology, into our service portfolio reduced turnaround times [by] over 75% compared [with] conventional methods,’ said Radislav Sedlacek, Director of the Czech Center for Phenogenomics. ‘Now rodents harbouring targeted genetic mutations, including knockin, point mutations, and fusion proteins, can be produced in as little as six weeks, and at a fraction of the previous cost.

‘Not surprisingly, service requests for these technologies have undergone substantial growth over the past year, reaching almost 100 projects at the end of 2014,’ he said, adding: ‘Our collaboration with Sigma-Aldrich will allow us to further improve our service efficiency and keep pace with our growing order book.’

Faster routes to hits

Rational design is one of the concepts widely touted to achieve faster and better drug hits. Accurately calculating binding affinities between a protein and a small molecule is critical to rational design of new drugs and companies have used ‘in silico’ drug discovery ­– i.e. computer modelling and simulation of molecules – for some time. Cloud Pharmaceuticals, in Durham, North Carolina, believes it has been breaking new ground in this field: ‘Our technology, called Inverse Design, computationally designs small molecules and peptides that inhibit the activity of protein targets, which are produced by the genes responsible for certain pathologies,’ says Shahar Keinan, CSO, Cloud Pharmaceuticals.

The company says this design process takes place much more quickly and effectively than traditional methods. Qualified drug candidates can be identified and advanced to the next stages of development more rapidly to reduce the cost, increase efficacy, reduce toxicity, and enable precision medicine by providing more than one drug per target.

We’re able to identify novel drug candidates that exhibit low probability of toxic side effects and high probability of success

Keinan says: ‘Past in silico methods, such as ‘docking,’ have inconsistent results due to inaccurate prediction of activity. Inverse Design overcomes these challenges by combining three different technologies – cloud computing, quantum mechanics/molecular mechanics, and molecular property simulation. This approach enables us to calculate accurate binding affinities in a fraction of the time and choose only molecules that could make a useful drug.

‘Plus we’re able to identify novel drug candidates that exhibit low probability of toxic side effects and high probability of success,’ says Keinan. ‘Very often, the same protein will mutate and cause different types of illness or disease. Therefore, targeting proteins at a molecular level helps to identify more effective treatment protocols.’

Bioinformatics growth

The increasing focus on genomics and proteomics and the growing number of government initiatives based on patient data means that bioinformatics are going play a key role in future drug discovery. The market for bioinformatics is forecast to grow to US$12.86bn by 2020, according to analyst However, it says the need for skilled personnel capable of dealing with the complexity of the bioinformatics tools and the lack of common data formats are limiting this market. What the industry needs is standardised databases and solutions that control data overload due to the piling-up of data from the numerous experiments conducted.


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Illustration of proposed design of AstraZeneca’s new Global R&D centre and corporate HQ in Cambridge, UK. © Herzog & de Meuron Figure 1 Global new active substances: first launches by region 2001-2013 Source: Scrip Magazine (2001–2006), Pharmaprojects/Citeline Pharma R&D Annual Review (2007–2014)

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