LEADING ARTICLE
`
`Drugs R&D 1999 Oct; 2 (4): 229-235
`1174-5886/99/0010-0229/$03.50/0
`
`© Adis International Limited. All rights reserved.
`
`Antiemetics for Cancer
`Chemotherapy–Induced Nausea
`and Vomiting
`A Review of Agents in Development
`
`André N. Rizk and Paul J. Hesketh
`St Elizabeth’s Medical Center, Boston, Massachusetts, USA
`
`Abstract
`
`Significant progress has been made in recent years in developing more effec-
`tive means of preventing nausea and vomiting induced by cancer chemotherapy.
`With appropriate application of currently available antiemetic regimens, the ma-
`jority of patients with cancer who are receiving chemotherapy can anticipate expe-
`riencing no emesis during their treatment. Nevertheless, incompletely controlled
`emesis remains a problem for a significant percentage of patients. Persistent chal-
`lenges include delayed emesis and emesis following high-dose chemotherapy
`regimens. The goal of complete prevention of emesis in all patients remains
`elusive. Therefore, there is a strong rationale for investigating new antiemetic
`approaches.
`New antiemetic agents currently under development target the neurotransmit-
`ters serotonin (5-hydroxytryptamine; 5-HT) and substance P. A number of new
`selective antagonists of serotonin 5-HT3 receptors are in clinical trials. Given the
`lack of clinically significant differences between the available 5-HT3 receptor
`antagonists, it appears unlikely that any of these new agents will have substantial
`advantages over currently approved agents. Several other serotonin receptors
`have been targeted including the 5-HT4, 5-HT1A and 5-HT2A receptors. Of these
`approaches, only agonism of the 5-HT1A receptor has produced an agent that has
`proceeded into clinical testing.
`The most exciting new class of antiemetics currently under development fo-
`cuses on antagonism of the effects of the neurotransmitter substance P. Results
`of early clinical trials with tachykinin neurokinin NK1 receptor antagonists demon-
`strate enhanced control of acute emesis with their addition to currently available
`agents and promising activity in controlling delayed emesis. Available evidence
`would strongly suggest that this class of agents will represent the next important
`advance in efforts to control nausea and vomiting induced by chemotherapy.
`
`From a patient’s perspective, chemotherapy-
`induced nausea and emesis (vomiting and/or retch-
`ing) are among the most troublesome adverse ef-
`fects of cancer treatment. Substantial progress has
`been made over the last decade in developing more
`
`effective and better tolerated antiemetic treatments.[1]
`Nevertheless, chemotherapy-induced nausea and vo-
`miting remain problems for a significant number
`of patients. Persistent challenges include delayed
`emesis, particularly following cisplatin, and emesis
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`PTX-088
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`Helsinn Healthcare Exhibit 2036
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
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`230
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`Rizk & Hesketh
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`following multicycle chemotherapy and high-dose
`chemotherapy.[2-8]
`Effort
`to prevent chemotherapy induced nausea
`and emesis have primarily been directed at block-
`ing neurotransmitter receptors involved in the eme-
`tic reflex, located predominately in the brain stem
`and the small intestine. Initially, the dopamine D2
`receptor was the main receptor of interest, given
`the demonstrated antiemetic activity of a number
`of dopaminergic receptor antagonists such as the
`phenothiazines, butyrophenones and metoclopra-
`mide.[9,10] The next major breakthrough occurred
`with the introduction of selective antagonists of the
`serotonin 5-HT3 receptor, such as ondansetron and
`granisetron. These drugs work primarily by antag-
`onism of serotonin binding to 5-HT3 receptors lo-
`cated on vagal afferent fibres within the gastroin-
`testinal system.[11-14]
`An additional class of antiemetics whose mech-
`anism of action remains incompletely elucidated is
`the corticosteroids. Although a variety of cortico-
`steroids have been employed in clinical trials, dex-
`amethasone has been the most extensively evalu-
`ated and is used to the greatest extent in clinical
`practice.
`Another important therapeutic advance in this
`area has been the recognition of the value of combi-
`nation antiemetic therapy. Corticosteroids add to the
`antiemetic efficacy of metoclopramide,[15,16] and the
`efficacy of selective serotonin receptor antagonists
`is increased by the addition of corticosteroids[17-22]
`and dopamine receptor antagonists.[23-25]
`At present, the combination of a selective 5-HT3
`receptor antagonist and a corticosteroid represents
`the antiemetic regimen of choice in patients receiv-
`ing chemotherapy with moderate to high emetogenic
`potential.[26] This combination completely prevents
`acute emesis in 70 to 80% and 60 to 70% of patients
`receiving moderately and highly emetogenic chemo-
`therapy, respectively.[19,20,22] However, the seroto-
`nin receptor antagonists are not as effective in pre-
`venting delayed emesis, particularly following cis-
`platin.[27,28] Currently, corticosteroids combined with
`dopaminergic receptor antagonists or 5-HT3 recep-
`tor antagonists are the treatment of choice in this
`
`setting. Even with the best available therapy, how-
`ever, approximately 50% of patients will still develop
`delayed emesis following cisplatin.[3,29] Therefore,
`there remains a need to develop more effective an-
`tiemetic therapeutic approaches, particularly in the
`setting of delayed emesis and emesis following high-
`dose chemotherapy. In this article, the status of a
`number of new antiemetic agents under develop-
`ment is reviewed. We focus on agents which target
`the neurotransmitters serotonin and substance P.
`
`1. Compounds that Target
`Serotonin Receptors
`
`1.1 Serotonin 5-HT3 Receptor Antagonists
`
`The development of 5-HT3 receptor antagonists
`as antiemetic agents represented a major advance in
`controlling chemotherapy-induced nausea and vom-
`iting. These drugs appear to primarily work by an-
`tagonising the binding of serotonin (released from
`the enterochrommafin cells in the wall of the gas-
`trointestinal tract following chemotherapy) to 5-
`HT3 receptors on vagal and splanchnic afferent fi-
`bres (also located in the wall of the gastrointestinal
`tract). Stimulation of the latter receptors leads to an
`increase in afferent input to areas in the hindbrain
`which control the emetic reflex.[30]
`A number of 5-HT3 receptor antagonists are now
`available in oral and intravenous formulations for
`clinical use, including azasetron, dolasetron, grani-
`setron, ondansetron, ramosetron and tropisetron. Al-
`though these agents have several preclinical differ-
`ences, they all seem to have comparable clinical effi-
`cacy and minimal adverse effects.[11,12]
`Despite the lack of meaningful clinical differences
`between the available 5-HT3 receptor antagonists,
`a limited number of efforts are being made to de-
`velop additional agents in this class. Compounds
`in varying stages of development include itasetron,
`lerisetron, palonosetron and N 3389.[31-34] Itasetron
`and N 3389, in addition to their activity as 5-HT3
`receptor antagonists, also function as antagonists of
`the 5-HT4 receptor.[34,35] The putative advantages
`of these new agents compared with approved 5-HT3
`receptor antagonists relate to increased affinity for
`
`© Adis International Limited. All rights reserved.
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`Antiemetics in Oncology
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`231
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`the 5-HT3 receptor, enhanced bioavailability or
`prolonged half-life. Given the appreciable differ-
`ences that already exist with respect to these fac-
`tors with approved 5-HT3 receptor antagonists, it
`seems doubtful that any of these new agents will
`prove to be superior to existing ones.
`
`1.2 Agonists of Other Serotonin Receptors
`
`Other serotonin receptors are being evaluated as
`potential therapeutic targets. 5-HT1A, 5-HT2A and
`possibly 5-HT4 receptors are involved in the genesis
`of emesis.[36] A number of compounds that have ag-
`onistic activity at these receptors have been devel-
`oped.
`In preclinical models, the 5-HT1A receptor ago-
`nist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-
`OH-DPAT) was shown to block emesis induced by
`a wide variety of stimuli, such as motion, xylazine
`and cisplatin in the cat.[37] Likewise, in the Suncus
`murinus, vomiting induced by a wide spectrum of
`stimuli such as nicotine, veratrine, cisplatin, copper
`sulphate and motion was blocked by 5-HT1A recep-
`tor agonists.[38] LY 228729, a well characterised
`5-HT1A receptor agonist, showed activity against
`motion-induced emesis in the cat,[39] and against
`conditioned-emesis and emesis induced by ditoly-
`guanidine, cisplatin, ipecac (ipecacuanha), emetine
`and the 5-HT3 receptor agonist m-(chlorophenyl)-
`biguanide in the pigeon.[40,41] There was also an
`indication that LY 228729 may be more efficacious
`than 5-HT3 receptor antagonists in controlling em-
`esis in these settings.[41] Despite these encouraging
`results, clinical studies with these agents have yet
`to be reported. A small comparative trial of ondan-
`setron and the 5-HT1A agonist buspirone in patients
`receiving cisplatin, showed superior antiemetic ac-
`tivity for ondansetron.[42]
`Agonists of the 5-HT2A/5-HT2C receptor have
`also shown potential value as antiemetics in pre-
`clinical systems. DO1 (+/–)-1-(2,5-dimethoxy-4-
`iodophenyl)-2-aminopropane, a centrally acting 5-
`HT2A/5-HT2C receptor agonist, dose-dependently
`blocked the emesis induced by motion and cispla-
`tin in Suncus murinus.[43]
`
`The 5-HT4 receptor has also been viewed as a
`possible target for antiemetic drug development.
`5-HT4 receptor agonists might theoretically be of
`value via 2 possible mechanisms: (i) inhibition of
`serotonin release from enterochromaffin cells; and
`(ii) restoration of caudally driven peristaltic waves in
`the upper gastrointestinal tract. A number of agents
`with mixed 5-HT4 agonist/5-HT3 antagonist activ-
`ity have been evaluated in preclinical models.[44]
`Despite the theoretical promise, to data limited
`clinical experience with these agents suggests a
`modest role in controlling chemotherapy-induced
`emesis.[45]
`There is a strong preclinical rationale for agents
`that act at serotonin receptors other than the 5-HT3
`receptor as antiemetics and further testing is war-
`ranted. A 5-HT1A receptor agonist is now entering
`phase I testing and further development of such
`compounds is awaited with interest.
`
`2. Tachykinin Neurokinin NK1
`Receptor Antagonists
`
`The most exciting new class of antiemetic agents
`currently under development is that which antag-
`onises the effects of the neurotransmitter substance
`P. Substance P is an 11–amino-acid neuropeptide of
`the tachykinin family of peptides, originally named
`for their vasorelaxant properties.[46,47] Substance P
`is found in the gut and CNS and is released in re-
`sponse to noxious stimuli such as pain. It can me-
`diate a number of vegetative responses including em-
`esis. When injected into ferrets, the animal model
`employed to demonstrate the therapeutic efficacy
`of the 5-HT3 receptor antagonists, substance P can
`induce emesis.[48,49]
`Substance P exerts its effects by binding to a
`specific neuroreceptor, the tachykinin neurokinin
`NK1 receptor. Anumber of peptide compounds that
`selectively block the NK1 receptor have been iden-
`tified.[48,50-54] A unique feature of NK1 receptor an-
`tagonists, not shared by the 5-HT3 receptor antag-
`onists or dopaminergic receptor antagonists, is their
`broad spectrum of antiemetic activity in preclinical
`models. The NK1 receptor antagonist CP 99994 has
`been shown to prevent emesis induced by a wide
`
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`232
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`Rizk & Hesketh
`
`range of emetic stimuli, such as apomorphine, mor-
`phine, nicotine, copper sulphate, ipecac, radiation,
`cyclophosphamide, cisplatin, motion and anaesthesia
`in the ferret, dog, cat and Suncus murinus.[55-60]
`Another interesting observation with this class of
`agents relates to their apparent site of action. Un-
`like the 5-HT3 receptor antagonists which appear
`to primarily work at a peripheral site, the NK1 re-
`ceptor antagonists require entry into the CNS to
`demonstrate an antiemetic effect. The quaternised
`NK1 receptor antagonist L 743310, which poorly
`penetrates the blood-brain barrier, was ineffective
`against cisplatin-induced emesis when injected sys-
`temically into ferrets. The same compound demon-
`strated comparable efficacy to L 741671, an NK1
`receptor antagonist that penetrates the brain, when
`it was injected centrally in the vicinity of the nu-
`cleus tractus solitarius.[50]
`A third preclinical finding which has signifi-
`cantly enhanced interest in this class of agents is
`the observation that they work not only in animal
`models of acute emesis but also in recently eluci-
`dated delayed emesis models. The NK1 receptor
`antagonists CP 99994 and GR 205171 showed ac-
`tivity in cisplatin-induced acute and delayed eme-
`sis in ferrets and piglets, respectively.[51-61]
`Given the unique features demonstrated by this
`class of agents in preclinical studies, there has been
`considerable anticipation of the first results of clin-
`ical trials of their use as antiemetics in humans.
`Over the past 2 years, results of the initial studies
`
`evaluating this class of agents for chemotherapy-
`induced emesis have begun to appear.
`Kris et al.[62] reported the first clinical experi-
`ence with an NK1 receptor antagoni t in cancer pa
`tients. In a small, dose-ranging, open-label trial of
`CP 122721 added to a regimen of 5-HT3 receptor
`antagonist and dexamethasone, they observed an
`improvement in the control of delayed emesis from
`17% without CP 122721 to 83% with the addition of
`a single dose of CP 122721 before cisplatin. When
`compared with ondansetron, another NK1 receptor
`antagonist, L 758298, was shown in a double-blind,
`randomised study in patients who were cisplatin-
`naive to be almost equal in efficacy when used alone
`to ondansetron alone in acute emesis but superior
`in the delayed phase.[63]
`Two other NK1 receptor antagonists were test-
`ed in separate multicentre, double-blind, placebo-
`controlled trials; CJ 11974 and MK 869 were found
`to be significantly superior to placebo in controlling
`cisplatin-induced delayed emesis (table I).[64,65] In
`the trial of MK 869, there was a nonsignificant im-
`provement in the control of delayed emesis when
`the drug was given before cisplatin and twice daily
`on days 2 through 5 after cisplatin as compared with
`its administration as a single dose prior to cisplatin.
`Both compounds also improved the prevention of
`acute emesis when combined with granisetron and
`dexamethasone, although this effect was only sig-
`nificant with MK 869. Both agents were well tol-
`erated, with no clear-cut significant drug-related
`toxicity noted. Similar results were obtained more
`
`Table I. Randomised trials evaluating the efficacy of tachykinin neurokinin NK1 receptor antagonists in acute and delayed cisplatin-induced emesis
`Reference
`Regimen
`n
`Antiemetic outcome (% of patients with no emesis)
`acute (day 1)
`acute (day 1)
`delayed (days 2-5)
`Granisetron + dexamethasone +
`66.7
`36.6
`placebo
`Granisetron + dexamethasone +
`CJ 11974
`Granisetron + dexamethasone +
`placebo
`Granisetron + dexamethasone +
`MK 869
`Granisetron + dexamethasone +
`MK 869
`* p<0.05 vsplacebo; † p<0.01 vsplacebo (acute); ‡ p<0.001 vsplacebo (delayed).
`
`31
`
`30
`
`51
`
`54
`
`54
`
`85.7
`
`57
`
`77
`
`83
`
`67.8*
`
`33
`
`82
`
`78
`
`Hesketh et al.[64]
`
`Navari et al.[65]
`
`delayed (days 2-5)
`Placebo
`
`CJ 11974
`
`Placebo
`
`MK 869
`
`Placebo
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`Antiemetics in Oncology
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`233
`
`recently in a double-blind, randomised, parallel
`group study that also evaluated MK 869 and L
`758298 (the prodrug of MK 869) for the preven-
`tion of cisplatin-induced emesis in patients who
`were cisplatin-naive.[66] In this trial, L 758298 com-
`bined with dexamethasone given before cisplatin
`was significantly inferior to ondansetron plus dex-
`amethasone in the prevention of cisplatin-induced
`acute emesis; however, as in prior trials, delayed
`emesis was better controlled in the arm receiving
`MK 869 following cisplatin.
`
`3. Conclusion
`
`Despite the significant progress made over the
`past 15 years in the development of more effective
`and better tolerated means to prevent chemother-
`apy-induced nausea and vomiting, a significant
`number of patients still experience nausea and em-
`esis, especially when treated with highly emetoge-
`nic chemotherapy regimens. Efforts continue to
`identify more effective antiemetic agents. Current
`studies focus on additional 5-HT3 receptor antag-
`onists, 5-HT1A receptor agonists and NK1 receptor
`antagonists. Of these, the latter agents appear to
`have the most potential to further enhance anti-
`emetic control.
`The NK1 receptor antagonists are well tolerated
`and not associated with unusual or severe toxic-
`ity.[62-67] The limited data available on this class of
`agents demonstrate that as single agents they are
`no better than 5-HT3 receptor antagonists in pre-
`venting cisplatin-induced acute emesis and when
`combined with dexamethasone may be inferior to
`the combination of 5-HT3 receptor antagonists and
`dexamethasone in the acute setting, although when
`combined with 5-HT3 receptor antagonists and
`dexamethasone they seem to enhance the control
`of acute emesis compared with 5-HT3 receptor an-
`tagonists and dexamethasone alone. However, the
`most interesting aspect of NK1 receptor antago-
`nists is the evidence that when given prior to cis-
`platin, whether combined with 5-HT3 receptor an-
`tagonists and dexamethasone or with dexametha-
`sone alone, they are superior to placebo for the
`control of cisplatin-induced delayed emesis.[64,65]
`
`The available data on the NK1 receptor antago-
`nists are still preliminary and exploratory in nature.
`Future studies are needed to address a number of
`critical issues, including: (i) confirmation that the
`addition of an NK1 receptor antagonist to a 5-HT3
`receptor antagonist and dexamethasone significantly
`improves the control of acute emesis; (ii) assess-
`ment of the value of NK1 receptor antagonists for
`cisplatin-induced delayed emesis as single agents
`and in combination with conventional agents such
`as dexamethasone and metoclopramide; (iii) the
`most appropriate schedule and timing that will op-
`timise the control of acute and delayed emesis; and
`(iv) evaluation of NK1 receptor antagonists with
`non-cisplatin chemotherapy, especially in the high-
`dose chemotherapy setting. The completion of well
`designed trials are necessary to address these is-
`sues and provide enough information to define the
`true utility and place of NK1 receptor antagonists
`in the management of chemotherapy-induced nau-
`sea and emesis.
`
`Acknowledgements
`
`The authors would like to acknowledge the kind assis-
`tance of Matti Aapro, MD, Jorn Herrstedt, MD, Alberto
`Macciocchi, MD, Miguel Martin, MD and Yutaka Natsu-
`meda, MD, PhD, in contributing information on the status of
`a number of new antiemetic agents under development.
`
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`Correspondence and reprints: Dr Paul J. Hesketh, Division
`of Hematology/Oncology, St Elizabeth’s Medical Center,
`736 Cambridge Street, Boston, MA 02135, USA.
`E-mail: phesketh@semc.org
`
`© Adis International Limited. All rights reserved.
`
`Drugs R&D 1999 Oct; 2 (4)
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`PTX-088.0007
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`Page 7 of 7