Further analysis of Phase III trial data underlines M6G's benefit compared to morphine in the treatment of post-operative pain
CAMBRIDGE, England, 7th March 2007 - CeNeS Pharmaceuticals plc (AIM: CEN), the Cambridge based biopharmaceutical company today announces additional data from the pivotal Phase III trial (M6G022) of M6G (morphine-6-glucuronide) in over 500 patients with post-operative pain. The preliminary data released on 20th February showed that M6G provided equivalent pain relief to morphine but induced significantly less post-operative nausea and vomiting (PONV).
Secondary Data Results
The additional secondary data now received by CeNeS shows that:
* less anti-emetic drugs (drugs used to control nausea and vomiting) were required in patients treated with M6G compared with those on morphine; and * M6G exhibited a long duration of analgesic action.
This was the first Phase III study where patients were given a complete pain management programme with M6G (rapid titration to comfort followed by PCA for up to 48 hours) and the first Phase III trial where nausea and vomiting were assessed as primary endpoints.
Management of PONV/use of anti-emetics
In addition to the clear nausea and vomiting reductions of over 25% announced last week, secondary data reveals that patients receiving M6G required over 20% less anti-emetic medication over the 0-24 hour period than those in the morphine group. This shows that not only does M6G induce significantly less nausea and vomiting than morphine, but also that the post-operative anti-emetic treatment required is considerably reduced.
The potential for reduced anti-emetic drug costs combined with the reduction in medical assistance and the improved patient comfort due to lower PONV supports CeNeS justification of a substantial price premium for M6G compared to morphine.
It has been sh own in previous studies that the dose of M6G required to provide analgesia immediately after surgery is three times that of morphine. In accordance with this, the M6G022 trial was designed such that M6G was available in a 3:1 ratio to morphine during the titration to comfort phase. Thereafter pain relief was provided using patient controlled analgesia (PCA) in a dose ratio of 2:1 (M6G:morphine). The secondary data announced today demonstrated again that in the initial phase after surgery the dose of M6G required to titrate patients to comfort was 3 times that required for morphine on a weight basis. However, during the prolonged PCA phase, the ratio was lower (0-24 hours 1.6:1; 24-48 hours 1.4:1). This shows that patients in the M6G group made less demands for pain relief after titration to comfort, as assessed by presses on the PCA button. These data support the hypothesis that M6G has a longer duration of analgesic action than morphine.
The M6G022 data shows that M6G patients experience lower levels of sedation compared to those on morphine for up to 48 hours. This is another advantage of M6G that has been indicated from previous clinical data and adds to the considerable package of potential benefits to patients and clinicians. The M6G patients also showed no adverse cardiovascular effects which again supports CeNeS claims that M6G has a very good safety profile.
There is a clear need for new drugs that can improve the quality of pain management currently given to patients by standard morphine regimens across the world and M6G is well positioned to address that market. Since the announcement of the successful data last week significant interest has been expressed by Pharma companies in reviewing the large M6G data package that CeNeS has assembled. CeNeS is confident that agreements can be finalised with partner(s) based on the existing set of clinical trial data. Concluding these deals will generate short term income and recurring revenue streams from a successful product launch in the future.
CeNeS preferred strategy is for a partner to be involved in the key decisions regarding regulatory filing strategies both in Europe and in United States. The strategy in the USA is clear. The strong data obtained from the most recent Phase III study validates the proposed product profile of M6G and strengthens CeNeS position with potential North American partners. Registration could be achieved in the USA in 2009 after conducting two Phase III studies to the requirements of the FDA. It is important to note that the quality and robustness of the clinical data produced by the current study significantly reduces the risk for the development of M6G by enabling optimal trial design and the selection of endpoints in the remaining Phase III studies.
In Europe the narrow failure to achieve statistical significance with the second chosen primary endpoint of incidence and severity of nausea (p=0.052 not p<0.050) offers three options:
1) Pursue a filing application in certain European countries with the comprehensive clinical data package that CeNeS has assembled. 2) Further strengthen the European package by conducting an additional European Phase III study which would complete in 2008 with product filing in 2009. 3) Use the USA Phase III trials to support the European application, potentially with a global partner.
CeNeS will continue to discuss the above strategies with regulatory consultants and potential partners.
Neil Clark, Chief Executive of CeNeS commented "The ongoing analysis of the Phase III results further confirms our belief in the excellent potential of M6G as a novel product for post- operative pain. The quality and breadth of the data contained in this large study supports M6G's anticipated product profile.
The potential for reduced anti-emetic drug costs combined with the reduction in medical assi stance and the improved patient comfort due to lower PONV supports CeNeS justification of a substantial price premium for M6G compared to morphine.
We are actively pursuing potential partners for M6G and are confident that agreements can be reached. We are well positioned to deliver significant value to shareholders by the successful commercialisation of M6G".
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CeNeS Pharmaceuticals plc will be announcing its preliminary results for the year ended 31 December 2006 on Wednesday 28 March 2007. On the same day the Company will be hosting an R&D presentation at the offices of Financial Dynamics. The presentation will start at 9:30am and is expected to conclude at 11am.
For more information please contact: CeNeS Pharmaceuticals plc Neil Clark, CEO Tel: +44 (0)1223 266 466
JM Finn Geoff Nash Tel: +44(0) 207 628 9688
Financial Dynamics Ben Brewerton/Emma Thompson Tel: + 44 (0) 207 831 3113
About CeNeS Pharmaceuticals CeNeS is a biopharmaceutical company specialising in the development and commercialisation of drugs for pain control, sedation and other CNS disorders such as Parkinson's disease. The company is based in Cambridge, England. For further information visit the CeNeS web site: www.cenes.com
About M6G Morphine formulations are the gold standard treatment for the relief of moderate to severe post-operative pain. A limitation of morphine treatment is often the unpleasant side effects experienced, of which nausea and vomiting are the most common. PONV is rated among patients as one of the most distressing after-effects of surgery and reduces their quality of life.
The active potent metabolite of morphine, morphine-6-glucuronide (M6G), may offer therapeutic advantages over morphine in having an equivalent analgesic effect, but with a reduced tendency to cause nausea, vomiting and respiratory depression. Phase II and III clinical trials have sho wn that M6G given intravenously produces equivalent analgesia to morphine to combat post-operative pain. Studies have also shown that M6G reduced the incidence of nausea and vomiting when compared directly with morphine. Other studies published recently in the scientific literature demonstrate that M6G also reduces respiratory depression compared to morphine.
The global market for opiate use in managing post-operative pain was estimated at $1 billion in 2000 and growing at a rate of 6-7%.
Summary of Phase III trial (M6G022) results
1. M6G matches morphine for analgesic effect
Importantly for a novel pain product, the trial results unequivocally show that M6G is as good as morphine in terms of analgesia achieved in patients up to 48 hours post-operatively. Successful achievement of this first primary endpoint supports data from previous clinical trials of M6G and is an essential component in the product profile of M6G.
2. M6G shows significant reduction in post-operative nausea and vomiting compared to morphine
The trial results confirm the excellent potential of M6G as an analgesic with a clinically significant improved side effect profile compared to morphine. The study results show that patients receiving M6G experienced a 28% reduction in the severity of post-operative nausea and vomiting (PONV) in the key 6 - 24 hours after treatment (statistically significant, p=0.018).
In addition, the incidence of dry retching/vomiting in the M6G arm compared to the morphine arm in the 24 hour period after treatment was reduced by 32% ( statistically significant, p= 0.044). The incidence and severity of post-operative nausea in the M6G arm was 27% less than that observed in the morphine arm in the period 6 - 24 hours after treatment. This was the second primary endpoint and approached statistical significance (p=0.052).
Morphine formulations are the gold standard treatment for the relief of moderate to severe post-operat ive pain. A limitation of morphine treatment is often the unpleasant side effects experienced, of which nausea and vomiting are the most common. PONV is rated among patients as one of the most distressing after-effects of surgery and reduces their quality of life.
M6G's lower propensity to cause nausea and vomiting in the post-operative period strongly supports CeNeS' belief in the potential of M6G as a novel product for the treatment of post-operative pain with clear advantages over morphine.
3. Safety profile/adverse events
The trial confirmed that M6G's safety profile is similar to morphine. Aside from nausea and vomiting, the adverse events reported were at levels similar to those experienced by patients receiving morphine in a post-operative setting.
M6G022 Study Design The study involved 24 centres in six European countries and recruited 517 patients. The study was designed primarily to provide key information on a comparison of effective intravenous pain management regimens of M6G or morphine treatment for a minimum of 24 hours (and up to 48 hours) following major abdominal surgery. Morphine is generally accepted as the "gold standard" drug for use in these circumstances. Initial pain management was achieved by administration of a loading dose and titration of either M6G or morphine to achieve acceptably low levels of pain for the patient to go onto the ward. In the ward, pain management treatment was achieved by patient controlled analgesia (PCA), whereby the patient was allowed to self administer a dose of M6G or morphine as required to control their pain. The study was randomised and double blind so that neither patient nor carer was aware of which treatment was being administered. The main purpose of the study was to demonstrate statistically that:
- Treatment with either M6G or morphine, particularly during PCA, results in similar levels of pain management; and
- Effective analgesic treatment during PCA results i n lower levels of nausea and vomiting in patients receiving M6G compared to those receiving morphine.
In addition, other important side effect, efficacy and safety features were determined throughout the study.