ATTENTION: anybody here friends with a urologist? Here is the information I have obtained about IDEV's new drug. This information is gold so please return the favor with your findings! Copy the competitive intelligence below and have your doctor friend compare and contrast this drug with similar drugs already in the US market; their opinion could be invaluble.
TROSPIUM CHLORIDE
May 25, 2004
Drug Name
Trospium chloride
Synonyms
IP 631, Regurin(R), Sanctura(TM), Spasmo-lyt(R)
Highest Phase
Launched
Chemical Name
3alpha-Hydroxyspiro[1alphaH,5alphaH-nortropane-8,1'- pyrrolidinium]chloride benzilate
Molecular Formula
C25 H30 N O3 . Cl
CAS Registry Numbers
10405-02-4
Latest Change
20040407
Introduction
Trospium chloride [Sanctura(TM), Spasmoplex sup((R)), Spasmo-lyt sup((R)), IP 631, Uraplex sup((R))] is a bladder-specific antimuscarinic agent, with a high level of selectivity for the M sub(2) and M sub(3) receptors, developed by Madaus AG of Germany. It has been launched as a treatment for overactive bladder in European countries including Germany, Austria, Spain and Switzerland. In the United Kingdom, it is marketed as Regurin sup((R)) by Galen Holdings.
Company Agreements
Licensing agreements: trospium chloride has been exclusively licensed to Indevus Pharmaceuticals (previously Interneuron Pharmaceuticals) in the USA. Indevus is responsible for all clinical development and regulatory activities, costs, manufacturing and marketing in the USA. Indevus is evaluating commercialisation alternatives for trospium, including seeking a corporate partner, since the company itself does not have the necessary sales and marketing capability or financial resources to market trospium.
There are no existing US patents covering the use of orally-administered trospium to treat overactive bladder and so Indevus expects to rely on the "Waxman-Hatch" act to obtain a period of market exclusivity in the USA. Indevus also intends to seek additional patent protection through the development of a once-daily formulation of the drug. On April 3, 2002, Interneuron Pharmaceuticals changed its name to Indevus Pharmaceuticals.
In 1999, a new market-leading company in the field of urology was founded under the name of HOYER-MADAUS. All urology drugs of Schwarz Pharma AG and Madaus AG are marketed by this joint venture, including trospium chloride.
US rights: in April 2004, Indevus Pharmaceuticals entered into a co- promotion and licensing agreement with PLIVA d.d. for the U.S. commercialisation of Sanctura(TM) for overactive bladder. The agreement provides for payments to Indevus from PLIVA that includes US$30 million upon signing and US$120 million upon the approval of Sanctura(TM) by the FDA. In addition, Indevus could receive up to US$45 million in future payments contingent upon the achievement of certain milestones related to the development of a once-a-day formulation of Sanctura(TM), as well as a payment of US$20 million related to the achievement of a long-term commercialisation milestone in 2013. Under the agreement, Indevus will be responsible for funding the development of the once-a-day formulation of Sanctura(TM). Indevus will purchase trospium from Madaus AG and will supply it to PLIVA. PLIVA will be responsible for product distribution and will record revenue for sales of the product.
For at least six months following the approval of Sanctura(TM), Indevus will receive a commission based on net sales of Sanctura(TM), a portion of which will fund its own sales force and certain advertising and promotional costs. PLIVA and Indevus will co-promote Sanctura(TM) through a joint sales force of approximately 500 sales representatives. At any time beginning six months after the approval of Sanctura(TM), each company has the right to convert the agreement into a royalty- bearing structure, whereby Indevus will receive royalties from PLIVA based on net sales of Sanctura(TM), and PLIVA will be responsible for promotional, advertising and sales force-related costs. Should this right be exercised, Indevus will retain a specialty sales force promoting Sanctura(TM) to urology specialists, obstetricians and gynaecologists, and high prescribers.
Key Development Milestones
Overactive bladder: Interneuron Pharmaceuticals (now Indevus Pharmaceuticals) announced in June 2000 that it believed a single phase III trial would be sufficient for approval in the US as extensive safety and efficacy studies (including comparative studies with tolterodine and oxybutynin) have already been conducted in Europe in more than 2000 patients.
In September 2002, Indevus Pharmaceuticals announced results to a 12- week phase III trial in patients with overactive bladder and urinary incontinence. Over 400 patients from this trial are participating in an ongoing nine-month open-label extension of the trial. Based on these results, Indevus filed a New Drug Application (NDA) for trospium with the U.S. Food and Drug Administration (FDA) in April 2003, the application includes European clinical trial data.
As a result of submission of additional data relating to Sanctura(TM), Indevus received a letter from the FDA on February 12, 2004, establishing a 90-day extension to the original Prescription Drug User Fee Act (PDUFA) action date of February 27, 2004, moving that date to May 28, 2004.
Financial Figures
Dow Jones Newswires reported on January 2, 2003, that Indevus is to spend another $US7 million on development of trospium, in addition to the approximately $US25 million already spent.
Company Information
Originator: Madaus, Germany
Licensee: Hoyer-Madaus, Europe
Licensee: Galen Holdings, United Kingdom
Licensee: Indevus Pharmaceuticals, USA
Development Status
Launched: Overactive bladder, Austria
Launched: Overactive bladder, Europe
Launched: Overactive bladder, Germany
Launched: Overactive bladder, Spain
Launched: Overactive bladder, Switzerland
Launched: Overactive bladder, United Kingdom
Pre-registered: Overactive bladder, USA
Mechanism of Action
Mechanism: Muscarinic receptor antagonists
Parent: Acetylcholine receptor antagonists
Child: Muscarinic M1 receptor antagonists
Mechanism: Muscarinic receptor antagonists
Parent: Acetylcholine receptor antagonists
Child: Muscarinic M2 receptor antagonists
Mechanism: Muscarinic receptor antagonists
Parent: Acetylcholine receptor antagonists
Child: Muscarinic M3 receptor antagonists
Mechanism: Muscarinic receptor antagonists
Parent: Acetylcholine receptor antagonists
Child: Muscarinic M4 receptor antagonists
Mechanism: Muscarinic receptor antagonists
Parent: Acetylcholine receptor antagonists
Child: Muscarinic M5 receptor antagonists
CLINICAL OVERVIEW
Route: PO
REVIEW
ADVERSE EVENTS: Urinary incontinence: trospium chloride (40 mg/day) was well tolerated when administered bid for 21 days, and had similar incidence and severity of adverse events as placebo in a trial in patients with urge urinary incontinence. At least one adverse event occurred in 40/210 (19%) patients in the treatment group, compared with 15/99 (15%) of placebo recipients. One case of faecal and urinary retention was reported in the treatment group and one case of urinary retention occurred among placebo recipients. Eight patients in each group withdrew as a result of adverse events.
In a trial in 76 patients with detrusor instability, tropsium chloride was most commonly associated with dry mouth, and was better tolerated at 10 and 20mg bid dose levels than 40mg bid doses or placebo.
In a phase III, double-blind trial, 523 patients with overactive bladder received either placebo or trospium during a 12-week period. Trospium was well tolerated as evidenced by its adverse event profile, with the most common adverse events being dry mouth and constipation. The incidence of dry mouth observed in trospium patients was 21.8%, while constipation was observed in 9.5% of these patients.
Urge incontinence: in a multicentre study in which 46 patients with motor urge incontinence, the frequency of adverse events was comparable between the trospium chloride (15mg; n = 25) and placebo groups. The most common adverse event was dry mouth, which occurred in 48% of trospium chloride recipients and 50% of placebo recipients.
In a phase III trial involving 357 patients with urge incontinence, trospium chloride and oxybutynin were associated with adverse events in 68% vs 77% of patients, including gastrointestinal events in 39% vs 51% and dry mouth in 33% vs 50%, respectively.
DRUG INTERACTIONS:
Pharmacokinetics: In humans, trospium is slowly absorbed with the maximum plasma levels peaking after 5-6 hours. Oral bioavailability is approximately 10% in man (around 85% of the drug is protein-bound), with dose linearity shown over a 20-60 mg dose range. There is currently no evidence of any age or gender differences in intestinal absorption or elimination. Less than 20% of the compound is metabolised, with no known active metabolites. Around 56% of trospium is excreted as the parent with a half-life of 12-18 hours.
Therapeutic Trials Text
Genitourinary Disorders
Neurogenic bladder: 309 patients with urge incontinence caused by detrusor instability received either oral tropspium chloride (40 mg/day) or placebo bid for 21 days. Maximum cystometric capacity, maximum detrusor pressure and volume at first unstable contraction and volume at maximum detrusor contraction were all significantly reduced in 99 evaluable trospium chloride recipients, but not in 48 placebo recpients. Cure or marked or slight improvement were reported in 73% of the treatment group, compared with 48% of placebo recipients.
Treatment with trospium chloride (10-40mg bid) significantly improved volume at first contraction in 76 patients treated for 21 days. Greatest efficacy was observed with the 10mg dose.
Indevus initiated a phase III trial in patients with overactive bladder and urinary incontinence in September 2001. Enrollment (n = 524) for this 12-week, double-blind, placebo-controlled, multicentre (n > 50) trial was completed on the 19th June 2002. The study will assess the incidence of urination and incontinence episodes among trospium-treated patients and placebo recipients. Data from this trial are expected in the third quarter of 2002.
In a phase III, double-blind trial, 523 patients with overactive bladder received either placebo or trospium (20 mg twice daily) during a 12-week period. Both the primary endpoint's were achieved, with significant reductions seen in both the frequency of urination and urinary incontinence episodes among patients treated with trospium, compared with patients who received placebo. The trial also met all of its secondary endpoint's. At week 12, trospium patients had 2.37 (p < 0.0001) fewer toilet voids per day, compared to baseline, while placebo patients had 1.29 fewer toilet voids per day compared to baseline. Trospium patients had 59% (p < 0.0001) fewer incontinence episodes per day at the end of the study, compared to baseline, and placebo patients had 44% fewer incontinence episodes at the end of the study, compared to baseline. Trospium patients increased their volume voided per void beginning at week 1 and continuing through week 12 (p<0.0001), with an increase of 32.1 mL at week 12, compared to an increase of 7.7 mL in placebo patients. Treatment with trospium also led to a significant improvement in average urgency severity . Compared with placebo, trospium chloride significantly reduced the frequency of voids at day 3; from day 7 through the 12-week end of the trial, a statistically significant reduction in frequency of voids was observed in trospium chloride recipients. In addition, trospium chloride significantly reduced the number of urge incontinent (UI) episodes at seven days after commencing treatment, and through the end of the trial. Researchers found that the reduction of a single UI episode from baseline to the end of week 1 was predictive of a 50% reduction in UI episodes at week 12.
Urge incontinence: orally administered trospium chloride increased maximum bladder capacity in a multicentre study in 46 patients with motor urge incontinence. Patients were randomised to receive oral trospium chloride 15mg (n = 25) or placebo, 3 times daily for 28 days. In per-protocol analysis, mean maximum bladder capacity was significantly increased from baseline at 28 days in trospium chloride recipients (+82.32ml), but was decreased in placebo recipients (-4.06ml). Intent-to-treat analysis revealed a greater increase from baseline in mean maximum bladder capacity among trospium chloride, compared with placebo, recipients (75.2 vs 16ml), and showed the same tendency as the per-protocol analysis.
In a phase III trial involving 357 patients with urge incontinence, long-term therapy with trospium chloride was as effective as standard oxybutynin (Dridase sup((R)); Sanofi-Synthelabo), with no significant differences between groups with respect to reductions in incontinence episodes, micturition frequency and urgency episodes.
Drug Development History
20010913: Phase-III clinical trials for Overactive bladder in USA (PO)
20010910: A study has been added to the adverse events and Genitourinary Disorders therapeutic trials sections (850825)
20010906: Launched for Overactive bladder in Austria (PO)
20010906: Launched for Overactive bladder in Germany (PO)
20010906: Launched for Overactive bladder in Spain (PO)
20010906: Launched for Overactive bladder in Switzerland (PO)
20001127: Launched for Overactive bladder in United Kingdom (PO)
20000801: A study has been added to the adverse events and Genitourinary Disorders therapeutic trials sections (698624)
20000609: Launched for Overactive bladder in Europe (PO)
20000609: New profile
20000609: Phase-II clinical trials for Overactive bladder in USA (PO)
REFERENCES
Chaliha C, Halaska M, et al. Trospium chloride for the treatment of detrusor instability: a placebo-controlled dose-finding study. British Journal of Obstetrics and Gynaecology. 105 (Suppl. 17): 92, Jul 1998. (English).
Alloussi S, Laval K-U, et al. Trospium chloride (Spasmo-lyt Rm) in patients with motor urge syndrome (detrusor instability): a double-blind, randomised, multicentre, placebo-controlled study. Journal of Drug Assessment. 2: 27-39, Part 1, 1999. (English).
Ulshofer B, Bihr A-M, et al. Randomised, double-blind, placebo-controlled study on the efficacy and tolerance of trospium chloride in patients with motor urge incontinence. Clinical Drug Investigation. 21: 563-569, No. 8, 2001. (English).
Halaska M, Ralph G, et al. Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability. World Journal of Urology. 20: 392-399, No. 6, May 2003. (English).
Indevus Pharmaceuticals Inc. Trospium chloride: non- confidential summary January 2003. Company Communication. : Jan 2003. Available from: URL: indevus.com. (English).
Indevus Pharmaceuticals Inc. Indevus Licenses Worldwide Rights to Anti-Inflammatory and Analgesic Compound; Company also updates status of other compounds in pipeline. Media Release. : 1 Jul 2002. Available from: URL: indevus.com. (English).
Indevus Pharmaceuticals Inc. Indevus Announces Positive Phase III Results With Trospium in Overactive Bladder. Media Release. : 24 Sep 2002. Available from: URL: indevus.com. (English)
Vanderbilt University. Phase III Data on New Overactive Bladder Medication Offers Promise For Millions of Sufferers. Media Release. : 29 Apr 2003. Available from: URL: vanderbilt.edu. (English).
Indevus Pharmaceuticals Inc. Indevus Submits New Drug Application For Trospium To Treat Overactive Bladder. Media Release. : 28 Apr 2003. Available from: URL: indevus.com. (English).
Indevus Pharmaceuticals. Presentations at International Continence Society Highlight Onset of Action, Urodynamic Data with Trospium, under Development by Indevus for Overactive Bladder. Media Release. : 9 Oct 2003. Available from: URL: indevus.com. (English).
Indevus Pharmaceuticals Inc. Early Patient Response Predicts Long-Term Success of Therapy With Indevus' Trospium for Overactive Bladder. Media Release. : 14 Oct 2003. Available from: URL: http:// www.businesswire.com. (English).
Indevus Pharmaceuticals Inc. Indevus and PLIVA Sign Co-Promotion and Licensing Agreement for SANCTURA -Trospium Chloride-; Indevus to Establish Specialty Sales Force. Media Release. : 7 Apr 2004. Available from: URL: indevus.com. (English). |
