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Future Oncology (London, England) Dec 2006Abarelix, a gonadotropin-releasing hormone antagonist, with its indication for advanced symptomatic prostate cancer, represents the newest category of hormonal therapy... (Review)
Review
Abarelix, a gonadotropin-releasing hormone antagonist, with its indication for advanced symptomatic prostate cancer, represents the newest category of hormonal therapy introduced in the past 15 years. Results from Phase II and III clinical trials demonstrate the advantages of abarelix over commonly used luteinizing hormone-releasing hormone (LHRH) agonist therapy: abarelix does not cause a surge in serum testosterone that can precipitate a flare phenomenon or worsening of disease, particularly dangerous for patients with metastatic, symptomatic disease, and produces medical castration more quickly. Abarelix was also demonstrated to promptly and substantially reduce follicle-stimulating hormone levels to lower than LHRH agonist. Study results demonstrate effective anticancer responses during extended exposure to abarelix: improvements in pain score and/or analgesic use, improvements in urinary symptoms (including urinary catheter removal) and complete avoidance of bilateral orchiectomy for patients undergoing at least 12 weeks of treatment. In Phase III clinical trials, abarelix demonstrated a similar overall safety profile when compared with LHRH agonist monotherapy, and a superior safety profile when compared with LHRH agonist plus antiandrogen combination therapy. Abarelix patients experienced a greater incidence of immediate-onset systemic allergic reactions as compared with control arms.
Topics: Antineoplastic Agents, Hormonal; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Prostatic Neoplasms; Treatment Outcome
PubMed: 17155895
DOI: 10.2217/14796694.2.6.677 -
Drugs in R&D 2003Abarelix [Abarelix-Depot-F, Abarelix-Depot-M, Abarelix-L, PPI 149, R 3827, Plenaxis] is a peptide consisting of natural and artificial amino acids. In females, abarelix... (Review)
Review
Abarelix [Abarelix-Depot-F, Abarelix-Depot-M, Abarelix-L, PPI 149, R 3827, Plenaxis] is a peptide consisting of natural and artificial amino acids. In females, abarelix is an estrogen production antagonist with potential for the treatment of breast cancer, endometriosis and other reproductive hormone diseases. In males it is a testosterone production antagonist and has potential as hormonal therapy of prostate cancer. Depot formulations of abarelix (abarelix-depot-M and abarelix-depot-F) are being developed for hormonally responsive prostate cancer and endometriosis, respectively. Clinical development of the depot formulations is currently being conducted by Praecis Pharmaceuticals, the originators of the agent. A non-depot formulation, abarelix-L, was also being conducted for prostate gland volume reduction. Praecis Pharmaceuticals has entered into a number of licensing agreements covering abarelix. However, all agreements have since been terminated leaving Praecis to develop and commercialise the agent on its own. The terminated agreements include an agreement between Praecis and Roche for the commercialisation of abarelix in the US. This agreement was terminated in November 1998. Praecis Pharmaceuticals also entered into a collaborative agreement with Amgen in March 1999, whereby the companies would develop abarelix and Amgen would commercialise the drug in the US, Canada, Australia, Asia and several secondary markets. However, in September 2001, Praecis and Amgen announced that they were terminating the agreement for all indications. Praecis stated at the time that it remained committed to developing abarelix for both prostate cancer and endometriosis. Amgen had submitted 'Lotestrol' to the US Patent and Trademarks Office as a possible tradename for abarelix-depot-M. Lotestrol may also have been under consideration as a tradename for abarelix-depot-F. Praecis had also sold European, African, Latin American and Middle Eastern rights to abarelix to Sanofi-Synthélabo. However, in October 2001, Sanofi-Synthélabo announced that it had waived its rights to abarelix. Praecis confirmed in December 2000 that it had filed an NDA seeking FDA approval for abarelix in the US. In January 2001, the FDA granted the abarelix application priority review status. However, in June 2001, the FDA rejected the NDA for prostate cancer. The FDA requested that Praecis use existing data from the completed trials to analyse the allergic reactions that occurred in a small subset of patients. The FDA also expressed concerns over the lack of maintenance of testosterone suppression beyond the 3-month timeframe that occurred in a subset of patients. In February 2003, Praecis announced the re-submission of its NDA to the US FDA. The submission seeks approval for the use of abarelix in a defined subpopulation of advanced prostate cancer patients for whom the current hormonal therapies are not appropriate. Praecis plans to submit its regulatory application in Europe during the second quarter of 2003. Following the completion of a phase I/II trial of abarelix-L in prostate gland volume reduction, a phase IIIb study of the depot formulation was initiated in September 2001. The trial is comparing the effects of neoadjuvant hormonal therapy with depot formulations of leuprorelin or abarelix for prostate gland volume reduction. Abarelix-L is no longer mentioned on Praecis' website, suggesting that development of this formulation is no longer being pursued. The Financial Times (ft.com) reported in May 2001 that approximately 12 new anti-cancer agents are expected to be approved by the FDA through to the end of 2002, with the potential to generate total sales of US dollars 2.6 billion--abarelix is one of these products. The paper quoted analysts at Salomon Smith Barney predicting that abarelix could reach sales of US dollars 120 million for the indication of prostate cancer. However, in June 2001 the FDA rejected Praecis Pharmaceuticale FDA rejected Praecis Pharmaceuticals' NDA filing; this was later re-submitted in February 2003. A year earlier, in May 2000, the Financial Times (ft.com) stated that Credit Suisse First Boston had forecast abarelix to reach peak sales of 1 billion US dollars . Other analysts, at SG Cowen, predicted annual sales of US dollars 200 million for the first 3 years; however, this could increase to 1 billion US dollars if abarelix is also approved for the indication of endometriosis. Abarelix' main competitors at the time were said to be Lupron [TAP Pharmaceuticals], Viadur [Alza] and Zoladex [AstraZeneca].
Topics: Antineoplastic Agents; Clinical Trials as Topic; Drugs, Investigational; Endometriosis; Estrogen Antagonists; Female; Humans; Male; Oligopeptides; Prostatic Neoplasms
PubMed: 12757402
DOI: 10.2165/00126839-200304030-00004 -
Abarelix: the first gonadotrophin-releasing hormone antagonist for the treatment of prostate cancer.Expert Opinion on Pharmacotherapy Oct 2004The high incidence of prostate cancer makes it a major healthcare problem and the second leading cancer-related cause of death among men in developed countries. The... (Review)
Review
The high incidence of prostate cancer makes it a major healthcare problem and the second leading cancer-related cause of death among men in developed countries. The hormonal treatment of prostate cancer is indicated for the palliation of symptomatic and metastatic disease in older patients, and as neoadjuvant treatment of different modalities of radiotherapy. This hormonal treatment is based on the study conducted by Huggins in 1940 and consists of androgen suppression. Since the clinical availability of the first luteinising hormone-releasing hormone (LHRH) agonist, no significant improvement has been made in the field of medical castration. Taking these data into consideration, the recent approval of abarelix by the FDA, the first gonadotrophin-releasing hormone (GnRH) antagonist, appears to be promising news. The pharmacology of the molecule and the clinical studies that led to FDA approval will be reviewed. The place of GnRH antagonists in the treatment modalities of prostate cancer will then be discussed.
Topics: Animals; Clinical Trials, Phase III as Topic; Drug Hypersensitivity; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Oligopeptides; Palliative Care; Prostatic Neoplasms; Testosterone
PubMed: 15461552
DOI: 10.1517/14656566.5.10.2171 -
BJU International Dec 2009Hormonal therapy is the main recommended treatment for locally advanced and metastatic prostate cancer. Luteinizing hormone-releasing hormone (LHRH) agonists, such as... (Review)
Review
Hormonal therapy is the main recommended treatment for locally advanced and metastatic prostate cancer. Luteinizing hormone-releasing hormone (LHRH) agonists, such as buserelin, goserelin, leuprorelin and triptorelin, stimulate the pituitary's gonadotrophin-releasing hormone (GnRH) receptor, ultimately leading to its de-sensitization and subsequent reduction of LH and testosterone levels. However, this reduction is accompanied by a well described increase or 'surge' in LH and testosterone levels, necessitating the concomitant administration of an antiandrogen to combat the potential effects of transient acceleration in cancer activity. Two pure GnRH antagonists have been developed, abarelix and degarelix, that are devoid of any agonist effect on the GnRH receptor and consequently do not result in testosterone flare. Abarelix was the first GnRH antagonist to be developed and was approved by the USA Food and Drug Administration in 2004 for the initiation of hormonal castration in advanced or metastasizing hormone-dependent prostate carcinoma, when rapid androgen suppression is necessary. Clinical data on both abarelix and degarelix show that they can produce rapid and sustained decreases in testosterone to castrate levels without the need for co-administration of an antiandrogen, and with a very low complication rate in the short term.
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Epidemiologic Methods; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Prostatic Neoplasms; Treatment Outcome
PubMed: 20053189
DOI: 10.1111/j.1464-410X.2009.08924.x -
Clinical Journal of Oncology Nursing Dec 2004
Topics: Antineoplastic Agents; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Gonadotropin-Releasing Hormone; Humans; Male; Nurse's Role; Oligopeptides; Oncology Nursing; Patient Education as Topic; Patient Selection; Prostatic Neoplasms
PubMed: 15637961
DOI: 10.1188/04.CJON.663-669 -
Current Opinion in Molecular... Oct 2000Abarelix (PPI-149) is a luteinizing hormone-releasing hormone (LHRH) receptor antagonist under development by Praecis, Amgen and Sanofi-Synthelabo for the potential... (Clinical Trial)
Clinical Trial Review
Abarelix (PPI-149) is a luteinizing hormone-releasing hormone (LHRH) receptor antagonist under development by Praecis, Amgen and Sanofi-Synthelabo for the potential treatment of prostate cancer, breast cancer and hormone-related disorders [285672,328910]. Abarelix has entered phase III clinical trials for hormonally responsive prostate cancer [311887], and a sustained-release formulation is in a phase I/II clinical trial for endometriosis [317822]. In June 1997, Praecis entered into a collaboration with Sanofi-Synthelabo for the continued development and future marketing of Abarelix for the treatment of prostate cancer and other hormone-related disorders in Europe [248307]. In June 1998, Roche gained marketing rights in the US and elsewhere, under a joint development agreement [289677], which was later terminated. In March 1999, Amgen gained rights to develop Abarelix in the US, Canada, Australia, Asia and other secondary markets [317822]. Sanofi-Synthelabo expects to launch the compound in Europe in 2001 [345341,346302]. In March 1999, Merrill Lynch predicted sales in 2001 of US$75 million, with peak sales of up to US$400 million [336561]. In October 1999, Merrill Lynch predicted sales in 2003 of EUR 100 million [346209] and Lehman Brothers predicted sales of US$50 million in 2002 rising to a peak of US$150 million in 2010 [346267].
Topics: Animals; Antineoplastic Agents; Biotechnology; Endometriosis; Female; Humans; Male; Neoplasms, Hormone-Dependent; Oligopeptides; Prostatic Neoplasms; Receptors, LHRH
PubMed: 11249760
DOI: No ID Found -
Clinical Prostate Cancer Mar 2004
Review
Topics: Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Metastasis; Oligopeptides; Prostatic Neoplasms
PubMed: 15072602
DOI: 10.1016/s1540-0352(11)70046-4 -
Anti-cancer Drugs Oct 2006Follicle-stimulating hormone has been shown to be a mitogen in preclinical models of androgen-independent prostate cancer and abarelix has been previously shown to...
Follicle-stimulating hormone has been shown to be a mitogen in preclinical models of androgen-independent prostate cancer and abarelix has been previously shown to significantly reduce follicle-stimulating hormone levels in patients when administered monthly. Consequently, we evaluated the safety of more frequent (biweekly) dosing of abarelix and characterized the effect of this dosing schedule on serum follicle-stimulating hormone levels in men with prostate cancer that is progressing despite luteinizing hormone-releasing hormone agonist therapy. Twenty-one patients with prostate cancer progressing on gonadotropin-releasing hormone agonist therapy discontinued the gonadotropin-releasing hormone agonist and received abarelix-depot 100 mg by intramuscular injection every 2 weeks for up to 12 weeks. Safety profile and effect on serum follicle-stimulating hormone were the primary end-points, while prostate-specific antigen response was a secondary end-point. Abarelix therapy was generally well tolerated. One patient experienced an acute immediate allergic reaction. The mean follicle-stimulating hormone serum concentration declined from 3.5 mIU/ml (95% confidence interval: 2.7-4.3) to 2.0 mIU/ml (95% confidence interval: 1.3-2.6) on day 57 and to 2.0 mIU/ml (95% confidence interval: 0.9-3.0) on day 85 (P=0.008 in a Kruskal-Wallis test), but no patient's follicle-stimulating hormone has reached the lower limit of quantitation (below 0.15 mIU/ml). No patient met criteria for prostate-specific antigen response. At the end of 12 weeks of therapy, three (14.3%) patients had no change in prostate-specific antigen levels on days 57 and 85 compared with baseline. Twelve patients (57%) had stable disease throughout treatment defined as percent change from baseline within -50 to 50% at a given time-point confirmed by a second measurement at least 4 weeks later. Treatment with biweekly abarelix in patients with androgen-independent prostate cancer is feasible with no unexpected toxicity, but fails to completely suppress serum follicle-stimulating hormone levels or produce prostate-specific antigen responses.
Topics: Aged; Aged, 80 and over; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone
PubMed: 17001181
DOI: 10.1097/01.cad.0000231476.84782.55 -
The Medical Letter on Drugs and... Mar 2004
Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Hypersensitivity; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Prostatic Neoplasms; Receptors, LHRH
PubMed: 15037857
DOI: No ID Found -
The Journal of Urology May 2001We contrasted the endocrinological and biochemical efficacies of abarelix depot, a pure gonadotropin-releasing hormone antagonist, with a prospective concurrent control... (Clinical Trial)
Clinical Trial Comparative Study
The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer.
PURPOSE
We contrasted the endocrinological and biochemical efficacies of abarelix depot, a pure gonadotropin-releasing hormone antagonist, with a prospective concurrent control cohort receiving luteinizing hormone releasing hormone (LH-RH) agonists with or without antiandrogen for treatment of patients with prostate cancer receiving initial hormonal therapy.
MATERIALS AND METHODS
In this phase 2 open label study 242 patients with prostate cancer requiring initial hormonal treatment received abarelix depot (209) or LH-RH agonists (33) with or without antiandrogen. A total of 100 mg. abarelix depot was delivered intramuscularly every 28 days with an additional injection on day 15. LH-RH agonists with or without antiandrogen were administered according to the depot formulation used. Endocrine efficacy was measured by the absence of testosterone surge and rapidity of castration onset. The rate of prostate specific antigen decrease was assessed.
RESULTS
No patient treated with abarelix depot had testosterone surge during week 1 compared with 82% of those treated with LH-RH agonists. The concomitant administration of antiandrogen had no effect. During the first week of drug administration, in 75% of patients treated with abarelix depot and in 0% of those treated with LH-RH agonist medical castration was achieved. Prostate specific antigen decrease was faster, with no flare or surge in patients treated with abarelix depot. Abarelix depot was well tolerated.
CONCLUSIONS
Abarelix depot represents a new class of hormonal therapy, gonadotropin releasing hormone antagonists, that has rapid medical castration and avoids the testosterone surge characteristic of LH-RH agonists.
Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Dihydrotestosterone; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Goserelin; Humans; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Oligopeptides; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testis; Testosterone
PubMed: 11342922
DOI: No ID Found