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Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis; 2010.

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Translational Pain Research: From Mouse to Man.

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Chapter 18Drug Discovery and Development for Pain

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18.1. INTRODUCTION

Two decades ago, systemic drugs indicated for pain belonged roughly to three mechanistic classes: the opioids, the nonselective NSAIDs, and the anticonvulsants, the latter class represented by a single member, carbamazepine. As of this writing, there are approximately 10 classes of drugs approved for use in the management of pain in the United States and Canada. Recent additions to the pharmacopoeia for pain exemplify two significantly differing pathways for bringing new pain therapies to market.

On the one hand, there are drugs that have been in clinical use for some time for other indications, which have been shown to have analgesic efficacy and subsequently have obtained additional label indications for the treatment of pain. Examples in this category include the alpha-2 adrenoreceptor agonist clonidine (launched as an antihypertensive in 1966; gained approval for epidural use in the treatment of cancer pain 1996), and the anticonvulsant gabapentin (launched as an anticonvulsant 1994; gained approval for neuropathic pain in 2002). A number of additional marketed drugs have repeatedly demonstrated therapeutic efficacy in pain states in controlled studies but lack specific label approval for this indication. For example, randomized, controlled studies have demonstrated the utility of older tricyclic antidepressants including amitriptyline, nortriptyline, and desipramine in chronic pain states; due to the preponderance of supportive evidence these drugs are considered useful pain therapeutics.

Ongoing advances in the understanding of pain mechanisms continue to reveal opportunities for the creative use of drugs of known pharmacology. In addition, many older, marketed drugs reveal a surprising richness of pharmacology when studied using new methods. Due to their potential for benefit, and also due in no small part to the lengthy and complex process required for the development and regulatory approval of novel drugs, there are many obvious advantages to the study of approved medications for the treatment of pain. The ability to conduct clinical trials with a substance that is already approved for use in humans provides for immediate testing of a hypothesis. Furthermore, since approved drugs have by definition already amassed the requisite preclinical and clinical safety data, positive results from such trials lead to a much shorter path to new regulatory approval, and thus the considerable costs of years of study involved in novel compound discovery and development are avoided.

There are, however, limitations to this approach. Existing drugs may not have the ideal pharmacological or pharmacokinetic properties required. In addition, while the cost outlay of repurposing approved drugs is far less than that of inventing new ones, the retur on investment may be poor. Market protection for drugs with older patents may be limited, and from a purely business standpoint, cost analyses of investing in new research for such older drugs may be unfavorable. In addition, as safety regulation becomes more stringent, pharmaceutical companies may be reluctant to assume safety liabilities of drugs that were originally approved under less rigorous requirements.

On the other hand, recent advances in research have resulted in the development of entirely novel classes of drugs, specifically developed as analgesics and brought forward with pain as an initial indication. These include COX2-selective inhibitors (celecoxib launched 1999 for pain and inflammation), the N-type calcium channel inhibitor ziconotide (launched 2005), the triptan class of serotonin receptor subtype 1B/D agonists (sumatriptan launched early 1990s), and newer cannabinoids such as Sativex, launched in Canada 2005 for the treatment of pain and spasticity due to multiple sclerosis.

Because of the lengthy and complex evaluation required to bring a compound to market, the failure rate of new compounds is extremely high, as are the costs of development. The current estimate of the expenditure required to bring a new compound to market hovers near US $1 billion.1,2 Hundreds of thousands of compounds may be screened in order to identify one or two compounds that are considered suitable clinical candidates. Industry estimates are that these clinical candidates have about a 90% chance of failure during the most costly stage of evaluation, clinical trials. In general, across therapeutic areas, reasons for failure include disappointing pharmacokinetic properties in humans,3 unacceptable clinical safety profiles,4 and lack of clinical efficacy.5 Compounds may also fail to reach the marketplace due to other advances in the therapeutic field (for example, the development of selective serotonin reuptake inhibitors supplanting the tricyclic antidepressants) or commercial reasons, such as the inability of a company to support an orphan drug program. Nevertheless, drug discovery for pain is an exciting, fast-paced, and rewarding field. Both the investigation of the analgesic effects of marketed drugs and the pioneering of novel drug classes are active areas of research and development: a survey of industry pipeline databases reveals more than 25 different mechanistic classes of compounds in various stages of evaluation.

18.2. OVERVIEW OF THE PROCESS OF DRUG DISCOVERY

Drug discovery and development are heavily multidisciplinary undertakings and can be broadly divided into preclinical and clinical phases.

  • Preclinical research requires a minimum of approximately 3 to 4 years and consists of target identification, lead identification, and lead optimization, including preclinical safety and toxicology investigation.
  • Clinical evaluation of proposed new drugs is closely regulated by governmental authorities. Evaluation of safety and efficacy prior to approval for launch of a new drug is divided into three phases as described below.
    • Investigational new drug (IND) (or Clinical Trial Authorization (CTA) filed
      • - Phase 1 or first in human (FIH), safety assessment first dose in human, healthy volunteers not patients; assessment of a biomarker, if applicable
      • - Phase 2: limited efficacy, patients
      • - Phase 3: efficacy, safety, patients
    • NDA filed, drug approved
    • Drug approval and launch
    • Phase 4, postmarketing studies (optional)

From first human dosing to New Drug Application (NDA) filing is a process that takes 5 to 8 years on average.

The discovery of drugs takes place in the preclinical phase and can be further divided as follows.

18.3. TARGET SELECTION/TARGET IDENTIFICATION

The role of folk medicine in drug discovery and the central place that natural products have played cannot be understated. The concept of a molecular receptor or target within the body that is specifically modulated by an exogenously dosed drug is quite recent. The origins of all drug development stretch back before recorded human history to the trial-and-error selection of plant products with beneficial properties. We can only imagine how long it must have taken our ancestors to discover that extracts of poppy, or willow bark, could be useful; however, we can imagine that they would have devoted considerable effort to finding analgesic treatments. The utility of Papaver somniferum poppy derivatives and Salix alba willow bark derivatives is recorded in some of the earliest Egyptian and Greek texts.6,7 The identification of their molecular targets represents a series of classic case studies in pharmacology, ultimately leading to the cloning of the mu opioid receptor 8-11 and the cyclooxyge-nase COX enzymes12,13,8 in the 1970s.

Therapeutic approach: In the early days of drug discovery, preclinical efficacy models were introduced as a means of compound selection. These models were developed using drugs with known efficacy in humans, studying their quantifiable effects in laboratory animals, or on isolated organs in tissue baths, and applying this knowledge in the selection of new compounds. The effects of modification of a chemical structure could be thus observed in their totality, but without an appreciation of their complex effects on specificity for a given molecular target, metabolic stability, or tissue distribution.

The therapeutic approach remains extremely useful where preclinical models with high predictive value exist,14 and particularly where some understanding of the structure-activity relationship (SAR) required for efficacy can be derived using in vitro tools. Many drugs developed in this way are still in widespread use. For example, the semi-synthetic and the synthetic mu opioids were developed using this approach, years before the cloning of the mu receptor, including fentanyl, synthesized in 1960 by the late Dr. Paul Janssen and still one of the most potent and selective opioids clinically available.

The development of gabapentin, and the subsequent development of pregabalin, is another more recent illustration of this approach. Gabapentin was first developed as a GABA analog, and selected on the basis of its activity in in vivo epilepsy models, and was brought to market in 1993 as an anticonvulsant with add-on efficacy in partial/complex epileptiform disorders.15,16 Observations in clinical practice led to identification of its utility in refractory pain states,17,20 then to research in preclinical models supporting this indication21,22 and ultimately to controlled clinical trials leading to regulatory approval in 2002 for the pain of post-herpetic neuralgia.23,24 With the experience gained from developing gabapentin, additional 3-substituted GABA analogs were profiled in the laboratory. Pregabalin was identified as an analog with notable potency in the mouse maximal electroshock-induced seizure assay, and subsequently shown to be active in neuropathic pain assays.16 Thus, the development of these two important neuropathic pain drugs followed a therapeutic pathway, rather than a molecular target pathway. Importantly, in 1996, approximately 5 years after the identification of pregabalin, a CNS binding site for gabapentin was identified, consisting of the α2δ1 calcium channel accessory protein.25 The mechanism whereby this interaction results in analgesia and the functional significance of this binding are still not entirely clear.26,27

The overall business model of pharmaceutical companies has in most cases evolved toward molecular target-directed drug discovery. Currently, most but not all drug development projects are centered on a target whose molecular identity has been deliberately selected a priori. This method of identifying candidate compounds fits best with the capabilities of modern pharmaceutical research facilities (see section Lead Identification and Optimization below). The ability to screen large compound collections for structures that selectively interact with the target, using recombinantly expressed target protein in binding assays and immortalized cell lines, is one of the many advantages to this approach. Knowledge of the molecular target also enables work in transgenic animals to further assess the primary and secondary pharmacology of compounds in development. Selection of a molecular target may be based on its validation in preclinical or clinical pain states, or may be on theoretical grounds. Expansion of the knowledge of the molecular pharmacology of known target families has provided numerous promising target candidates; for review see e.g., Dray (2008).28 Pharmacological investigations of the pathways providing components of nociceptive processing (in other words, hypothesis-driven explorations of the known molecular pharmacology of pain) have arguably been the most directed and productive of the methods of selecting novel targets. The development of high-throughput technologies for systematically scanning the genome/proteome has given the ability to launch major unbiased exploratory efforts using comparisons of gene expression profiles between normal and chronic pain states.29 In addition, these technologies have enabled the identification of numerous potential therapeutic targets in the so-called orphan receptors, ion channels, and enzymes and are the foundation of subsequent efforts to identify their respective ligands/substrates and physiological functions.

18.4. TARGET VALIDATION

A fully validated target has undergone proof of concept in man, meaning that pharmacological manipulation of the target has been demonstrated to achieve the desired endpoint and to be physiologically tolerable. Such clinical validation comes in one of three ways: through folk use of a natural product, through clinical observations of the analgesic benefits of a drug used primarily for another indication (e.g., gabapentin, amitriptyline), or through a successful clinical trial of a drug tareting a novel pain mechanism (examples below).

While many research laboratories are willing and eager to develop drugs for as-yet clinically unvalidated targets, target validation is extremely useful at the preclinical level to support compound development efforts. Evidence from the phenotype of knockout or transgenic animals in support of the validity of a target is desirable when available. Pharmacological demonstration that the target is relevant to pain pathways is critical. The ability to modulate the target in vivo and record an effect on pain in a preclinical species provides a means to correlate the pharmacokinetic/pharmacodynamic relationship of compounds in development. A preclinical in vivo model may also provide for development of a clinical biomarker or imaging strategy, that is, a means of acutely measuring a dose-response to the pharmacological effects of the compound that can be used as a practical tool in the clinic to gauge whether an exposure in the presumed efficacious range has been attained. Notwithstanding some debate about the ability of preclinical models to predict success in clinical trials, preclinical models of pain have very high “face validity,” or commonsense resemblance to the clinical phenomenon in man, a decided advantage in the search for novel therapies.31,32

One example of a target that was preclinically validated in pain models and has since been successfully validated in clinical populations is the N-type voltage-dependent calcium channel (N-VDCC). The N-VDCC blocker ziconotide (Prialt®) is one of the first examples of prospective development of a compound with a novel molecular analgesic mechanism. Compound binding to the spinal cord dorsal horn led investigators to hypothesize that the target in question was involved in pain pathways. Initial proof of concept in animal models showed the lack of utility in acute pain but showed efficacy in tonic and neuropathic pain models. Clinical trials have been positive in pain states of multiple etiologies in man, and ziconotide is approved for intrathecal delivery for management of severe chronic pain refractory to other treatments.35,36

The 5HT1B/D receptor agonists exemplify novel target validation using an exclusively mechanistic set of preclinical models. The development of the triptans is a remarkable example of hypothesis-based thinking that has proven to be successful in the clinic. Behavioral animal models of migraine pain were not described at that time, and are as yet not widely validated. Sumatriptan was originally developed using preclinical models of inhibition of evoked cerebral vasodilatation based on the presumed contribution of this phenomenon to migraine pain. Later preclinical experiments showed that triptans prevented other clinically relevant migraine-associated phenomena, including calcitionin-gene related peptide and substance P release produced by electrical stimulation.37

Despite the fundamental similarities in mammalian physiology and pharmacology, pharmacogenomic and other differences between species commonly studied in the laboratory and used in drug development are widely appreciated, and some targets that are valid in rodents have been shown to fall short of expected efficacy in humans. In particular, experience with the development of neurokinin-1 (NK-1) receptor antagonists has illuminated gaps in our understanding of pain at a theoretical level. Although compounds have been effective in multiple preclinical pain models, modest efficacy at best has been seen in clinical trials. The basis for this difference remains the subject of debate. A lack of selectivity for the neurokinin receptors may have impeded the evaluation of the first antagonist widely used in preclinical work. Important species differences are suggested by the observations that the role of substance P differs between humans and rodents: Rodent neurons secrete substance P as a result of noxious stimulation, which contributes to neurogenic effects including vascular permeability, edema, and inflammation. Human neurons appear not to release substance P in response to the varieties of stimuli used to simulate neurogenic inflammation. Although humans do display neurogenic inflammation, the composition of the neurosecretion is different from that of the rat.

18.5. LEAD IDENTIFICATION

18.5.1. Assay Development and Compound Screening

Contemporary compound screening relies on high-throughput methodologies. The goal is to gain a rapid understanding of the chemical SAR of compound interaction with the unique target, and thus enable rational medicinal chemistry strategies for optimizing target interaction.

Challenges in assay development are common, and may include a lack of positive control compounds to use as tools to develop an assay at a novel target, or an incomplete understanding of the native configuration of a receptor or ion channel complex and thus of its in vivo pharmacology. High-throughput assays need to be robust enough to be adapted to automated formats, need to provide a signal that can be readily quantified by a machine, and must be able to be performed in a time frame compatible with the workflow of a department.

Automated machinery may handle multiples of 96-well formats; 384-well format is becoming increasingly common, and higher multiples are not unheard of. The higher the density of wells on a compound screening plate, the smaller the volume of each well, so accuracy/precision of measurements becomes quite challenging; this does minimize reagent consumption though. Large compound libraries can be screened in a matter of days or weeks using this approach.

Challenges inherent in compound libraries include how to obtain sufficient variety and diversity of high-quality compounds to provide for adequate chances to identify structures that interact with the target, quality control of the long-term stability and purity of the library elements, accurate dispensing into the tiny wells of high-content screening plates, and correct tracking of the identities of a large number of compounds through the assay and data analysis stages.

18.5.2. Lead Identification and Optimization

Completion of a successful high-throughput screening campaign is expected to produce a number of “hits,” or compounds with significant affinity for the target and with sufficient medicinal chemistry tractability to allow for exploration of their SAR and improvement of any suboptimal properties. Problems may include lack of potency; lack of selectivity over other targets of pharmacological significance; and lack of druglike properties such as acceptable solubility, chemical stability, or ability to be readily absorbed from the digestive tract and distributed into appropriate bodily compartments. Compounds may exhibit rapid metabolism, or other sources of poor pharmacokinetics, interference with CYP450 metabolic enzyme function, problems related to elimination, or unacceptable toxicity/safety profiles. Some of these problems can be identified using specific in vitro tests, but some must still be screened for using more broadly aimed physiological assays, including observation for signs of toxicity after repeated administration to animals.

Since the move away from in vivo screening in the last 20 years, the medicinal chemist is now quite often faced with highly potent molecules (in vitro) that are not druglike. In the old days, in vivo models only identified compounds with druglike pharmacokinetic properties; compounds with poor properties just didn’t work.

It is the object of a lead optimization campaign to identify and improve upon undesirable properties of potent compounds, by delineating an SAR and altering the properties of the molecule to make it more acceptably druglike. If the crystal structure of the target is available, or if techniques such as structure-activity determination by nuclear magnetic resonance (NMR) or site-directed mutagenesis experiments to build models (for review see Powers)49 can be applied, these additional rational principles can help improve the interaction with the target.

Particular challenges may be associated with different families of targets. For example, the absence of natural ligands, close structural homology, and large numbers of related genes has made identification of potent and selective voltage-gated ion channel modulating compounds historically difficult. Some targets have problematic CNS side effects that have been difficult to eliminate through compound optimization, whether for improved selectivity or for CNS exclusion. Examples of the latter include NMDA receptor antagonists51,52 and selective kappa opioid receptor agonists53; in both cases, clinical acceptability of drugs in these classes has been largely limited by their unacceptable CNS effects.

18.6. CANDIDATE SELECTION

Compounds with acceptable profiles become clinical candidates. In order to support further evaluation, a clinical candidate compound must be produced in large quantities, or “scaled up.” Compound synthesis at the bench research level is typically linear and designed to allow specific modifications to explore SAR, but for large-scale synthesis, these algorithms must often be substantially revised. In addition, the process must be conducted in accordance with exacting Good Manufacturing Practice (GMP) standards55,56 in order that the compound with which toxicological studies are conducted is as free of contaminants as possible and most closely resembles the substance that will be used in human subjects. Predominant considerations for scale-up synthesis are aimed toward the fewest synthetic steps, the highest product yields, convergent reactions (where multiple components are synthesized in parallel and joined in a modular fashion), and minimization of costs. Clinical candidates must undergo rigorous toxicological studies in at least two species prior to dosing in man. These studies call for prolonged administration of high doses of (impurity-free) compound. Acceptable outcome of toxicological evaluation allows for the filing of an application to regulatory authorities for an IND/CTA.

18.6.1. Phase I: First in Man

Phase I Trials: Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness; may include healthy participants and/or patients….In Phase I trials, researchers test an experimental drug or treatment in a small group of people (20–80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects, (http://clinicaltrials.gov/ct2/info/understand)

Phase I studies are usually divided into single ascending dose (SAD) followed by multiple ascending dose (MAD) studies to determine the safe and tolerable limits of administration.

Increasingly, attention is paid to the effort to incorporate the study of biomarkers, or clinical/laboratory findings that signal whether a pharmacologically efficacious dose has been attained, into early clinical trials. No physiological biomarker exists for pain, but pharmacological biomarker strategies are often possible based on the mechanism of the compound in question (ex vivo demonstration of inhibition of COX2 in non-platelet blood elements, for example).

Demonstrations of receptor occupancy are highly useful biomarkers in healthy volunteer studies. Numerous positron emission tomography (PET) studies have been conducted using radiolabeled NK1 ligands in human volunteers. It must be pointed out that PET ligands for novel targets, at the same time that they add tremendous value to drug development programs, call for the invention of novel (radiolabeled) compounds. Radiolabel incorporation into compounds of interest is likely to alter critical properties, from target affinity to pharmacokinetics. The identification of a good PET ligand for a novel target represents a parallel but separate drug discovery project in its own right, and, such projects are expensive and time-consuming. Additional brain imaging techniques are being pioneered as well; functional magnetic resonance imaging (fMRI) to examine regional changes in cerebral blood flow that are indicative of localized alterations in neuronal activity patterns can be used to observe patterns associated with analgesia as well as aversive subjective effects. In some cases, with adequate safety data, it is possible to incorporate proof of pharmacological activity into Phase I studies with the use of various pain threshold tests in healthy compound- versus placebo-treated volunteers.

18.6.2. Phase II

Phase II Trials: Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks…. In Phase II trials, the experimental study drug or treatment is given to a larger group of people (100–300) to see if it is effective and to further evaluate its safety.” (http://clinicaltrials.gov/ct2/info/understand)

There are particular challenges associated with efficacy trials in pain drug development. One challenge is the selection of an appropriate patient population. Ethical study design considerations related to the use of placebo versus active treatment as a control are significant. Compared with other therapeutic areas where determination of efficacy requires prolonged use of a drug in order to observe its effect on disease manifestations, pain trials can be comparatively short and the primary outcome measure (patients’ reports of pain relief) can be straightforward. However, measurement of the intensity of pain in the clinic is hampered by a pervasive anxiety that subjective pain reports may be subject to influence by environmental and experiential influences other than the test drug, and a desire for more objective organic measures of pain has long existed. The mechanics of analgesic clinical trial design are such that dropout rates can be high enough to render trials uninterpretable. Regulatory guidelines for the design of efficacy trials in analgesic development are still in development, meaning that to some degree, clinical trials are conducted at risk.

18.6.3. Phase III

Phase III Trials: Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling….In Phase III trials, the experimental study drug or treatment is given to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely, (http://clinicaltrials.gov/ct2/info/understand)

Again, trial design and outcome measurement can be challenging. The significant placebo effect expected in pain trials is difficult to minimize and may obscure the identification of all but very substantial drug effects. Statistical imputation methods for handling patients who do not complete these trials remain a controversial topic.

18.7. NDA

For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization. The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the United States. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA.

The goals of the NDA are to provide enough information to permit FDA reviewers to reach the following key decisions:

  • Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.
  • Whether the drug’s proposed labeling (package insert) is appropriate, and what it should contain.
  • Whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity.
  • The documentation required in an NDA is supposed to tell the drug’s whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged. (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsare DevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/default.htm)

While some experience has been gained from the development of neuropathic pain drugs, specific guidelines to enable label indications for specific forms of pain, such as visceral pain, are still to come.

18.8. CONCLUSION

Pain is a very active field of drug discovery. As of this writing, hundreds of compounds are listed in various stages of development for analgesic uses. The diversity of targeted mechanisms is substantial. Based on statistical predictions, few new com- pounds are likely to make it to the market; still, the wealth of active target-directed drug discovery efforts is impressive.

These experiences reflect really only a few decades of combined preclinical and clinical research investment, and basic mechanisms of nociception and hyperalgesia remain incompletely elucidated. The more the basic science in the field continues to provide scientific guidance for the selection of novel targets, the more new developments in pain therapeutics can be anticipated.

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