Further Statistical Analysis of the Recent Phase III trial on Lead Product M6G Shows Additional Benefits
* Statistically significant reduction in sedation during the early post-operative period compared to morphine
* Statistically significant reduction in nausea in the female patient population compared to morphine
Cambridge, UK, 8th June 2007 - CeNeS Pharmaceuticals plc (AIM: CEN), the Cambridge based biopharmaceutical company, announces additional data from post-hoc analysis of the recent Phase III trial (M6G022) of M6G (morphine-6-glucuronide) in over 500 patients with post-operative pain. The Phase III data released on 20 February 2007 confirmed M6G's planned product profile and showed that M6G provided equivalent pain relief to morphine but induced significantly less post-operative nausea and vomiting (PONV).
Analysis of the sedation data from the M6G022 trial showed statistically significant reductions in sedation in the M6G group compared to morphine in the first four hours after surgery reaching a reduction of 15% at 4 hours (p=0.007). Discussions with clinicians support the view that this is a clinically important benefit. Opiates such as morphine are well known to induce sedation and respiratory depression. Excessive sedation in the early post-operative period is associated with depression of the respiratory system, which can, in some cases, be fatal.
Nausea in female patients
It is well established that female patients undergoing surgery have a higher risk of experiencing nausea and vomiting in the post-operative period. New data analysing the female patient group (approximately 70% of the patients in the M6G022 Phase III clinical trial) showed a statistically significant reduction in nausea in the period 6-24 hours after treatment (p=0.034). The overall incidence and severity of post-operative nausea in the M6G arm for both males and females was 27% less than that observed in the morphine arm but narrowly missed statistical significance, p=0.052 (versus target of p<0.05), as previously reported. This was the second primary endpoint.
Implications of these additional data
The significantly reduced sedation seen with M6G provides additional support to our view that M6G is equivalent to morphine in controlling pain but has a superior side-effect profile. This should give clinicians more confidence that patients are less likely to experience sedation with M6G. Sedation is one of the side effects of most concern associated with agents like morphine, along with respiratory depression.
The additional analysis announced today will be used to improve further the designs of the planned US Phase III clinical studies by targeting higher risk patient groups and surgical procedures where the clinical benefits from M6G will be maximised.
Neil Clark, Chief Executive of CeNeS, commented: "This further analysis of the recent Phase III trial data supports our stated goal of delivering M6G to the market as a novel analgesic for post-operative pain that has clearly defined benefits compared to morphine and other opiates. The large body of statistically significant Phase III efficacy and side effect/safety data also suggest that M6G could be uniquely positioned as an opiate analgesic for day case surgery - an additional growing market to the current focus on hospital based post-operative pain.
"It is estimated that at least 277 million units of injectable analgesics were used to treat pain in the United States in 2006. The US post-operative pain market is estimated to be $1.7 billion. CeNeS is confident that M6G will establish a strong position in the large global pain market."
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 shown 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.
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 in 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.
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-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.
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.
4. Management of PONV/use of anti-emetics
Secondary data revealed 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.
5. Drug consumption
It has been shown 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.
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Posted: June 2007