Document date: Tue 27 Aug 2002 Published: Tue 27 Aug 2002 10:16:43 Document No: 193843 Document part: A Market Flag: Y Classification: Progress Report METABOLIC PHARMACEUTICALS LIMITED 2002-08-27 ASX-SIGNAL-G
HOMEX - Melbourne
+++++++++++++++++++++++++ POSITIVE RESULTS FROM AOD9604 OBESITY DRUG ORAL PHASE 2A HUMAN CLINICAL TRIAL
* RESULTS INDICATE AOD9604 IS ACTIVE AFTER ORAL DOSING * MAXIMUM MARKET POTENTIAL * DAILY DOSE SAFETY TRIALS SCHEDULED FOR Q4 2002 * DAILY DOSE EFFICACY TRIALS PLANNED FOR 2003
Metabolic is very pleased to announce the successful completion of its Phase 2A human clinical trial of obesity drug AOD9604 by single-dose oral administration, showing positive results.
"This landmark result is the company's most important milestone achieved to date. Oral administration, the preferred mode of drug delivery, will maximize the commercial potential of AOD9604," said Chris Belyea, Managing Director.
"In all the trials performed so far, AOD9604 has consistently shown that humans respond to AOD9604 with increased fat metabolism, without side effects having been seen. This latest result provides key evidence that the oral activity shown in animals also applies to humans. We look forward with anticipation to forthcoming trials and our expectation is that AOD9604 will safely produce a meaningful weight reduction after daily oral dosing."
Increased average fat breakdown compared to placebo was observed at all dose levels of AOD9604 (9, 27 and 54 mg) lasting several hours after administration, reaching statistical significance at 27 mg. Fat breakdown, a signal of drug activity, is followed in the blood by measuring levels of non-esterified fatty acids (NEFA). NEFA is a marker, evident after a single dose, of fat metabolic changes that are expected to result in weight loss after extended daily dosing.
Preparations are now under way for a safety study dosing once-daily for one week to be conducted before year end in preparation for an extensive weight reduction study for 2003.
TRIAL DESIGN AND RESULTS
The double-blind trial was conducted in 16 clinically obese but otherwise healthy male volunteers aged 35 to 60. Each received the following single oral doses of AOD9604 in random order: placebo (0), 9, 27 or 54 mg. Each dose was separated by an interval of 2 weeks.
The aim of the trial was to assess oral activity, safety and tolerability of the drug in clinically obese volunteers after single oral doses. The decision end-point to assess oral activity was observation of an increase in fat breakdown that was expected to occur over several hours after each dose.
As with the previous two clinical trials there were no safety or tolerability concerns associated with the drug at any dose.
In the previous Phase 2A study by intravenous AOD9604 administration, fat breakdown was measured before dose and at several times in the hours after dose while fasting. The volunteers broke their fast after the two-hour measurement. Fat breakdown naturally increases during fasting and drops substantially after a meal. The enhancing effect of the AOD9604 action was observed in these studies during the two hours after dose, where fat breakdown increased more on average in treated volunteers compared to placebo volunteers.
In this oral study, the design was similar except we extended the fast to 4 hours after the dose to gather more data during fasting. We saw the same effect of a similar magnitude, continuing for the duration of the fast. For all times later than 30 minutes after the dose and at all oral dose levels of AOD9604, the rise in fat breakdown during the fast was greater than placebo.
The 27 mg dose showed the greatest response, reaching 38% more than placebo at 4 hours, after which the fast was broken. The effect at the 27 mg dose was statistically significant compared with placebo. See graph below of the placebo-subtracted response. The plotted values indicate how much greater the increase in NEFA from pre-dose was after AOD9604 treatment than after placebo treatment. The "error bars" are plotted for the 27 mg dose.
The lower response observed at the highest (54 mg) AOD9604 oral dose, if it is confirmed in later studies, would be consistent with observations at high doses in the Phase 1 trial by intravenous administration (conducted in lean patients). It would also be consistent with results from in vitro tests on isolated fat tissue from humans and animals, and with whole animal studies.
This single dose oral study, like the previous intravenous study, was not designed to measure weight reduction, which would be expected to be observed only after extended daily dosing. However, in this trial the most active fat breakdown dose (27 mg) resulted in the greatest average weight change one week after dose, a reduction of 0.2 kg relative to placebo. Although this change is in the right direction, it is not statistically significant, and therefore is not conclusive evidence that the drug will cause weight loss in humans. The study projected to take place next year will be designed to provide this evidence, in which 40 or more patients will be treated at several doses once daily for 1 or more months.
NEXT STEPS
A manuscript of these trial results combined with the results from the intravenous trial will be submitted to a peer-reviewed journal.
The protocol for a safety trial involving one week of once-daily dosing has been submitted for ethics approval. In this trial safety and tolerability are the only end-points. Young and old obese male adults (nine only in each dose group) will be given oral AOD9604 daily for one week to check for any adverse effects. This is a regulatory requirement before conducting longer term daily dosing studies.
Assuming successful completion of the one week safety trial, expected by year end, an extensive Phase 2B weight reduction trial in at least 150 patients will commence in 2003. The timing of the commencement will depend on the design, to be determined with input from the US Food and Drug Administration. The main aim will be to establish weight loss after extended dosing and to determine the best dose range.
With $11.5 million currently on hand and $12 million expected to be received on the exercise of the MBPO options by July 31 2003, the company has sufficient funds for its activities until at least the end of 2003.
9TH INTERNATIONAL CONGRESS ON OBESITY
Assoc. Prof Gary Wittert MD at the Royal Adelaide Hospital, principal investigator of the trial, will be presenting these clinical results at the 9 th International Congress on Obesity, in Sao Paulo Brazil, later today.
NEXT ANNOUNCEMENT
We will provide our regular quarterly shareholder update in relation to the Company's other projects and activities shortly.
AOD9604 OBESITY DRUG - BACKGROUND
Metabolic's candidate obesity drug, AOD9604, invented at Monash University, acts specifically on the body's fat cells to enhance the breakdown of stored fats and inhibit the synthesis of new fat. This result is biochemically similar to the slimming effects of physical exercise. AOD9604 has proven to be effective in reducing obesity in laboratory animals through once daily oral administration, with no effect on food intake.
The drug is modelled on the active fat reducing portion of the human Growth Hormone (hGH) molecule. hGH occurs naturally in the body and is involved in promoting growth. In addition it has pronounced effects on body fat. Scientists at Monash University have shown that, when dosed to animals, AOD9604 has the fat-reducing effects of the intact growth hormone without its other unwanted effects having been observed.
Obesity is the Western world's most pressing health problem, suffered by over 20% of the population. The obese as a group spend 77% more on health care, compared with 28% more by smokers. AOD9604 may provide a safer and more effective obesity treatment than currently available drugs. The anticipated absence of adverse side effects on mood or digestion may lead to a high level of doctor and patient acceptance.
CONTACT DETAILS
website www.metabolic.com.au CEO Chris Belyea +61 3 9826 0949 CFO David Kenley +61 3 9826 0949
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