anesthesia - Organon reports positive results from phase II studies with novel a

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Organon reports positive results from phase II studies with novel

agent to reverse muscle relaxation in anesthesia

Tuesday, May 31, 2005 (Oss, The Netherlands)

N.V. Organon announced today positive top-line findings from three

phase II studies of Org 25969, the first of a new class of agents to

reverse neuromuscular block. Org 25969 - widely anticipated as " the

most significant advance in neuromuscular pharmacology in the last 20

years " - is currently entering phase III clinical trials.

" We are very pleased with the results of these studies. If

successful in further development - and all the signs are very

positive - Org 25969 will allow anesthesiologists to switch off

muscle relaxation at will with major advantages for patient safety, "

commented Dr Willem de Laat, the Executive Vice President,

Development and Medical Affairs of Organon.

Reversal agents are administered after surgical procedures involving

the use of muscle relaxants (neuromuscular blocking agents or NMBAs)

to enable spontaneous breathing to recommence earlier. Current

reversal agents can only be administered when muscle relaxation is

starting to wear off and may take up to 30 minutes to reverse

blockade. Phase I studies involving Org 25969 - a selective relaxant

binding agent (SRBA) - show it can achieve reversal following

Esmeron® (rocuronium bromide; one of the most widely used NMBAs)

administration within three minutes regardless of the depth of block,

and with minimal adverse effects. The phase II studies were designed

to determine the clinically appropriate and effective dose of Org

25969.

Two of the phase II studies explored the dose-response relationship

of Org 25969 after prolonged Esmeron-induced neuromuscular block and

high dose (profound) Esmeron- induced neuromuscular block (studies

203 and 206 respectively). The third study - 210 - investigated the

efficacy and safety of Org 25969 when used with either sevoflurane or

propofol maintenance anesthesia. Study investigators presented full

details of the studies at the European Society of Anesthesia congress

currently taking place in Vienna, Austria.

The above studies confirm that Org 25969 shows a dose-response effect

for time to recovery regardless of duration of or depth of Esmeron

blockade. The fastest achievable time to recovery with Org 25969

after prolonged blockade was 1.59 minutes. Profound neuromuscular

blockade was on average reversed within 3 minutes when appropriate

doses of Org 25969 were used. In both studies Org 25969 was well

tolerated and there was no evidence of recurarization (the re-

establishment of neuromuscular blockade.) Study 210 showed that the

efficacy of Org 25969 was not influenced by the type of general

anesthetic regimen.

" The revolutionary capabilities of Org 25969 are eagerly awaited by

anesthesiologists throughout the world, " said study investigator Dr.

Rajinder K Mirakhur, Professor of Anaesthetics at the Queen's

University of Belfast, UK. " On the basis of evidence available today,

Org 25969 appears to offer safe, fast and effective reversal of

Esmeron-induced neuromuscular block in almost every situation

providing ultimate control in neuromuscular block management. As Org

25969 shows no muscarinic side effects in the current studies, there

seems to be no need to co-administer anticholinergic drugs with it,

thus further increasing the safety of reversal of neuromuscular

blockade This agent is widely anticipated as the most significant

advance in neuromuscular pharmacology in the last 20 years and will

truly revolutionize neuromuscular block management in the daily

practice of anesthesiologists. "

About Org 25969:

Org 25969 is a gamma cyclodextrin compound, modified to bind a

molecule of rocuronium with high affinity and high selectivity (a

process known as encapsulation). Once bound, the muscle relaxant is

no longer able to produce effect. Org 25969 and the captured muscle

relaxant are then removed from the body through renal elimination.

Cyclodextrins by themselves are inert. Therefore, Org 25969 is

unlikely to be associated with side effects.

About neuromuscular blockade and its reversal:

Muscle relaxants or NMBAs were introduced into anesthetic practice in

1942 to inhibit muscle movement in anesthetized patients during

surgery. They allow a wide range of surgeries to be performed without

the risk of patient movement but at relatively lesser depths of

anesthesia with greater safety for the patient. More importantly

muscle relaxants are one of the crucial drugs required for safe

intubation of a patient and are used frequently to control patients'

breathing. (Intubation is the process of placing a tube in the throat

to facilitate artificial ventilation.) Reversing neuromuscular

blockade allows the patient to breathe unaided earlier thus

facilitating the earlier removal of the breathing tube. Currently

available agents require the muscle relaxant to start to wear off

before reversal can take place. In addition, the results of reversal

are variable, still take an appreciable amount of time, and can be

associated with various untoward effects, including cardiovascular

side effects.

Organon - with shared head offices in Roseland, NJ, USA and Oss, The

Netherlands - creates, manufactures and markets prescription

medicines that improve the health and quality of human life. Through

a combination of independent growth and business partnerships,

Organon strives to remain or become one of the leading pharmaceutical

companies in each of its core therapeutic fields: reproductive

medicine, psychiatry and anesthesia. Organon products are sold in

over 100 countries, of which more than 60 have an Organon subsidiary.

Organon is the human health care business unit of Akzo Nobel.

Further study detail:

Study 206 was designed to explore the dose-response relation of Org

25969 given for reversal of high dose Esmeron-induced neuromuscular

block.

87 patients aged 18-80 years of age received 1.0 mg/kg Esmeron - a

dose sufficient to induce profound muscle relaxation - followed

either three or 15 minutes later by placebo or Org 25969 in doses of

between 2.0 and 16.0 mg per kg.

The study showed that the profound neuromuscular block after high

dose Esmeron was on average reversed within 2.5 minutes for doses of

=8.0 mg/kg Org 25969. No serious adverse events related to Org 25969

were reported.

Study 203 was designed to explore the dose-response relation of Org

25969 given after prolonged Esmeron-induced neuromuscular block.

30 adult patients aged 19-76 years with anticipated duration of

anesthesia of more than 2.5 hours received an initial dose of 0.6

mg/kg Esmeron followed by increments to maintain a deep block. At

recovery of T2 - the common reference point for administration of a

reversal agent - patients were randomly assigned to receive Org 25969

in doses between 0.5 and 6.0 mg/kg.

Results revealed a dose-related decrease in the time taken to

recovery. Regression analysis showed that the fastest achievable time

to recovery was 1.59 minutes. Org 25969 was also well tolerated.

There were no serious adverse events related to treatment and no

evidence of recurarization.

Study 210 was designed to study the efficacy and safety of Org 25969

when used with either propofol and sevoflurane maintenance anesthesia.

42 patients aged 19 to 82 years of age with an anticipated duration

of anesthesia for more than 45 minutes were enrolled. Each received

an IV intubation bolus dose of Esmeron after propofol induction. For

maintenance of anesthesia, subjects were randomized to receive

propofol or sevoflurane according to clinical need. At reappearance

of T2, 2.0. mg/kg of Org 25969 was administered as a single IV bolus.

Anesthesia was maintained until the end of surgery.

Mean recovery time from Org 25969 administration to recovery was 1

min 50 sec. in patients maintained on propofol and 1 min 48 sec. for

patients switched to sevoflurane - well within the predefined range

for equivalence. No recurarization was observed.