ReGen and the Zolpidem Project The sedative zolpidem (marketed by Sanofi-Aventis under the trade names Stilnox™ and Ambien™) has been used for the last twenty years as a hypnotic/sedative by millions of people. It is now off patent and an alternative use has now been discovered which is owned by ReGen. In a case report published in a South African medical journal in 2000, Dr Nel, a South African General Practitioner and his co-worker Dr Ralf Clauss described how approximately fifteen minutes after an oral dose of zolpidem was administered to a patient who had suffered a road traffic accident three years previously, he awoke from his semi-comatose condition and remained awake for the next 3-4 hours and when drug action subsided he returned to his previous state. That same patient is now awake for up to 10 hours a day on a daily treatment with zolpidem. Further studies in Dr Nel’s clinic have now shown that many subjects with brain-injury caused in various ways and with various degrees of severity have consistent and reproducible improvement in their clinical features when given zolpidem. While Dr Nel continued his work in South Africa, Dr Clauss moved to the UK, where he teamed up with Dr Andrew Sutton (a medical consultant to ReGen). Together with Dr Nel, they formed Sciencom Ltd and filed an international patent application covering this new use for zolpidem. This patent has since been approved in South Africa and is still pending in other countries. In February 2006, ReGen Therapeutics Plc acquired the entire share capital of Sciencom and with it the rights to the company’s patent application and the rights to continue to develop its zolpidem project. In August 2007, ReGen reported on a clinical study, which confirmed that a 2.5mg novel formulation of zolpidem is non-sedating when used on conscious, fully perceptive, ambulant patients having various debilities as a consequence of brain damage. The study was performed by investigators at the Walko Medical Centre in Springs, South Africa where the 'antidormancy' effect of zolpidem was first discovered. Investigators compared various single doses of a novel sublingual spray formulation (placebo, 2.5mg, 5mg, 10mg) with an existing tablet formulation (placebo, 10mg) in terms of the onset and degree of sedation. It also looked for preliminary signs of efficacy. The results showed that a 2.5mg spray was no more sedating than a placebo. The 10mg and 5mg sprays induced sedation in a dose responsive manner and the spray showed faster onset of action (sedative effect) than the tablet. The 5mg spray induced the same peak level of sedation as the 10mg tablet - 15 minutes compared with 90 minutes respectively. In June 2008, the Company announced that collaborators at Aston University, Birmingham UK had discovered new evidence of zolpidem’s unique mode of action using pharmaco-magneto-encephalography (MEG) brain imaging. They found that non-functioning areas of the brain within the stroke damaged area of a patient were being kept in a dormant state by excessive slow wave activity that zolpidem reversed. This effect could not be reproduced with either a placebo or another sedative with a similar pharmacological action (zopiclone). ReGen has filed a new patent application around this important discovery. Most recently, in November 2009, the Company reported the findings of a completely independent study at the University of Pretoria, South Africa, which gave further evidence of the activity of zolpidem in this area. The University plans a further study in 2010. ReGen believes that both a clear “therapeutic need” and a significant commercial opportunity exist for new, low-dose, non-sedating formulations of zolpidem, to enable this important clinical benefit to be optimally delivered to a diverse range of patients. The Company is reviewing options to continue the development of novel zolpidem formulations for the treatment of brain dormancy. Given that stroke alone is the largest single cause of severe disability in England and Wales, with over 250,000 people being affected at any one time, the Company estimates the global market for this product would be worth US$4.3 billion. Further general information on this new use for zolpidem, including details of the independent research that has been conducted in connection with the project, can be found at the following address:- http://sites.google.com/site/zolpidemtherapy/ Last updated 8th June 2010
The sedative zolpidem (marketed under the names Stilnox™ and Ambien™ by Sanofi-Aventis) has been used as a hypnotic/sedative by millions of people for over twenty years. Technically speaking it belongs to the imidazopyridine class and is chemically distinct from other sedatives such as barbiturates, antihistamines, benzodiazepines and cyclopyrrolones. It is a selective stimulant of gamma-aminobutyric acid (GABA) action that functions as one of the most widely distributed inhibitory neurotransmitters within the brain. It has a short half-life of 2.4 hours meaning it is rapidly cleared from the body and its action is relatively short-lived. It does not accumulate with repeated administration.
What is the new clinical use for zolpidem that has been discovered?
Several years ago Dr Wally Nel, a General Practitioner in South Africa, discovered that zolpidem might promote remarkable recoveries for some patients after traumatic brain injury or stroke when given zolpidem to treat insomnia.
In the first case report (References 1 & 2 below), Dr Nel and his co-worker Dr Ralf Clauss describe how approximately fifteen minutes after a 10mg oral dose one patient, who had suffered a road traffic accident three years previously, awoke from his semi-comatose condition and remained awake for the next 3-4 hours. When drug action subsided he returned to his previous state. He is now awake for up to 10 hours a day on a daily treatment with zolpidem. When he first started on zolpidem, he was awake for only 4 hours. Further studies in Dr Nel’s clinic have now shown that many subjects with brain-injury caused in various ways and with various degrees of severity have consistent and reproducible improvement in their clinical features when given zolpidem.
An international patent on this ‘new use’ (now owned by ReGen) has been approved in South Africa and is pending in other countries.
References:
(1) Clauss RP, Güldenpfennig WM, Nel HW, Sathekge MM, Venkannagari RR. Extraordinary arousal from the semi-comatose state on zolpidem: A case report. SAMJ 2000; 90 (1): 68-72.
(2) Clauss RP, van der Merwe CE, Nel HW. Arousal from a semi- comatose state on zolpidem. S.Afr.Med.J. 91(10) 788- 789 (2001)
How does zolpidem exert its anti-dormancy effect?
Initially there was no rational explanation of the mechanism of drug action until Dr Clauss discovered by using Single Photon Emission Computed Tomography (SPECT) brain imaging that when zolpidem is present, seemingly dormant areas become active (3). The presence of “dormant” areas of the brain - physiologically inactive but where activity is capable of being restored - is a condition that is sometimes concurrent with a well-established phenomenon called diaschisis, who’s purpose is unknown (4). Possibly it has a protective origin, by preventing right-left imbalances or the functioning of areas that are partially damaged.
Further studies on the mechanism of action have included a study in animals, which showed that zolpidem had no significant effect on normal brains but in a damaged brain, where there were areas of poor perfusion, its application caused perfusion to normalise (5). This work showed that the effect of zolpidem in brain injury could be reversed by flumazenil (a compound known to block GABA receptors), which therefore suggests that the anti-dormancy effect of zolpidem is somehow achieved by its interaction with this receptor (6). Further studies are ongoing to better define this interaction. As GABA receptors are found all over the brain, agonists (compounds which stimulate them) such as zolpidem may have effects in a wide area (7).
References:
(3) Clauss RP, Nel HW. The effect of zolpidem on brain injury and diaschisis as detected by 99mTc HMPAO Brain SPECT in humans. Arzneim.-Forsch./Drug Res. (accepted for publication).
(4) Seitz RJ, Azari NP, Knorr U, et al., The role of diaschisis in stroke recovery. Stroke Sep 30(9) 1844-50 (1999)
(5) Salva P, Costa J. Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications. Clin Pharmacokinet 1995; 29: 142- 153.
(6) Clauss RP, Dormehl IC, Kilian E, et al., Oliver W. Cerebral blood perfusion after treatment with zolpidem and flumazenil in the baboon. Arzneim.-Forsch./Drug Res. 52(10) 740-4 (2002)
() Farhad F, Shadan, J Steven Poceta and Lawrence E Kline. Zolpidem for Post anoxic Spasticity. Southern Medical Journal, Vol 97, 8 August 20th
What benefits have been seen with zolpidem?
The widespread nature of GABA receptors may explain the surprisingly wide range of conditions that have responded to zolpidem in Dr Nel’s clinic. These have included the return to function of the facial nerve after Bell’s Palsy following a viral infection and the new found ability to speak or use scissors years after a stroke (an early recovery is promoted by the patient being able to speak or vocalise). In severe head injury patients, zolpidem has caused swallowing reflexes to return, which allows a patient to have feeding tubes removed, reducing the risk of chest infections and the need for antibiotics and intensive nursing care. These effects may be wide-ranging but the one thing they all have in common is the reactivation of dormant areas of the brain whilst zolpidem is present in the system.
Can it be predicted which patients will respond and how well they might respond?
Any beneficial effect is probably determined by the degree and importance of dormant areas and correlates with drug levels in these areas. It might be of benefit to patients who have been brain injured only recently or to those who are debilitated from a brain injury sustained many years previously.
There is, no way to reliably predict whether an individual patient will respond to zolpidem or how well they will respond from assessing either their clinical condition or brain scans. Based on Dr. Nel’s experience in South Africa and now in several other parts of the world by independent physicians, it is possible for any physician to easily administer a ‘test-dose’ of zolpidem using current formulations to see if there is a positive response. Zolpidem is currently only available as 10mg and 5mg tablets but the latter can be broken in two to give an approximate 2.5mg dose. It should be noted however, that even low-dose tablet regimens are unsuitable for many patients, particularly those who are ambulant, causing a significant degree of sedation. In essence, this is the basis of the commercial opportunity for ReGen.
What is the commercial opportunity for ReGen?
ReGen believes that a clear “therapeutic need” and a significant commercial opportunity exists for new, low-dose, non-sedating formulations of zolpidem to enable this important clinical benefit to be optimally delivered to a diverse range of patients. This of course assumes that useful efficacy can be achieved at levels where sedation is minimal or non-existent.
At it’s simplest this might be deliverable by a new ‘low-dose’ tablet regimen. To fully exploit the opportunity however will probably require a range of formulations to accommodate the differing and changing clinical needs of a wide-ranging patient population i.e. for basal dosing; a low-dose controlled-release tablet for patients who are able to swallow; a solution for adding to the feed line of patients unable to swallow or alternatively a patch. For ‘top-up’ or ‘test’ dosing, a fast acting self or carer-administrable formulation (nasal/sublingual spray) might be useful.
To maximise this commercial opportunity, it would be best if the desired benefit (anti-dormancy and non-sedation) could only be achieved or could most conveniently be achieved by patented ‘low-dose’ formulations exclusive to ReGen. Whilst this would be the ideal situation, the successful approval of the pending ‘new-use’ patent will offer significant commercial protection. Other low-dose formulations might be created by a third-party, but ownership of the use patent will prevent these being promoted and allow their specific creation as “low-dose formulations with no other possible use” to be clearly seen as an infringement of ReGen’s rights or will make ReGen the only real commercial partner for a formulation developer.
What is ReGen doing to exploit this opportunity?
In August 2007, ReGen reported on a Clinical Study, which confirmed that a 2.5mg novel formulation of zolpidem is non-sedating when used on conscious, fully perceptive, ambulant patients having various debilities as a consequence of brain damage. It was performed by investigators at the Walko Medical Centre in Springs, South Africa where the 'antidormancy' effect of zolpidem was first discovered.
The study compared various single doses of a novel sublingual spray formulation (placebo, 2.5mg, 5mg, 10mg) with an existing tablet formulation (placebo, 10mg) in terms of the onset and degree of sedation. It also looked for preliminary signs of efficacy.
The results showed that a 2.5mg spray was no more sedating than a placebo. The 10mg and 5mg sprays induced sedation in a dose responsive manner and the spray showed faster onset of action (sedative effect) than the tablet. The 5mg spray induced the same peak level of sedation as the 10mg tablet - 15 minutes compared with 90 minutes respectively.
Most recently, in November 2009, the Company reported the findings of a completely independent study at the University of Pretoria, South Africa, which gave further evidence of the activity of zolpidem in this area. The University plans a further study in 2010.
ReGen believes that both a clear “therapeutic need” and a significant commercial opportunity exist for new, low-dose, non-sedating formulations of zolpidem, to enable this important clinical benefit to be optimally delivered to a diverse range of patients. The Company is reviewing options to continue the development of novel zolpidem formulations for the treatment of brain dormancy. Given that stroke alone is the largest single cause of severe disability in England and Wales, with over 250,000 people being affected at any one time, the Company estimates the global market for this product would be worth US$4.3 billion.
Last updated 15th January 2010.
|
