alvimopan

Drugs R D 2006; 7 (4): 245-253ADIS R&D PROFILE 1174-5886/06/0004-0245/$39.95/0

2006 Adis Data Information BV. All rights reserved.

AlvimopanADL 8-2698, ADL 82698, Entrareg, LY 246736

Alvimopan [ADL 82698, LY 246736, Entereg] is an oral, peripherallyAbstractselective µ-opioid receptor antagonist. It was originally developed by Eli Lilly inthe US for the treatment of gastrointestinal (GI) dysfunction, such as irritablebowel syndrome, idiopathic constipation and GI adverse effects caused by opiateanalgesics. Alvimopan was licensed to Roberts Pharmaceutical from Eli Lilly forfurther development and marketing.

Adolor Corporation acquired an exclusive worldwide license from RobertsPharmaceutical (now Shire Pharmaceuticals Group) for alvimopan for the treat-ment of acute and chronic opiate-induced constipation in June 1998. Under theAugust 2002 Adolor-Lilly licensing agreement, Adolor paid Roberts an up-frontfee of $US300 000, thereby expanding their intellectual property rights related toalvimopan. Both Eli Lilly and Roberts will receive royalties based on productsales.

In April 2002, Adolor Corporation and GlaxoSmithKline entered into a collab-orative agreement for the exclusive worldwide development and commercialisa-tion of alvimopan. Both companies agreed to co-develop alvimopan for a numberof other indications, including both acute-care and chronic-care indications.Under the terms of the agreement, GlaxoSmithKline payed Adolor a signing feeof $US50 million, followed by clinical and regulatory milestone payments of upto $US220 million over the term of the agreement, depending on the progress ofthe various indications. In the US, Adolor and GlaxoSmithKline will co-developand co-promote alvimopan, sharing both development expenses and commercialreturns. Adolor will lead the development, marketing and co-promotion strategyfor acute-care indications, which will be targeted to hospitals and surgeons.GlaxoSmithKline will lead the development, marketing and co-promotion forchronic-care indications targeted to community-based physicians. Outside the US,GlaxoSmithKline will be responsible for the development and commercialisationof alvimopan, with Adolor receiving royalties on any sales revenues.[1]

Adolor submitted an NDA for alvimopan in the US in 2004. The tradename foralvimopan is Entereg.

Adolor has successfully completed its phase II clinical programme foralvimopan for the management of opioid-induced bowel dysfunction. Phase IItrials in patients undergoing chronic opioid therapy have shown that alvimopanrelieves or prevents opioid effects on the GI tract (constipation) withoutantagonising narcotic analgesia or withdrawal. In November 2002, Adolorannounced preliminary results in a phase III clinical trial of alvimopan for relief ofopioid-induced bowel dysfunction, enrolling 168 patients from 15 to 22 centres inthe US. Additional clinical trials will be required before filing any regulatoryapproval applications.

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According to information presented at the JP Morgan H&Q 23rd HealthcareConference (JP Morgan – 2005), GlaxoSmithKline is conducting two phase IIbclinical trials with alvimopan. These double-blind trials are of longer duration andinvolve patients with cancer pain and non-malignant pain who are receivingchronic opioid therapy. The studies are being carried out at centres in NorthAmerica, Europe and Asia-Pacific. NDA/MAA submissions for this indication inthe US and Europe are being targeted for 2007.

GlaxoSmithKline is also evaluating alvimopan in an early stage phase II studyinvolving patients with chronic constipation. Alvimopan 3mg twice daily will becompared with placebo in 22 patients with chronic constipation. Results from thistrial are expected in the second quarter of 2005. Preliminary data have shownalvimopan to have a 32% faster GI transit rate compared with placebo.

Adolor plans to submit an MAA application in Europe for alvimopan for thetreatment of postoperative ileus in the first half of 2005.

Adolor reported initial top-line results from the completed phase III study(SB-767905/001), Study 001, of alvimopan capsules for the management ofpostoperative ileus in December 2004. GlaxoSmithKline conducted this study inEurope, Australia and New Zealand, and results from this study will support theMAA in the EU.[2]

In May 2004, Adolor submitted the first portion of its NDA for alvimopancapsules in the management of postoperative ileus in the US. The submission wasmade under the US FDA’s Continuous Marketing Application (CMA) Pilot 1Program. Adolor submitted NDA Item 5, which is nonclinical pharmacology andtoxicology data.[3] Adolor submitted the second reviewable unit of its NDA inJune 2004, Item 4: Chemistry, Manufacturing and Controls (CMC), for alvimopanin the management of postoperative ileus and completed the entire NDA submis-sion at the end of June 2004.[4] The FDA accepted this NDA submission forreview in September 2004 and subsequently extended the Prescription Drug UserFee Act (PDUFA) action date from 25 April 2005 to 25 July 2005 for completionof its NDA review of alvimopan capsules for the management of postoperativeileus. The final component of the requested information, the clinical study reportfrom GlaxoSmithKline Study 001, was submitted to the FDA in April 2005.[5]

Adolor received an approvable letter from the FDA in July 2005. Prior toapproval, the company has to provide additional proof of efficacy to the FDA tosupport the use of alvimopan following bowel resection surgery. This could beaddressed with positive results from Adolor’s ongoing Study 14CL314 or from anadditional study.[6]

Under the CMA Pilot 1 Program, Adolor can submit a limited number ofpredefined portions of the NDA, known as reviewable units, for FDA reviewbefore submitting the complete NDA for alvimopan. The FDA requested informa-tion from the GlaxoSmithKline European phase III clinical study (SB-767905/001) of alvimopan in postoperative ileus in January 2005, as part of its review ofAdolor’s NDA for alvimopan. Study 001 was conducted by GlaxoSmithKline inorder to support a MAA in the EU.[7]

Preliminary results from the phase III study 14CL314 have been reported. Thestudy enrolled 654 bowel resection patients who received alvimopan 12mg orplacebo, twice daily; the primary study endpoint was time to recovery of GIfunction. The initial dose of alvimopan was administered 30–90 minutes prior to

2006 Adis Data Information BV. All rights reserved. Drugs R D 2006; 7 (4)

Alvimopan 247

surgery. In previous phase III studies, the first dose of alvimopan was adminis-tered 120 minutes prior to surgery. Alodor expects to submit final results from thestudy to the FDA by June 2006.[8]

Adolor announced results from its first phase III trial, 14CL302, of alvimopanfor the treatment of postoperative ileus in April 2003. This double-blind, placebo-controlled, postoperative ileus phase III trial enrolled 451 patients who wereundergoing partial colectomies, simple or radical hysterectomies, using both a6mg and a 12mg twice-daily dose of alvimopan.

Adolor completed two more pivotal phase III trials of alvimopan for thetreatment of postoperative ileus, known as study 14CL313 and study 14CL308.These two double-blind, placebo-controlled, phase III trials enrolled patients fromapproximately 30 centres in the US or Canada. The primary endpoint in the abovethree studies is a composite measure of the time to recovery of both the upper andlower GI function, as defined by time to tolerability of solid foods and time to firstflatus or first bowel movement. Adolor announced results from its secondphase III trial, 14CL313, in September 2003 and announced results from its thirdphase III trial, 14CL308, in January 2004.[9]

In October 2003, top-line results from a fourth phase III clinical trial, known as14CL306, which was designed to assess the safety of alvimopan, was announced.This double-blind, placebo-controlled, multicentre study enrolled 519 patientsscheduled to undergo total abdominal simple hysterectomy while receivingopioids for pain relief. Patients were randomised to receive either alvimopan12mg or placebo, with patients receiving initial doses of alvimopan in the hospitaland continuing to take alvimopan twice daily at home for a maximum of 7 days ofcontinuous treatment. This study assessed the safety and efficacy of alvimopan inthis postoperative ileus patient population.[10]

This study will also allow Adolor to assess the potential for conductingadditional clinical trials in acute opioid bowel dysfunction. If successful, Adolorintends to develop alvimopan for this indication by submitting a supplementalNDA to the FDA, following approval of Adolor’s NDA for the management ofpostoperative ileus.

In August 2002, Adolor expanded their intellectual property rights related toalvimopan by entering into an exclusive licensing agreement with Eli Lilly, underwhich Adolor obtained an exclusive license to six issued US patents and relatedforeign equivalents and know-how relating to peripherally selective opioid antag-onists.

Adolor have rights to patents related to alvimopan, which expire between 2011and 2019, and include a US patent claiming composition of matter, which expiresin 2011 and may be eligible for a patent term extension.

Adolor was granted two additional patents related to alvimopan from the USPatent and Trademark Office. The US Patent 6,469,030 (issued on 22 October2002) covers novel methods for use of alvimopan in the treatment or prevention ofileus, including postoperative ileus, postpartum ileus, and other forms of post-surgical ileus. The second patent, Patent 6,451,806 (issued on 17 September2002), covers methods of use and fixed-dose combinations of alvimopan,methylnaltrexone and other peripheral µ-opioid antagonists in combination with a


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variety of opioid analgesics for the treatment of pain. Both these patents expire in2019.[11]

Table I. Features and properties

Chemical name [[(2S)-2-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpacid

Molecular formula C25 H32 N2 O4 . 2 H2 O

CAS number 170098-38-1

WHO ATC code A03F-A (Propulsives)N02A (Opioids)

EphMRA ATC code N2A (Narcotics)A3F (Gastroprokinetics)

Originator Eli Lilly: USA

Licensee companies Adolor Corporation: World GlaxoSmithKline: World

Highest development phase Phase III (North America, Australia, Europe, New Zealand)

Properties

Mechanism of action Opioid mu receptor antagonists

Pharmacodynamics Reversed morphine inhibition of GI transit in animal models

Route Oral

(0.5mg or 1mg) or placebo daily for 21 days. Al-1. Profile vimopan was well tolerated. The most frequently

occurring adverse events versus placebo were diar-rhoea, abdominal cramps, nausea and vomiting.[14]

1.1 PharmacokineticsIn a double-blind, placebo-controlled, multicen-

Preclinical studies: In dogs, IV administration of tre, phase III study (14CL302), 450 patients whoalvimopan caused a dose-dependent increase in were scheduled to undergo partial colectomies orpeak plasma concentrations and AUC values. The simple or radical hysterectomies and who were tomean t1/2 was 10 min. Alvimopan had low oral receive opioid analgesics, were randomised to re-bioavailability of approximately of 0.03%. In rats, ceive placebo or 6mg or 12mg doses of alvimopan.after administration of alvimopan (200 mg/kg oral- The drug was given at least 2 hours prior to surgery,ly) the plasma concentration reached its peak of and then twice a day beginning on the first postoper-20 ng/mL at 1 hour postdose; 22% and 15% of ative day until hospital discharge or for a maximumintravenously administered alvimopan was excreted of 7 days postoperative treatment. Alvimopan wasinto the urine and bile, respectively. Alvimopan as generally well tolerated in this study. The mostan unchanged form was found in the bile along with frequently observed adverse events in both the pla-its major polar metabolite.[12]

cebo and treatment groups were nausea, vomitingand hypotension.[15]

1.2 Adverse EventsIn a double-blind, placebo-controlled, multicen-

One hundred and thirty-two patients undergoing tre, phase III study (14CL313), 510 patients whoabdominal surgery were randomised to receive al- were scheduled to undergo small bowel resections,vimopan (3, 6 or 12mg bid) or placebo. No serious large bowel resections or radical hysterectomiesadverse events were associated with alvimopan and while receiving opioids for pain relief werethere was no loss of analgesia.[13] randomised to receive placebo or alvimopan at

In phase III study 304, 168 patients with opioid- doses of 6mg or 12mg. Alvimopan was generallyinduced bowel dysfunction received alvimopan well tolerated in this study. The most frequently


Alvimopan 249

Table II. Drug development history

Mar 1996 Preclinical development for Irritable bowel syndrome in the US (Unknown route)

Aug 1996 Phase-I for Constipation in the US (Unknown route)

Jul 1999 Phase-II for Constipation in the US (oral)

Oct 1999 Adolor Corporation is the worldwide licensee for LY 246736

Jan 2000 Roberts Pharmaceutical has been merged into Shire Pharmaceuticals Group

Aug 2000 Shire Pharmaceuticals is no longer involved in the development of LY 246736

Mar 2001 Phase-III for Postoperative ileus in the US (oral)

Jul 2001 Phase-III for Constipation in the US (oral)

Nov 2001 Phase-I for Pain in the US (Unknown route)

Nov 2001 ADL 82698 in combination with morphine investigated for use in moderate tosevere pain

Apr 2002 Adolor and GlaxoSmithKline have entered into an agreement to co-develop andco-promote Alvimopan Worldwide (9002562)

May 2002 Phase-II in Pain in the US (unspecified route)

Sep 2002 Adolor has completed enrolment in a phase III trial of alvimopan for relief ofopioid-induced bowel dysfunction

Nov 2002 Adolor has received two additional patents for ADL 82698 in the US (9015036)

Dec 2002 Adolor has completed enrolment in a phase III trial for postoperative ileus in theUS

Jul 2003 Phase-II in Constipation in the US (oral)

Nov 2003 Adolor has completed enrolment in a phase III trial (14CL308) for postoperativeileus in the US

Dec 2003 Phase-I in Irritable bowel syndrome in the US (oral)

Feb 2004 Alvimopan has received fast-track status for the management of postoperativeileus in the US

Apr 2004 Phase-III in Postoperative ileus in Europe (oral)

Apr 2004 Phase-III in Postoperative ileus in Australia (oral)

Apr 2004 Phase-III in Postoperative ileus in New Zealand (oral)

May 2004 Preregistration for Postoperative ileus in the US (oral)

Jun 2004 Adolor has submitted the second reviewable unit of its NDA for alvimopan for themanagement of Postoperative ileus in the US

Jun 2004 Adolor has submitted the entire NDA for alvimopan for the management ofPostoperative ileus in the US

Sep 2004 The US FDA accepted for review the NDA submission for alvimopan capsulesfor the management of postoperative ileus

Jan 2005 Phase-II in Constipation in Europe (oral)

Jan 2005 Phase-II in Constipation in Asia (oral)

Apr 2005 The FDA has extended the PDUFA to 25 July 2005 for its NDA review ofalvimopan capsules in the management of postoperative ileus

Jul 2005 Adolor has received an approvable letter from the FDA for alvimopan in themanagement of postoperative ileus

Sep 2005 GSK and Adolor have initiated an international phase III trial for alvimopan forthe treatment of opioid-induced bowel dysfunction

Sep 2005 Phase-III in Constipation in North America (oral)

Sep 2005 Phase-III in Constipation in Europe (oral)

Nov 2005 Adolor has completed enrolment in the 14CL314 trial for postoperative ileus inthe US

Dec 2005 Discontinued – Phase-I for Irritable bowel syndrome in the US (oral)

Apr 2006 GlaxoSmithKline and Adolor have completed enrolment in the SB-767905/012-4trials for opioid-induced bowel dysfunction


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observed adverse events in both the 6mg and 12mg surgery, and then twice a day beginning on the firsttreatment groups and the placebo groups were nau- postoperative day until hospital discharge or for asea, vomiting and hypotension.[16] In this study, the maximum of 7 days.[2]

incidences of nasogastric tube (NGT) reinsertionafter surgery were 8.4% and 4.8% in the 6mg and 1.3 Pharmacodynamics12mg alvimopan treatment groups, respectively,compared with 14.8% for placebo. This difference

1.3.1 Digestive System Disorderswas statistically significant for the 12mg alvimopanPreclinical studies: In guinea-pig ileum andgroup only.[17]

mouse vas deferens, alvimopan had pA2 values ofIn a double-blind, placebo-controlled, multicen-9.7, 7.8 and 8.7 for µ-, κ- and σ-receptors, respec-tre, phase III study (14CL306), 519 patients withtively. In mice, the peripheral and central opioid-postoperative ileus scheduled to undergo total ab-antagonising effects of alvimopan, respectively,dominal simple hysterectomy, while receivingwere determined by its ability to precipitate diar-opioids for pain relief, were randomised to receiverhoea in morphine-dependent animals and by itseither alvimopan (12mg) or placebo, at least 2 hoursability to suppress morphine-induced analgesia. Af-prior to surgery, and then twice a day for a maxi-ter intravenous administration, alvimopan precipi-mum of 7 days beginning in the hospital on the firsttated diarrhoea with an ED50 of 0.04 mg/kg andpostoperative day. Alvimopan was generally wellantagonised morphine analgesia with an AD50 oftolerated in this study, with 93% of patients com-9.0 mg/kg. In comparison, naloxone had a peripher-pleting treatment in the alvimopan 12mg treatmental vs central selectivity ratio of about 5. In mor-group and 92% of patients completing treatment inphine-dependent mice and rats, oral administrationthe placebo group. The most frequently observedof alvimopan precipitated diarrhoea with ED50s ofadverse events in both groups were nausea, vomit-<1 mg/kg. The compound also dose-dependentlying and constipation. Discontinuations due to ad-antagonised morphine-induced inhibition of char-verse events were 4% in the treatment group and 5%coal meal transit in mice. Orally administered al-in the placebo group.[10]

vimopan (3 mg/kg) almost completely reversed theIn a double-blind, placebo-controlled, multicen- inhibitory effects induced by the same dose of mor-

tre, phase III study (14CL308), 666 patients who phine. The inhibitory effects of alvimopan were ofwere scheduled to undergo large or small bowel rapid onset, of maximal value at 30 min postdose,resections, or simple or radical hysterectomy were and lasted for at least 8 hours.[12]

randomised to receive placebo or alvimopan at Alvimopan has high affinity for opioid receptorsdoses of 6mg or 12mg. Alvimopan was generally (Ki = 0.77, 40, and 4.4 nM for µ-, κ- and δ-receptors,well tolerated in this study. The most frequently respectively). It is a potent µ-receptor antagonistobserved adverse events in both the 6mg and 12mg following parenteral and oral administration andtreatment groups and the placebo groups were nau- distributes selectively (>200-fold selectivity) to pe-sea, vomiting and pruritus.[9]

ripheral receptors.[18]

Alvimopan was generally well tolerated in a mul- In a randomised, crossover study, 14 volunteersticentre, double-blind, parallel-group clinical trial received morphine (IV) + alvimopan (orally), mor-(Study SB-797905/SB-767905/001), which enrolled phine (IV) + placebo (orally) or placebo (IV +a total of 911 subjects that included 741 bowel orally). Alvimopan prevented the prolonged gastro-resection patients and 170 radical hysterectomy pa- intestinal transit time that was observed with mor-tients. The latter group was not included in the phine. Gastrointestinal transit times were 69 min atprimary analysis. Patients were randomised into baseline, 103 min with morphine and 76 min withthree arms, with patients receiving placebo, 6mg or alvimopan. Furthermore, other morphine-associated12mg doses of alvimopan orally 2 hours prior to adverse effects such as pupil constriction were also


Alvimopan 251

prevented with alvimopan in 45 patients receiving In one study, 132 patients undergoing abdominalmorphine whilst undergoing molar extraction.[19] surgery were randomised to receive alvimopan (3, 6

or 12mg bid) or placebo. Median time for recoveryof gastrointestinal function improved by 16 hours1.4 Therapeutic Trials(p < 0.05) in patients treated with the 12mg dose.[13]

In a double-blind study, 78 patients who were1.4.1 Digestive System Disorders

undergoing abdominal surgery (partial colectomy orOpioid-induced constipation: In a randomised, abdominal hysterectomy) were randomised to re-

double-blind study, 26 patients with chronic opioid- ceive alvimopan (1 or 6mg) or placebo. Patients whoinduced constipation received increasing doses of received 6mg of alvimopan experienced significant-alvimopan or placebo over four consecutive days. ly greater improvements in gastrointestinal functionAlvimopan was considered effective if stimulating a following surgery compared with placebo. Signifi-bowel movement within 24 hours of administration. cant reductions were observed in the time to firstEffective doses ranged between 0.5 and 4.5mg.[20]

passage of flatus (from 70 to 49 hours), the time toSeventy-six patients with opioid-induced consti- first bowel movement (from 111 to 70 hours), and

pation were randomised to receive placebo or one of the time until patients were ready for discharge (91three doses of alvimopan (0.5, 1.5 or 3.0mg). Com- to 68 hours).[22]

pared with placebo, significantly more patients whoIn a double-blind, placebo-controlled, multicen-received alvimopan experienced a bowel movement

tre, phase III study (14CL302), 450 patients whowithin 12 hours after administration (30% vs 68%,were scheduled to undergo partial colectomies, sim-77% and 100% of patients receiving alvimopan 0.5,ple or radical hysterectomies while receiving1.5 or 3.0mg, respectively).[20]

opioids for pain relief were randomised to receiveIn phase III study 304, 168 patients with opioid-placebo or alvimopan at doses of 6mg or 12mg. Theinduced bowel dysfunction received alvimopandrug was given at least 2 hours prior to surgery, and(0.5mg or 1mg) or placebo daily for 21 days. Thethen twice a day beginning on the first postoperativeprimary endpoint, the proportion of patients havingday until hospital discharge or for a maximum ofa bowel movement within 8 hours after each dose7 days’ postoperative treatment. The primaryduring the 21-day treatment period, was achieved byendpoint of the study, time to recovery of gastroin-43%, 55% and 29% of patients receiving alvimopantestinal function, achieved a statistically significant0.5mg, alvimopan 1mg and placebo, respectively,difference in patients receiving alvimopan 6mgwith bowel movements showing a significant differ-compared with patients receiving placebo. A differ-ence compared with placebo.[14]

ence in favour of the alvimopan 6mg treatmentIn a phase IIb study (SB-767905/011), 522 pa-group versus placebo was observed for all secondarytients taking opioids for persistent non-cancer painendpoints, including time to hospital discharge orderwere randomised to receive alvimopan 0.5mg twicewritten. A positive trend was observed in the prima-a day (group 1), alvimopan 1mg once a day (groupry endpoint of the study for the alvimopan 12mg2), alvimopan 1mg twice a day (group 3) or placebotreatment group; however, the difference from pla-for 6 weeks. The average increase in spontaneouscebo was not statistically significant.[15]

bowel movements per week was approximately 3.5in groups 1 and 2 (p < 0.001), and 4.3 in group 3 (p < In a double-blind, placebo-controlled, multicen-0.001), compared with 1.7 in the placebo group. The tre, phase III study (14CL313), 510 patients whoincrease in spontaneous bowel movements for each were scheduled to undergo small bowel resections,alvimopan dose group became apparent within 1 large bowel resections or radical hysterectomiesweek and was sustained throughout the 6-week while receiving opioids for pain relief weretreatment period, returning to baseline promptly af- randomised to receive placebo or alvimopan atter discontinuation of study therapy.[21] doses of 6mg or 12mg. In the primary endpoint of


252

study 313, time to recovery of gastrointestinal func- mean times to hospital discharge order written wereapproximately 17 hours and 21 hours sooner for thetion, a statistically significant difference was6mg and 12mg treatment groups, respectively, eachachieved in both the alvimopan 6mg and 12mgas compared with the placebo group.[9]treatment groups, compared with the placebo group.

The primary endpoint (GI3) of time to recoveryMean times of recovery were 120 hours, 105 hoursof gastrointestinal function in bowel resection sub-and 98 hours for the placebo, 6mg and 12mg groups,jects, the primary population for this analysis,respectively. A difference in favour of alvimopanshowed an HR of 1.22 for the 6mg alvimopan group,was observed for all of the secondary endpoints inand an HR of 1.13 for the 12mg group (p = 0.20),both the 6mg and 12mg treatment groups, includingcompared with the placebo group. These resultsa difference in time to hospital discharge order writ-were not statistically significant because of the mul-ten in the 6mg treatment group and a statisticallytiple-dose comparison to a single placebo group.significant difference in the 12mg treatment group.Secondary endpoints included an additional mea-Mean times to hospital discharge order written weresure of time to recovery of gastrointestinal functionapproximately 13 hours and 20 hours sooner for the(GI2). Results in GI2 were (Cox proportional hazard6mg and 12mg treatment groups, respectively, com-model) for the 6mg group, HR = 1.39; (p < 0.001);pared with placebo.[16] In the modified intent-to-and for the 12mg group, HR = 1.30; (p = 0.008),treat population of 451 bowel resection and 18 radi-compared with the placebo group. The secondarycal hysterectomy patients, GI function returnedendpoint of time to hospital discharge order writtenmore rapidly for the alvimopan 6mg (hazard ratiofavoured the alvimopan treatment groups, as com-[HR] = 1.28) and 12mg (HR = 1.54) groups, with apared with placebo, but was not statistically signifi-mean difference of 15 and 22 hours, respectively,cant. This multicentre, double-blind, placebo-con-compared with placebo. Alvimopan treatment didtrolled, parallel-group clinical trial (studynot interfere with opioid analgesia. The number ofSB-797905/SB-767905/001) enrolled a total of 911patients who were reported as returning to the hospi-subjects, which included 741 bowel resection pa-tal within 10 days after discharge was approximatelytients and 170 radical hysterectomy patients. The4% in each of the alvimopan treatment groups,latter group was not included in the primary analy-compared with 8% in the placebo group.[17]

sis. Patients were randomised into three arms, withIn a double-blind, placebo-controlled, multicen- patients receiving placebo, 6mg or 12mg doses of

tre, phase III study (14CL308), 666 patients who alvimopan orally 2 hours prior to surgery, and thenwere scheduled to undergo large or small bowel twice a day beginning on the first postoperative dayresections, or simple or radical hysterectomy, were until hospital discharge or for a maximum of 7randomised to receive placebo or alvimopan at days.[2]

doses of 6mg or 12mg. The primary endpoint ofstudy 14CL308, which was mean time to recovery Referencesof gastrointestinal function, was approximately 8 1. Adolor Corporation, GlaxoSmithKline. Adolor and Glaxo-

SmithKline announce worldwide development and commer-hours and 10 hours sooner for the alvimopan 6mgcialization agreement for alvimopan. Media Release: 15 Apr

and 12mg treatment groups, respectively, compared 2002. Available from URL: http://www.adolor.com2. Adolor Corporation. Adolor Reports Initial Results from GSKwith the placebo group. A difference in favour of

European Phase 3 Study of Alvimopan. Media Release: 23 Decalvimopan was observed for all of the secondary 2004. Available from URL: http://www.adolor.comendpoints in both the 6mg and 12mg treatment 3. Adolor Corporation. Adolor Submits First Portion of NDA for

Entereg(TM) (alvimopan) in Postoperative Ileus. Media Re-groups. Mean times to hospital discharge order writ-lease: 7 May 2004. Available from URL: http://www.

ten were approximately 14 and 15 hours sooner in adolor.com4. Adolor Corporation. Adolor Completes Submission of NDA foreach of the 6mg and 12mg treatment groups, respec-

Entereg (TM) (alvimopan) in Postoperative Ileus. Media Re-tively, compared with the placebo group. In the lease: 28 Jun 2004. Available from URL: http://www.subgroup of 437 subjects with bowel resection, adolor.com


Alvimopan 253

5. Adolor Corporation. FDA Extends PDUFA Action Date for function. Media Release: 11 Nov 2002. Available from URL:Entereg(TM) (alvimopan) Capsules to July 25, 2005. Media http://www.adolor.comRelease: 19 Apr 2005. Available from URL: http://www.

15. Adolor Corporation. Adolor Announces Top-Line Results ofadolor.comAlvimopan Phase 3 Clinical Study. Media Release: 2 Apr

6. Adolor Corporation. Adolor Receives FDA Approvable Letter 2003. Available from: URL: http://www.adolor.comfor Entereg(R) (Alvimopan). Media Release: 22 Jul 2005.

16. Adolor Corporation. Adolor Corporation Announces PositiveAvailable from URL: http://www.adolor.comTop-Line Results in 2nd Phase 3 Study of Alvimopan in7. Adolor Corporation. Adolor Announces FDA Update. MediaPostoperative Ileus. Media Release: 23 Sep 2003. AvailableRelease: 10 Jan 2005. Available from URL: http://www.from URL: http://www.adolor.comadolor.com

17. Adolor Corporation, GlaxoSmithKline. Data Published from8. Adolor Corporation, GlaxoSmithKline Corporation. Adolor andEntereg(TM) (alvimopan) Phase 3 Clinical Trial in Annals ofGlaxoSmithKline Report Positive Top-Line Results in Phase 3Surgery. Media Release: 23 Sep 2004. Available from URL:Study 314 of Entereg(R) (Alvimopan) in Postoperative Ileus.http://www.adolor.comMedia Release: 7 Feb 2006. Available from URL: http://

www.adolor.com 18. Zimmerman DM, Gidda JS, Cantrell BE. Discovery of a potent,9. Adolor Corporation. Adolor Corporation Announces Top-Line peripherally selective trans-3,4-dimethyl-4-(3-hydroxy-

Results in Entereg(TM) Phase 3 Clinical Study 308 in Postop- phenyl)piperidine opioid antagonist for the treatment of gas-erative Ileus. Media Release: 13 Jan 2004. Available from trointestinal motility disorders. Journal of Medicinal Chemis-URL: http://www.adolor.com try 37: 2262-2265, 22 Jul 1994

10. Adolor Corporation. Adolor Corporation Announces Top-Line 19. Liu SS, Hodgson PS, Carpenter RL, et al. ADL 8-2698, aResults In Phase 3 Safety Study of Entereg(TM) (alvimopan) trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, preventsin Postoperative Ileus. Media Release: 22 Oct 2003. Available gastrointestinal effects of intravenous morphine without af-from URL: http://www.adolor.com

fecting analgesia. Clinical Pharmacology and Therapeutics 69:11. Adolor Corporation. Adolor Corporation Receives Patents Cov- 66-71, Jan 2001

ering Novel Uses and Compositions Containing Alvimopan.20. Adolor Corporation. Adolor Corporation successfully com-Media Release: 13 Nov 2002. Available from URL: http://

pletes two phase 2 clinical trials of ADL 8-2698 in opioidwww.alolor.cominduced bowel dysfunction - plans to begin phase 3 clinical

12. Zimmerman DM, Gidda JS, Cantrell BE. LY246736 dihydrate: trials. Media Release [3 pages], 18 Jan 2001. Available frommu opioid receptor antagonist. Drugs of the Future 19: URL: http://www/adolor.com1078-1083, Dec 1994

21. GlaxoSmithKline, Adolor Corporation. GlaxoSmithKline and13. Adolor Corporation. Adolor Corporation completes phase 2Adolor Present Positive Results From a Clinical Study ofclinical trials in post-operative ileus second phase 3 pivotalalvimopan (Entereg(R)). Media Release: 4 May 2006. Availa-clinical trial to begin shortly. Media Release [3 pages], 28 Junble from URL: http://www.gsk.com2001. Available from URL: http://www.adolor.com

22. LY 246736 speeds postoperative recovery of intestinal function.14. Adolor Corporation. Adolor Corporation Announces ToplineInpharma 1308: 8, 6 Oct 2001Results of Alvimopan Phase 3 Study in Opioid Bowel Dys-


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