Development of Anti-Inflammatory Drugs - the Research and Development Process

MiniReview

Development of Anti-Inflammatory Drugs – the Research andDevelopment Process

Richard Graham Knowles

Arachos Pharma Ltd, Stevenage Bioscience Catalyst, Stevenage, UK

(Received 28 June 2013; Accepted 21 August 2013)

Abstract: The research and development process for novel drugs to treat inflammatory diseases is described, and several currentissues and debates relevant to this are raised: the decline in productivity, attrition, challenges and trends in developing anti-inflammatory drugs, the poor clinical predictivity of experimental models of inflammatory diseases, heterogeneity within inflam-matory diseases, ‘improving on the Beatles’ in treating inflammation, and the relationships between big pharma and biotechs.The pharmaceutical research and development community is responding to these challenges in multiple ways which it is hopedwill lead to the discovery and development of a new generation of anti-inflammatory medicines.

This MiniReview describes the research and development(R&D) process for novel drugs to treat inflammatory diseasesand raises several current issues and debates relevant to this.This is written from the point of view of a drug discovery biolo-gist who has sought new candidate drugs for 27 years withinbig pharmaceutical companies (Wellcome/GlaxoWellcome/GlaxoSmithKline), headed Inflammation/Respiratory Biologygroups/departments, most recently Director of Clinical Biologyresponsible for asthma biomarkers, and advised late-stage devel-opment teams in Respiratory on biomarker discovery. Theauthor is now CEO of Arachos Pharma: a start-up Biotechwhich is seeking the investment to fund development of twoanti-inflammatory medicines, as well as being a visiting Profes-sor of Pharmacology at the University of Hertfordshire, UK.Much of the discussion on the issues facing drug discovery inthis and other areas is based on a series of articles in NatureReviews Drug Discovery [1–3] and elsewhere [4,5].

The Drug Research and Development Process

The drug research and development process is long, arduousand costly and so is typically broken down into multiplestages with checkpoints between each of these stages to man-age the risks and costs. These checkpoints govern the processfrom idea to medicine, asking critical questions appropriate toeach stage before proceeding to the next (fig. 1).

Early Drug Discovery

The early, pre-clinical part of the process takes scientific ideasfor new medicines and subjects them to scrutiny (fig. 2).

Target validation consists of a series of activities, whichaim to build confidence that a drug which acts by modifyingthe function of the target or pathway will deliver the efficacyand safety required. The degree of target validation varies,depending upon the nature of the disease, type of target, etc.These days, there is increased emphasis 1) on target validationin human primary cells, tissues and explants, especially if theycan be obtained from patients with the relevant disease; 2) rel-evant clinical information such as evidence for activation of aspecific pathway in the disease tissue; 3) complex and chronicanimal models and humanized models of diseases; and less oneffects in simple, acute animal models. Despite what may be agreat deal of careful and skilled scientific study of this kind, atarget is never fully validated until a drug acting on it worksin patients! Therefore, significant risk carries over into theclinical efficacy studies.The other major components of starting a drug discovery

project besides target validation and selection are establish-ment of appropriate biological assays, and finding appropriatechemical or biological starting points for an optimization pro-cess to work on, called ‘lead discovery’ or ‘lead generation’.To start the discovery of (usually) synthetic organic com-pounds that may be optimizable into medicines, the two majorapproaches used are a) high throughput screening (millions ofcompounds), carried out in multi-well plates (384 or 1536well), performed with automated equipment including roboticsand b) knowledge-based rational design, likely to includecomputer modelling, structural knowledge, for example, X-raycrystallography and cheminformatics. Biologicals such as anti-bodies or decoy proteins (see [4] or nucleotide-based therapiessuch as antisense or siRNA drugs have rather different routesto their initiation and optimization which will not be discussedin detail here.

Author for correspondence: Richard Graham Knowles, ArachosPharma Ltd, Stevenage Bioscience Catalyst, Stevenage, SG18 9LZ,UK, e-mail [email protected]

© 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd

Basic & Clinical Pharmacology & Toxicology, 2014, 114, 7–12 Doi: 10.1111/bcpt.12130

Identification of candidate medicines starting from the leadmolecules identified require a rigorous iterative process ofhypothesis generation, molecular design, synthesis and thentesting (fig. 3). The tests used have usually been refined andextended from those used in lead generation: refined to pro-vide robust and highly quantitative estimates of their efficacy,potency and mechanism of action on the molecular target andextended into assays that give more information on the func-tion of the molecular target, often in an appropriate cellularcontext. In addition, other assays will be added to the evalua-tion process, to assess early indications of how the moleculesmay be handled in an intact human being, how specific it is tothe intended target and whether there are any signals warningof potential safety or tolerability issues. As the optimizationprogresses, small numbers of the most promising compoundsmay be assessed in animal models to demonstrate efficacy onthe target pathway and processes related to the target disease.In parallel with this lead optimization, work will have been

proceeding to define what the desired medicine candidateshould look like. This is often referred to as the target product

profile (TPP) and will include the clinical proposition (e.g.minimum/desired efficacy, route and frequency of adminis-tration, sensitivities to taste or tolerability) and the unmetpatient needs, market dynamics, current therapies, competitor

Fig. 1. The R&D process: checkpoints governing the process from idea to medicine.

Fig. 2. The pre-clinical part of drug discovery.

Fig. 3. Lead optimization from leads to candidate medicines. Abbrevi-ation: Drug metabolism and pharmacokinetics (DMPK).


8 RICHARD GRAHAM KNOWLES MiniReview

landscape, scientific breakthroughs and disease understanding.The synthesized molecules can then be bench-marked againstthis TPP to see whether it has been achieved. Also, in parallelwith lead optimization, a programme of work is likely to becarried out to discover, develop and validate biomarkers touse in early clinical studies, to demonstrate that the candidatemedicine affects the target pathway(s) as planned.As indicated in fig. 3, the lead optimization process is likely

to require multiple rounds of synthesis and testing to find can-didate drugs with the right combination of properties, and itwill typically take ~2 years from leads to a candidate medi-cine, with a team of 10–20 scientists. Nonetheless, it is notguaranteed to succeed, with some target classes proving moretractable than others.

Into the Clinic

Having identified a candidate medicine, then, an intensiveprocess of developing and characterizing the selected com-pound is initiated that will continue through pre-clinicalstudies, phases 1, 2 and 3 clinical studies and on to its usein patients on the market (phase 4 and post-launch monitor-ing (fig. 4). During this time, pre-clinical and clinicalknowledge of the candidate medicine will increase, and if ithas the right safety and efficacy, this knowledge will enableit to be launched as a medicine; even then, knowledge willcontinue to accumulate either for better (e.g. long-term bene-fits becoming evident) or worse (e.g. low incidence sideeffects becoming apparent only with larger numbers ofpatients taking it as with Vioxx).This will include an extensive programme of safety and tol-

erability studies as required by regulatory authorities and ethi-cal review bodies which over time will extend in terms ofduration and numbers and variety of exposed subjects. This iscritical for new anti-inflammatory medicines as they will needto have either safety/tolerability or efficacy benefits over theexisting drugs, and inflammatory diseases are very oftenchronic in nature, and these will usually need to be maintained

in chronic use. The programme will also include drug absorp-tion distribution metabolism and excretion (ADME) studies:pharmacokinetics/toxicokinetics, in vitro metabolism/enzymol-ogy, ADME in toxicology species, metabolite identification,progressing on to identify routes of human metabolism tocompare human and animal metabolism, a human radiolabelstudy and bioanalysis for clinical and toxicity studies. Further-more, synthesis of the candidate will need to scaled up fromthe research scale (typically <1 g) to the large scales neededfor the development and clinical studies (typically >1 kg) andeventually to supply the market (may be >1Tonne per annum)and a suitable formulation developed in parallel; this lattermay be very simple for initial studies (e.g. dispersed powderin water for oral; nebulized solution for inhaled drugs) butmay eventually need to be sophisticated, with controlled ortargeted release to specific regions of the gut, skin or lung, orcombining it with other medicines.Many groups contribute their expertise to the design, run-

ning and reporting of clinical trials on candidate medicines(fig. 5). Although large pharmaceutical companies may carryout these functions internally, smaller companies and biotechsmay outsource many or all these required functions, and evenin the larger companies, there is an increasing trend to out-source more.

Translational Medicine: Translating the Pre-clinicalScience into Clinical Findings

A prime aim of early studies is to see how the pre-clinical sci-ence on a candidate medicine translates into its clinical use.This can be represented by a series of questions. Does the ani-mal and in vitro pre-clinical biology with the candidate link toman? How to monitor pre-clinical findings: efficacy-related,safety-/tolerability-related, and do we have biomarkers ofthese? Can the expected/predicted pharmacology be seen involunteers? Are clinical challenges or other short-term efficacymodels validated? What does the Gold Standard or currentStandard-of-Care medicines do in comparison?

Fig. 4. Progression of candidate medicines into clinical trials.


MiniReview THE ANTI-INFLAMMATORY DRUG DISCOVERY PROCESS 9

The answers to these questions are used to design and carryout a series of phases of clinical study:

• Phase 1 studies in healthy volunteers to establish thesafety, tolerability, pharmacokinetics and hopefully phar-macodynamics (PD, i.e. the time and dose dependenceof effect on the molecular target) on initially single doseand subsequently on repeat dosing with the candidatemedicine.

• Phase 2a studies in subjects with an inflammatory dis-ease, dosed with the candidate medicine at a dose ordoses chosen based on the phase 1 data; this may be ashort course looking at efficacy on symptoms and bio-markers of the inflammatory process, either in stable dis-ease or after a challenge to cause a mild exacerbation ofthe disease. Examples include looking at the effect of a14- or 28-day course of treatment on the signs andsymptoms of rheumatoid arthritis, or looking at the effectof a 7-day course of treatment on allergen challenge inmild asthma patients, seeking decreases in airwayresponses and inflammatory biomarkers. If positive, suchstudies are likely to be regarded as clinical proof of con-cept (PoC): clinical evidence giving confidence that thedrug works in an appropriate population and is likely tomeet the required target product profile. Increasingly,such studies may be based on a ‘stratified medicine’approach, where the target population is selected basedon biomarkers or other characteristics to optimize thechances of success. Well-designed and carried out PoCstudies are of pivotal importance in drug discovery, as ifthey are positive, they will trigger the large spendingrequired for phase 2b and 3 studies, whereas if they areconvincingly negative, they may cause the abandonmentof the whole enterprise of drug discovery based on thatmolecular target.

• Phase 2b studies are carried out in patients with targetedinflammatory diseases, sometimes selected for to maxi-mize the chance of success or at least stratified to allow

the analysis to determine this. For example, treatmentsthat are appropriate for the treatment of eosinophilicasthma (such as anti-IL-5 antibodies or CRTh2 antago-nists) have been tested either in groups selected (fromblood or sputum eosinophil numbers) to be highly eosin-ophilic at baseline, or else this is measured in a broadergroup to allow post hoc analysis by eosinophil numbersfor use in future studies. The primary aim of phase 2bstudies is to confirm the phase 2a findings, often in alarger number of patients and during a longer period oftreatment, and to determine the dose response of anybeneficial effects (and of any safety or tolerability find-ings), to select the optimum dose or doses for use inphase 3 studies.

• Phase 3 studies are carried out to provide the pivotalevidence for both clinical efficacy and safety/tolerability,and thence, pharmacoeconomic benefit is in the chosenpopulation; this will provide the key evidence to allowthe compilation of a package of information to submit toregulatory authorities, seeking their approval to launchthe candidate medicine onto the market. They are typi-cally carried out at a single dose level, carefully selectedon the basis of the phase 2 data. They may further refinethe population of patients you are aiming to treat. Usu-ally, evidence of benefit in two similar but independentphase 3 studies will be required for regulatory approval,although in rare disease indications a single study maybe agreed with the authorities to suffice. These phase 3studies will need to be randomized, double-blind, pla-cebo-controlled trials carried out to the highest standards,with large numbers (hundreds to thousands) of patientsper arm, and often including marketed gold standardmedicines to demonstrate equivalence or superiority.

• Phase 4 and post-launch monitoring. Hopefully, theresult of all this work and expense is a new anti-inflam-matory medicine to meet unmet clinical needs, launchedonto the market. However, even then, further studies are

Fig. 5. Departments and functions contributing to clinical trials of a candidate medicine. Blue: likely external contributions even in a large pharma-ceutical company.



likely to be carried out, both in continuing to monitorfor adverse events in clinical use in large numbers onthe market and in phase 4 studies which may be toextend the medicine’s use into different patient popula-tions or else to evaluate further any perceived safety ortolerability risks. In the latter case, these may be man-dated by regulatory authorities.

Issues and Debates in Inflammatory Medicine Researchand Development

The decline in drug discovery productivity, and conversely,the cost of successfully launching a new medicine have beenpointed out to have been worsening over several decades(fig. 6, Scannell et al. 2012). Some postulated reasons are1 The ‘better than the Beatles problem’: regulators andhealthcare payers require that new drugs will improveupon all the previous medicines to justify being sold for aprescription medicine price. To justify premium prices,highly innovative medicines that result in markedlyimproved health outcome are needed. Clearly, thisbecomes increasingly difficult over time. Nonetheless,there remain clear unmet needs for novel anti-inflamma-tory medicines, both with better efficacy in either specifictargeted groups or more broadly, or with a better therapeu-tic index, or both. These will also need to be competitivein terms of convenience of administration and price.

2 The ‘cautious regulator problem’: progressive lowering ofthe risk tolerance of drug regulatory agencies obviouslyraises the bar for the introduction of new drugs and couldsubstantially increase the associated costs of R&D. Eachreal or perceived drug safety issue leads to a tightening ofthe regulatory requirements, and these are rarely loosenedagain, even if it seems as though this could be achievedwithout causing significant risk to drug safety.

3 The ‘throw money at it tendency’ is the tendency to addhuman and other resources to R&D, which – until recentyears – has generally led to a rise in R&D spending in

major companies and for the industry overall. It is proba-bly due to several factors, including good returns oninvestment in R&D for most of the past 60 years. Theargument is that much of this increased spending has beenill-advised and unproductive.

4 The ‘basic research–brute force bias’ is the expectationthat increased automation and use of robotics, togetherwith advances in molecular biology, would increase drugdiscovery productivity. Arguably, this has been the intel-lectual basis for a shift of resources and emphasis awayfrom older and perhaps more productive methods for iden-tifying drug candidates. For example, although highthroughput screening performed with robotics and recom-binant expressed target proteins has become highly effi-cient and rapid, it may well be that this is a less fruitfulstrategy in the long-term than knowledge-based strategiesfor lead discovery, linked to lower throughput assays offunctional responses under ‘native’ conditions, that is clo-ser to classical pharmacology in native human cells andtissues. It could also be interpreted that the industry chasednumbers and probability of success through process, ratherthan by valuing the intellect and experience required todevelop a drug, that is, as quantity over quality or processover people. Culture is just as important as technology increating innovation.

A related area of debate is that of how to reduce attrition indrug discovery [1,2]. A substantial proportion of the cost ofdrug discovery comes from the costs of those projects thatfailed, especially those that fail at a late stage after substantialexpenditure has already taken place. Any given project failsbecause of either technical or non-technical reasons. Non-tech-nical attrition occurs for various reasons, such as a change ofstrategy or termination of research in a therapeutic area forscientific or commercial reasons: it can be a considerable,potentially avoidable but sometimes sustained source of costsand lowered R&D efficiency.Challenges and trends in developing anti-inflammatory

drugs include the poor clinical predictivity of experimental

Fig. 6. The decline in drug discovery productivity as indicated by the risk- and inflation-adjusted costs. From Scannell et al. 2012 ‘Eroom’s Law’:the number of new FDA-approved drugs per billion US dollars of R&D spending in the drug industry has halved approximately every 9 yearssince 1950, in inflation-adjusted terms.


MiniReview THE ANTI-INFLAMMATORY DRUG DISCOVERY PROCESS 11

models of inflammatory diseases. Knock-out and transgenicmice have become ‘industrialized’ in how efficiently and rap-idly they can be generated (see point 4 above), and this hasbecome a significant element in target validation for novelanti-inflammatory targets; however, such work is only as pre-dictive as is possible based on the homology or otherwisebetween mouse and human inflammation biology and ofcourse are dependent on the clinical predictivity of the specificinflammatory models used in these mice, which has turned outto be a lot lower than hoped for. For example, much work hasbeen and continues to be published using sensitization to andacute challenge with ovalbumin as a model allergen (typicallydaily exposures to the lung over 3 days), as a ‘model ofallergic asthma’; however, this has been shown to have poorpredictivity for anti-inflammatory mechanisms/candidate medi-cines in clinical allergen challenge to asthma patients.A related problem for modelling the treatment of inflamma-

tion is the heterogeneity within inflammatory diseases. Toagain use asthma as the example, the inflammation and mech-anisms may be very different and require different treatments,in allergic versus non-allergic asthma, or severe versus mildasthma, or neutrophilic versus eosinophilic asthma, etc.Nevertheless, it is difficult to realistically assess the likely

impact (positive and negative) of interventions without demon-strating these in animal models that are reasonable and as pre-dictive as possible, in which the inflammed tissue is integratedwith the endocrine, nervous and cardiovascular systems. In con-sequence, substantial efforts are being put into seekingimproved models, including cross-company collaborations andsymposia, for example the recent Cross Company Models ofRespiratory Disease Symposium [6]. Moreover, they can be use-ful for pharmacokinetic/pharmacodynamic studies to allow dosemodelling to man, even if the comparative biology is different.One consequence of these challenges to drug R&D is that

many of the large pharmaceutical companies have beendecreasing their internal investment into (in particular) theearly stages of drug discovery, with mergers, head-countreductions, exits from certain therapy areas and site closureshappening across the world. This is to a significant degree todecrease the cost base but also to focus internal budget andresources on the late stage of drug discovery, from PoC tolaunch. This loss of effort is being, at least in part, taken upby small biotechs funded mostly by venture capital to takedrug discovery through to clinical PoC, with subsequent saleto or partnership with large companies for the late-stage

development. It remains to be seen what the long-term conse-quences of this shift will be.

Responses to the challenges in anti-inflammatory drugdiscovery

There continue to be many significant unmet clinical needs inpatients with inflammatory diseases, and so, despite the seriesof challenges described, there continues to be substantialefforts to discover and develop new medicines for thesepatients. The pharmaceutical research and development com-munity is responding to these challenges in several ways:

• Greater collaboration and open sharing of data (negativeand positive) between pharmaceutical companies: biotechand academia

• Improved practices in pre-clinical research

• Continued refinement in models of inflammatory dis-eases

• Greater use of human (and especially disease-relevant)cells, tissues and explants

• Greater emphasis on discovery and use of biomarkers

• Stratified medicine to target new medicines to those whowill get most benefit

• Greater risk sharing between large pharma and smallbiotechs

It is hoped that these responses will result in a range ofnovel medicines becoming available for the treatment ofinflammatory diseases in due course, improving patients’ livesand reducing healthcare costs.

References

1 Kola I, Landis J. Can the pharmaceutical industry reduce attritionrates? Nature Rev Drug Disc 2004;3:711–5.

2 Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH,Lindborg SR et al. How to improve R&D productivity: the pharma-ceutical industry’s grand challenge. Nature Rev Drug Disc2010;9:203–14.

3 Scannell JW, Blanckley A, Boldon H, Warrington B. Diagnosingthe decline in pharmaceutical R&D efficiency. Nature Rev DrugDisc 2012;11:191–200.

4 Dinarello CA. Anti-inflammatory agents: present and future. Cell2010;140:935–50.

5 Knowles RG. Challenges for the development of new treatments forsevere asthma: a pharmaceutical perspective. Curr Pharm Des2011;17:699–702.

6 Knowles RG, Abbott-Banner KH (eds). 2nd Cross Company Respi-ratory Symposium. J Inflammation 2013;10(Suppl 1):I1–P19.



Development of Anti-Inflammatory Drugs - the Research and Development Process

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