Academia Big Pharma collaboration in drug development

Sir Mark Pepys

We are extremely fortunate to be living in an era of unparalleled biomedical progress, dramatically improved fundamental understanding of physiology and pathophysiology, and capacity to intervene and implement new therapies. And yet it has become increasingly difficult to develop new medicines and make them available to patients with unmet medical needs. Indeed, drug development, the painful process of creating new medicines, demonstrating their effectiveness, and then bringing them successfully through the regulatory process to approval as licensed products available for commercial prescription to patients, is the slowest, most expensive and difficult undertaking conducted by the human race.

To put this into perspective, building and commissioning a new nuclear power station, a new aircraft model, any huge civil engineering project or, for example, putting a man on the moon, may each take the same 10 – 15 years and cost more than the mere one billion US dollars it costs to produce a new drug and there is a high degree of certainty that once started and funded, the project will succeed. This is never the case with new drugs as about 95 per cent of them fail before the finishing post is reached.

The many reasons for this egregious attrition rate have been comprehensively analysed and discussed elsewhere. I will not revisit this territory here except to note, as have many others, that the regulatory environment, imposed on drug development by society through its elected legislators, is so strict as to be, frankly, punitive. Nobody wants medicines prescribed to patients, for the purpose of benefiting their health and alleviating suffering, to cause damage instead. However the quest for absolutely safe medicines is in vain because it ignores the fact that all pharmacological interventions have unavoidable dose dependent side effects. In other words, all medicines can be poisons if administered inappropriately or in excess. The goal is to have an acceptable therapeutic index; the ratio between the beneficial therapeutic dose and the poisonous one. The goalposts for acceptability have now shifted so far that, almost certainly, many potentially very helpful compounds are discarded during development and never become medicines. Scares about licensed new medicines, often ill founded or based on premature and inexpert epidemiology, also pose inappropriate threats to the availability of helpful drugs. Whilst there may be discussion about the scale and importance of this problem, it is unarguable that many life saving medicines from an earlier era would never be licensed nowadays. Think of aspirin, digoxin, colchicine, for example, with their adverse side effects within or close to the therapeutic dose range.

Of course there are also many other reasons why drug development is now so difficult, key among which are the challenges of, firstly, gaining a deep understanding of the pathobiology of disease so that specific therapeutic targets can be validated, and secondly, designing suitable and acceptable interventions. Fortunately, within the past 10 years major changes in the way in which Big Pharma conducts its R&D give solid grounds for optimism that these challenges can be met. These changes spring from the recognition in industry that cutting edge, state-of-the-art, fundamental work in biomedicine is very largely conducted in academic institutions. It is from these laboratories, not Big Pharma, that the major scientific breakthroughs in mechanistic, molecular and cellular understanding and the corresponding publications emerge. Excellent scientists within Big Pharma have expertly reviewed the literature, testing new results as they emerged and crucially have often found that they are not reproducible, even when published in the most prestigious high-impact journals. But few if any of the major steps forward in basic biomedical science have come from industry in recent years. On the other hand, academics have no expertise or competence in the major essential activities required to find developable compounds and progress them through the regulatory labyrinth of preclinical pharmacology, toxicology, clinical pharmacology and then clinical trials in humans. This requires vast, wide ranging skills, experience and enormous amounts of money. Even in the few areas where academics have great competence such as synthetic organic chemistry, solving a difficult synthetic problem is not the same as the often essential, arduous iteration through hundreds or more variations on a structural theme to overcome a medicinal chemistry problem. Then there are the matters of scaling, production, formulation and much else besides. All these skills reside in industry not academia. The Pharma industry is also the only place with competence in large scale production of biopharmaceuticals, pharmaceutical grade monoclonal antibodies and recombinant proteins. Clearly what is needed is a synergistic collaboration bringing together the respective competence and expertise of academia and industry.

All the major pharmaceutical companies have recognised this need and have introduced a range of different models for association with academia and small biotech or biopharma companies. Attempted solutions range from outright acquisition of small companies to several different collaborative arrangements with academia. At one extreme, companies have paid very large sums for exclusive rights to all commercialiseable output from particular institutions or parts thereof. At the other extreme are much smaller, discrete, collaborations between individual academic scientists and Big Pharma. The latter is the model in which I personally am currently engaged, in association with GlaxoSmithKline (Table 1), and it has been extremely effective.

The other major recent change in the drug discovery and development landscape involving academia has been the focus on rare diseases. Although some drugs were developed for small indications, no typical Big Pharma company had any substantial interest in specifically developing medications for rare or orphan conditions until about 10 years ago. That has now radically changed and it has become the norm for large companies to be active in this space, often in collaboration with academic scientists or small biotech companies with highly specialised expertise in such disorders.

My own efforts in drug discovery and development started with our publication in 1984 of the first small molecule compound which, in vitro under physiological conditions, specifically dissociated the two major protein components of amyloid deposits¹. I suggested that this could be developed into a new therapeutic approach for systemic amyloidosis, which was then an almost untreatable and inevitably fatal condition. Systemic amyloidosis is rare, with an approximate prevalence in developed countries of up to about one per 10,000 of the population, and is the recorded cause in about one per 1,000–1,500 deaths. After publishing the 1984 paper, I enthusiastically hawked my new therapeutic idea around many of the large pharmaceutical companies, proposing a possible new treatment for amyloidosis. The universal response was “What is amyloidosis?” and there was absolutely no interest. However at just that time, Dr. George Glenner ‘rediscovered’ the long forgotten association between amyloid deposits in the brain and Alzheimer’s disease. His characterisation of the actual protein which formed the cerebral amyloid deposits provoked a sudden avalanche of interest in amyloid. My proposed therapeutic approach targeted the normal plasma protein, serum amyloid P component (SAP), which was known to be universally present in all amyloid deposits of all types, and which I had previously shown to be due to the specific binding of SAP to the amyloid fibrils which constitute the bulk of amyloid deposits². The fact that any treatment which eliminated amyloid deposits could be relevant to Alzheimer’s disease made the project much more attractive and I therefore continued my efforts to interest Big Pharma.

By the mid 1990s, the 3D crystal structure of SAP had been solved in collaboration with Professor Tom Blundell’s team³, I had invented and patented a high throughput screen for inhibitors of SAP binding to amyloid fibrils⁴, and we had created SAP knockout mice which did not develop amyloidosis as rapidly or extensively as wild type mice, thus validating SAP as a therapeutic target⁵. Thus in 1996, Roche in Basel eventually took up the project. A spectacularly successful collaboration then ensued with rapid identification of a very promising lead from high throughput screening, followed by a fertile mixture of good science, serendipity and professional medicinal chemistry which delivered a potent, safe, new medicinal compound, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), with a novel and unique mechanism of action⁶. CPHPC potently depletes almost all SAP from the circulation and this depletion persists for as long as the drug is administered⁷.

Although Roche decided not to develop CPHPC for either amyloidosis or Alzheimer’s disease, the company did allow us to work on it, which enabled me to evaluate the drug in small clinical studies in amyloidosis⁷, and, in collaboration with Professor Martin Rossor, also in patients with Alzheimer’s disease⁸. We are convinced that CPHPC has important potential for treatment and possibly prevention of both conditions. Availability of CPHPC from Roche enabled me to invent a further novel approach to treatment of systemic amyloidosis. Plasma SAP depletion by CPHPC permits the safe and effective administration of anti-SAP antibodies, which then target amyloid deposits in the tissues and trigger their elimination by macrophages⁹. In 2008, Roche divested CPHPC entirely to us and in 2009, GSK licensed the new CPHPC plus anti‑SAP antibody invention¹¹. Intensively collaborative development has proceeded under the auspices of GSK’s Academic Discovery Performance Unit¹² and the therapy is currently in clinical trials in patients with systemic amyloidosis¹³. We have also had another project in collaboration with GSK’s Discovery Partnerships with Academia (see Table 2).

This is a wonderfully positive development for the patients suffering from a rare disease with a potentially grave prognosis. It exemplifies several key aspects of the power of appropriately constructed and conducted academia‑Big Pharma collaboration in drug development. The academic contribution has comprised two key aspects: (i) world leading expertise in the basic science and knowledge of the pathobiology of the proposed therapeutic indication, enabling target identification and major contributions to drug design; (ii) world leading expertise in, and access to, the target patient population. In our case, the UK NHS National Amyloidosis Centre, which I founded in 1999 after specialising in the care of patients with this disease since the 1970s, has become the largest clinical and research centre for amyloidosis in the world. Led by Professor Philip Hawkins, the multidisciplinary team of about 55 clinical, scientific, technical and administrative staff now sees more than 3,500 patients per year and follows the largest and most diverse cohort of amyloidosis patients. These are invaluable resources for drug development. On the other side, Big Pharma has its vast array of drug development knowledge, experience, competence and funds, which uniquely can enable academic aspirations to achieve reality for the benefit of suffering patients. The experience of academics and Pharma industry personnel working together has been exhilarating and rewarding, with extensive mutual exposure to our respective expertise and working cultures. Ultimately, the effectiveness of this new model will be established by the emergence of prescribeable and reimbursed new medicines. We are not there yet, but so far so good.

The systemic amyloidosis programme is just one of the current programmes in the Wolfson Drug Discovery Unit at University College London. Others are directed at very common conditions, Alzheimer’s disease and Type 2 diabetes, in both of which amyloid deposits are always present but not yet proven to be directly pathogenic. We also have a programme in cardiovascular disease, heart attacks and strokes, as well as many inflammatory tissue damaging diseases. The target molecule in all of these is C‑reactive protein (CRP), the classical human acute phase protein¹⁰. We are fortunate to have various different levels of invaluable advice, consultation and collaboration from GSK on each of these programmes. Like all drug discovery and development, progress is always slow, difficult and expensive. Whether all or any of the programmes will deliver new drugs and whether our present model of academic‑Big Pharma collaboration is the best among the different forms which are available, remains to be seen. But after 30 years of trying, we are not about to give up. Watch this space!

References

1. Hind CRK, Collins PM, Caspi D, Baltz ML, Pepys MB. Specific chemical dissociation of fibrillar and non-fibrillar components of amyloid deposits. Lancet 1984;ii:376-378
2. Pepys MB, Dyck RF, de Beer FC, Skinner M, Cohen AS. Binding of serum amyloid P component (SAP) by amyloid fibrils. Clin. Exp. Immunol. 1979;38:284-293
3. Emsley J, White HE, O’Hara BP, Oliva G, Srinivasan N, Tickle IJ, et al. Structure of pentameric human serum amyloid P component. Nature 1994;367:338-345
4. Pepys MB, Blundell, TL. Screening assays to identify therapeutic agents for amyloidosis. Great Britain patent 9317120.5. 17 August 1993
5. Botto M, Hawkins PN, Bickerstaff MCM, Herbert J, Bygrave AE, McBride A, et al. Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene. Nature Med. 1997;3:855-859
6. Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 2002;417:254-259
7. Gillmore JD, Tennent GA, Hutchinson WL, Gallimore JR, Lachmann HJ, Goodman HJB, et al. Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis. Br. J. Haematol. 2010;148:760-767
8. Kolstoe SE, Ridha BH, Bellotti V, Wang N, Robinson CV, Crutch SJ, et al. Molecular dissection of Alzheimer’s disease neuropathology by depletion of serum amyloid P component. Proc. Natl. Acad. Sci. USA 2009;106:7619-7623
9. Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch A, Gilbertson JA, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 2010;468:93-97
10. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006;440:1217-1221
11. http://pentraxin.wordpress.com
12. The Academic Discovery Performance Unit is a ppecialist team working specifically with academics on a portfolio of novel targets, which enables academic partners to make their ideas reality by providing the unique capabilities and expertise of Big Pharma, and allowing them to benefit from GSK drug discovery infrastructure and support.
13. http://www.clinicaltrials.gov/ct2/show/NCT01777243?term=amyloid+gsk&rank=2

Biography

Professor Sir Mark Pepys is a clinician scientist whose work on systemic amyloidosis has transformed diagnosis and improved management and patient survival. He invented serum amyloid P component (SAP) scintigraphy; enabling the first non-invasive diagnosis and monitoring of systemic amyloidosis, and established the UK NHS National Amyloidosis Centre in 1999. He identified SAP and CRP as therapeutic targets, devised new compounds to inhibit and deplete them, and is developing drugs in collaboration with GlaxoSmithKline, and with UK Medical Research Council and British Heart Foundation funding. Professor Pepys is a Fellow of the Royal Society, Founder Fellow of the Academy of Medical Sciences, and has been a member of both academies’ Councils. In 2007, he was Royal College of Physicians Harveian Orator and won the Royal Society GlaxoSmithKline Prize; in 2008 he received the Ernst Chain Prize for medical discovery. On retiring as UCL Royal Free Campus Head of Medicine in 2011 he became the first Director of the UCL Wolfson Drug Discovery Unit, created with Wolfson Foundation funding. He was made Knight Bachelor for services to biomedicine in the 2012 New Year Honours.