10 April 2006 Pain Relief Drugs from the Sea For most of us,...

10 April 2006

Pain Relief Drugs from the Sea

For most of us, pain relief for headaches, backaches and most other aches is as close as the nearest packet of aspirin or paracetamol. But there is one form of pain that painkillers just cannot touch.


TRANSCRIPT:

BLANCH : It's called neuropathic pain and it is caused by nerve fibres that signal pain switching on when they shouldn't. It's a common complication of shingles and diabetes and for those who suffer from it, it can be agony. Now, scientist Dr Bruce Livett and his colleagues from the University of Melbourne may have found the answer in the sea, in the toxin from cone shells.

So Bruce, first a little bit about cone shells. How do we recognise them, how common are they and where are they found?

DR LIVETT : They're quite common and they're found throughout the Indo-Pacific area. They're particularly present in large numbers up on the Great Barrier Reef and in the reefs surrounding the Philippines, but some are also found in the Atlantic, off the coast of Florida, in the warmer waters there and there is one species that's known to be present in the Mediterranean Sea, and there are others in the Red Sea. So yes, they're pretty widely distributed, but it's known that they originated in the Philippines and then radiated from there.

BLANCH : And there are many, many different types then by the sound?

DR LIVETT : There are, there's over 500 different species and these have been collectors' items for hundreds of years and some of them are quite valuable. There was one that went up for auction in the 1600's in Amsterdam and it brought more than a Vermeer painting that was auctioned at the same time, yes. And of course that's a reflection of the fact that they were very difficult to get hold of and I guess they were brought in by people who belonged to the East India Company, and so they were collectors' items that everybody wanted to have in their cabinet.

These are very pretty and so they were highly sought after.

BLANCH : So why do cone shells have such dangerous venom? How do they use it?

DR LIVETT : They use it to hunt down their prey. Cone shells as all shells are marine snails and that was new to me when I came to this area. I thought of garden snails, but I never thought that the shell that you find on the beach is actually a snail. Because in fact you only see dead shells, you don't see the animal inside them. But if you get underneath the water and you find them in their natural habitat, you find that they've got a foot and they've got eye stalks, just as the garden snail has and they've got a nose, that they use to sniff out their prey and then they have this marvellous appendage, which is a long tongue, that comes out of their mouth and on the end of the tongue, they have the modified tooth that's hollow and it's barbed and that's full of venom, and they impale their victim with that. So, they're amazing creatures.

BLANCH : So how does their toxin work? What do they do?

DR LIVETT : The toxin works by inhibiting nerve transmission, so in order for us to be able to move around we need nerve connections to work properly and their toxin targets the area between the end of a nerve and a muscle cell, for example, and so if you're unlucky enough to be stung by one of these venomous cone shells, then the first thing that will happen to you is that your diaphragm will slowly stop and then you stop breathing, because it targets the nerve muscle junction and inhibits that.

BLANCH : So cone shells also have an analgesic, now why?

DR LIVETT : Yes, well they have over 20 different active components in their venom and one of these is a potent analgesic that they use to immobilise or calm their prey. I guess that's important, because if they're going to take the prey into their mouth and eat it, they don't want it wriggling around and struggling around and so they put it to sleep and then they continue with their meal.

BLANCH : Well they couldn't really chase them, could they? Snails they're slow?

DR LIVETT : No, that's one problem. In fact they're rather cunning, they hide underneath the sand and then they put up this red tongue, in some species it's bright red and it looks like a little worm and so a fish coming along there, sees this tender morsel and thinks 'ooh, that's be nice' and as it gets close, then the cone shell prods and puts its harpoon into it. So yes, they're very slow moving and I guess they've developed this armoury in order to be able to effectively survive.

BLANCH : So from toxins to analgesics, what have you discovered about their analgesic that is creating such excitement?

DR LIVETT : Well, what we've found out is that it's effective against a form of pain that you mentioned in the introduction there, the neuropathic pain, that other analgesics don't treat very well.

People who have these conditions, these chronic pain conditions with neuropathic pain, are treated currently with morphine, but morphine while it's a wonderful analgesic, it's not good if you have to have it over a prolonged period of time, because the more you have, the more you need and you have to ramp up the amount needed to get effective pain treatment and when you ramp up the amount, then the unwanted side effects come in and the unwanted side effects include things like constipation, a feeling of dysphoria as if you are outside your own body looking down on yourself, very disturbing, tunnel vision, and respiratory depression also. So it's quite difficult for patients who have to be on morphine for a long period of time and that includes many cancer patients.

BLANCH : So how powerful an analgesic do you believe is possible with your version?

DR LIVETT : Well, our tests have shown that this cone shell analgesic is between a thousand and 10,000 times more potent than morphine, but it is not habit forming it's not addictive, so we really believe there's a great future for this kind of analgesic.

BLANCH : So would you need extractions from lots of cone shells or would it be possible to copy what Nature's provided?

DR LIVETT : Fortunately it's possible to copy what Nature's provided and when we went looking for this novel conotoxin as it's called--cone shell toxin, we used the techniques of modern molecular biology so that although we knew that the toxin was a small protein, a peptide, it's there in extremely small quantities, because it's very active. It doesn't need to be there in large amounts. But that posed a problem for us as chemists and bio-chemists and so I enlisted the help of my colleague who's a molecular biologist and who knows about DNA and this was Professor Ken Gayler in our department, and he used his magical molecular biology techniques to extract the RNA and then, from that we got the DNA and then he walked along that with selective probes and found out where the conotoxin signature sequence was and from that DNA sequence, we were then able to predict what the protein sequence, the peptide sequence would be and then we just had a series of amino acids written down on a piece of paper, which was that sequence. We got on the phone to a local company here in South Melbourne that makes these peptides, a company called Auspep and we read out the sequence to them and then they synthesized the peptide from chemicals and we ended up with a little vial of 20 milligrams of pure peptide, having paid over a thousand dollars or something like that for the synthesis and then we were able to use that pure peptide to test it in animal models and in cell culture models.

For the biological testing of the conotoxin that was just synthesised, I drew upon my very good colleague, Dr Zeinab Khalil who has developed the assays for testing pain thresholds in animal models of human neuropathic pain.

BLANCH : So explain how your analgesic would work and why it's different from what is now available in pain relief?

DR LIVETT : Our analgesic works through administering it peripherally, that is we give it by injection, either under the skin subcutaneously or intramuscularly. It would be ideal if we could give it orally as a tablet and the company who is developing this for us, Metabolic Pharmaceuticals here in Melbourne, are working on trying to get an oral version of this. But even if we don't manage to get an oral version, it's going to be very effective as we know when given by injection.

It differs from the analgesics that are presently available in that it's not an opiate, it's not habit forming, it doesn't cause respiratory depression, yet it's very effective as a painkiller.

There is one other cone shell toxin that has been developed as an analgesic and it's passed through all of the various stages of testing in humans and is now available to patients in the United States and in Europe and this is a cone shell toxin called Ziconotide or "Prialt" The limitation with that one is that it has to be given directly into the spinal fluid and that means you have to have the patient fitted with an indwelling injectable pump and it's not only inconvenient, but it's expensive and difficult to replenish. So we think that ours has the distinct advantage that it can be given by injection and doesn't need to go into the spinal cord and it also does not have the side effects that some of these other drugs have.

BLANCH : And expensive?

DR LIVETT : Um expense?, Most of these drugs are quite expensive, but our compound is only 16 amino acids as distinct from the competitor's which is about 35. It's a much simpler drug. It only has two disulfide bridges as against three, that makes it cheaper and easier to synthesise and more bio available. It's smaller and can get through quickly.

BLANCH : What period of time have you spent doing this?

DR LIVETT : I've been doing this for about 8 years now, mmm, and it takes a long time to get there, that's because your at the front of research and everything's unknown. It's exciting actually.

BLANCH : Well, trials are being conducted as we speak. At what stage are they?

DR LIVETT : The trials are just finished phase one. There are three phases in the development of a drug and there are a whole lot of phases before you get to the clinical phases. So the first thing was the discovery and then we had to test these drugs out for their toxicity in animals and that takes about two years and having passed through those studies where they were tested on mini pigs, because mini pigs have a metabolism more close to humans than any other animal.

BLANCH : You mean baby pigs?

DR LIVETT : Eh yeah, they're well that's right, but they're a special kind of breed of pig called a mini pig and they would be like a suckling pig in size I imagine.

Yes, so that work was done in England and then they were tested for possible cardio vascular effects in dogs. That work was done at the Research Institute at the Baker Research Institute in Melbourne and then following that we knew that we had a safe drug and so then the drug entered into phase one clinical trials in Adelaide last year and so that work was completed in November and now Metabolic Pharmaceuticals are ramping up for phase two clinical trials which they hope to begin in April and they will take about two years. And then if they get through those, the drug will go into phase three clinical trials, where a much larger number of patients with different pain conditions will be given the opportunity to trial the drug and it will be done probably in a double blind fashion so the person doesn't know whether they're receiving the pain killer or on a placebo. Although, current thinking is that it's unfair to give a patient a placebo if they're in pain. So more people actually, receive the pain killer than receive the placebo. And some of those trials will be open so they'll know which they're on.

And that trial may not occur in Australia, because to my knowledge, no pharmaceutical company has been able to mount a phase three trial in Australia, because they cost about 60 million dollars US for the trial, so that means that Metabolic Pharmaceuticals will probably be looking to on-licence this to a larger international pharmaceutical company--a Pfizer or Glaxo or somebody like that.

Then once it gets through those phase three trials, it has to get FDA approval, Federal Drug Administration approval, and that takes about another year. So we're probably looking at another seven or eight years before the drug would be on the market.

BLANCH : That's worth waiting for by the sound of things though, the way it's going?

DR LIVETT : It certainly is and if you look at the pile of letters that I've received and emails that I've received over the period I've been working, there is a great unmet need out there and there's so many people in pain and they've tried everything, they're desperate and they just can't wait for this drug to come on the market.

BLANCH : Dr Bruce Livett, from Bio21 Molecular Science and Biotechnology Institute , at the University of Melbourne, and whose research has found pain relief drugs from the beautiful, but dangerous cone shell.

10 April 2006

Pain Relief Drugs from the Sea

For most of us, pain relief for headaches, backaches and most other aches is as close as the nearest packet of aspirin or paracetamol. But there is one form of pain that painkillers just cannot touch.

Contact: Dr. Bruce Livett
Bio21 Molecular Science & Biotechnology Institute, 30 Flemington Road, The University of Melbourne, VIC 3010
International Telephone: +61 3 8344 5911 FAX: +61 3 9348 1421
Email: [email protected]
Website: http://grimwade.biochem.unimelb.edu.au/cone/
Website: http://www.bio21.org





TRANSCRIPT:

BLANCH : It's called neuropathic pain and it is caused by nerve fibres that signal pain switching on when they shouldn't. It's a common complication of shingles and diabetes and for those who suffer from it, it can be agony. Now, scientist Dr Bruce Livett and his colleagues from the University of Melbourne may have found the answer in the sea, in the toxin from cone shells.

So Bruce, first a little bit about cone shells. How do we recognise them, how common are they and where are they found?

DR LIVETT : They're quite common and they're found throughout the Indo-Pacific area. They're particularly present in large numbers up on the Great Barrier Reef and in the reefs surrounding the Philippines, but some are also found in the Atlantic, off the coast of Florida, in the warmer waters there and there is one species that's known to be present in the Mediterranean Sea, and there are others in the Red Sea. So yes, they're pretty widely distributed, but it's known that they originated in the Philippines and then radiated from there.

BLANCH : And there are many, many different types then by the sound?

DR LIVETT : There are, there's over 500 different species and these have been collectors' items for hundreds of years and some of them are quite valuable. There was one that went up for auction in the 1600's in Amsterdam and it brought more than a Vermeer painting that was auctioned at the same time, yes. And of course that's a reflection of the fact that they were very difficult to get hold of and I guess they were brought in by people who belonged to the East India Company, and so they were collectors' items that everybody wanted to have in their cabinet.

These are very pretty and so they were highly sought after.

BLANCH : So why do cone shells have such dangerous venom? How do they use it?

DR LIVETT : They use it to hunt down their prey. Cone shells as all shells are marine snails and that was new to me when I came to this area. I thought of garden snails, but I never thought that the shell that you find on the beach is actually a snail. Because in fact you only see dead shells, you don't see the animal inside them. But if you get underneath the water and you find them in their natural habitat, you find that they've got a foot and they've got eye stalks, just as the garden snail has and they've got a nose, that they use to sniff out their prey and then they have this marvellous appendage, which is a long tongue, that comes out of their mouth and on the end of the tongue, they have the modified tooth that's hollow and it's barbed and that's full of venom, and they impale their victim with that. So, they're amazing creatures.

BLANCH : So how does their toxin work? What do they do?

DR LIVETT : The toxin works by inhibiting nerve transmission, so in order for us to be able to move around we need nerve connections to work properly and their toxin targets the area between the end of a nerve and a muscle cell, for example, and so if you're unlucky enough to be stung by one of these venomous cone shells, then the first thing that will happen to you is that your diaphragm will slowly stop and then you stop breathing, because it targets the nerve muscle junction and inhibits that.

BLANCH : So cone shells also have an analgesic, now why?

DR LIVETT : Yes, well they have over 20 different active components in their venom and one of these is a potent analgesic that they use to immobilise or calm their prey. I guess that's important, because if they're going to take the prey into their mouth and eat it, they don't want it wriggling around and struggling around and so they put it to sleep and then they continue with their meal.

BLANCH : Well they couldn't really chase them, could they? Snails they're slow?

DR LIVETT : No, that's one problem. In fact they're rather cunning, they hide underneath the sand and then they put up this red tongue, in some species it's bright red and it looks like a little worm and so a fish coming along there, sees this tender morsel and thinks 'ooh, that's be nice' and as it gets close, then the cone shell prods and puts its harpoon into it. So yes, they're very slow moving and I guess they've developed this armoury in order to be able to effectively survive.

BLANCH : So from toxins to analgesics, what have you discovered about their analgesic that is creating such excitement?

DR LIVETT : Well, what we've found out is that it's effective against a form of pain that you mentioned in the introduction there, the neuropathic pain, that other analgesics don't treat very well.

People who have these conditions, these chronic pain conditions with neuropathic pain, are treated currently with morphine, but morphine while it's a wonderful analgesic, it's not good if you have to have it over a prolonged period of time, because the more you have, the more you need and you have to ramp up the amount needed to get effective pain treatment and when you ramp up the amount, then the unwanted side effects come in and the unwanted side effects include things like constipation, a feeling of dysphoria as if you are outside your own body looking down on yourself, very disturbing, tunnel vision, and respiratory depression also. So it's quite difficult for patients who have to be on morphine for a long period of time and that includes many cancer patients.

BLANCH : So how powerful an analgesic do you believe is possible with your version?

DR LIVETT : Well, our tests have shown that this cone shell analgesic is between a thousand and 10,000 times more potent than morphine, but it is not habit forming it's not addictive, so we really believe there's a great future for this kind of analgesic.

BLANCH : So would you need extractions from lots of cone shells or would it be possible to copy what Nature's provided?

DR LIVETT : Fortunately it's possible to copy what Nature's provided and when we went looking for this novel conotoxin as it's called--cone shell toxin, we used the techniques of modern molecular biology so that although we knew that the toxin was a small protein, a peptide, it's there in extremely small quantities, because it's very active. It doesn't need to be there in large amounts. But that posed a problem for us as chemists and bio-chemists and so I enlisted the help of my colleague who's a molecular biologist and who knows about DNA and this was Professor Ken Gayler in our department, and he used his magical molecular biology techniques to extract the RNA and then, from that we got the DNA and then he walked along that with selective probes and found out where the conotoxin signature sequence was and from that DNA sequence, we were then able to predict what the protein sequence, the peptide sequence would be and then we just had a series of amino acids written down on a piece of paper, which was that sequence. We got on the phone to a local company here in South Melbourne that makes these peptides, a company called Auspep and we read out the sequence to them and then they synthesized the peptide from chemicals and we ended up with a little vial of 20 milligrams of pure peptide, having paid over a thousand dollars or something like that for the synthesis and then we were able to use that pure peptide to test it in animal models and in cell culture models.

For the biological testing of the conotoxin that was just synthesised, I drew upon my very good colleague, Dr Zeinab Khalil who has developed the assays for testing pain thresholds in animal models of human neuropathic pain.

BLANCH : So explain how your analgesic would work and why it's different from what is now available in pain relief?

DR LIVETT : Our analgesic works through administering it peripherally, that is we give it by injection, either under the skin subcutaneously or intramuscularly. It would be ideal if we could give it orally as a tablet and the company who is developing this for us, Metabolic Pharmaceuticals here in Melbourne, are working on trying to get an oral version of this. But even if we don't manage to get an oral version, it's going to be very effective as we know when given by injection.

It differs from the analgesics that are presently available in that it's not an opiate, it's not habit forming, it doesn't cause respiratory depression, yet it's very effective as a painkiller.

There is one other cone shell toxin that has been developed as an analgesic and it's passed through all of the various stages of testing in humans and is now available to patients in the United States and in Europe and this is a cone shell toxin called Ziconotide or "Prialt" The limitation with that one is that it has to be given directly into the spinal fluid and that means you have to have the patient fitted with an indwelling injectable pump and it's not only inconvenient, but it's expensive and difficult to replenish. So we think that ours has the distinct advantage that it can be given by injection and doesn't need to go into the spinal cord and it also does not have the side effects that some of these other drugs have.

BLANCH : And expensive?

DR LIVETT : Um expense?, Most of these drugs are quite expensive, but our compound is only 16 amino acids as distinct from the competitor's which is about 35. It's a much simpler drug. It only has two disulfide bridges as against three, that makes it cheaper and easier to synthesise and more bio available. It's smaller and can get through quickly.

BLANCH : What period of time have you spent doing this?

DR LIVETT : I've been doing this for about 8 years now, mmm, and it takes a long time to get there, that's because your at the front of research and everything's unknown. It's exciting actually.

BLANCH : Well, trials are being conducted as we speak. At what stage are they?

DR LIVETT : The trials are just finished phase one. There are three phases in the development of a drug and there are a whole lot of phases before you get to the clinical phases. So the first thing was the discovery and then we had to test these drugs out for their toxicity in animals and that takes about two years and having passed through those studies where they were tested on mini pigs, because mini pigs have a metabolism more close to humans than any other animal.

BLANCH : You mean baby pigs?

DR LIVETT : Eh yeah, they're well that's right, but they're a special kind of breed of pig called a mini pig and they would be like a suckling pig in size I imagine.

Yes, so that work was done in England and then they were tested for possible cardio vascular effects in dogs. That work was done at the Research Institute at the Baker Research Institute in Melbourne and then following that we knew that we had a safe drug and so then the drug entered into phase one clinical trials in Adelaide last year and so that work was completed in November and now Metabolic Pharmaceuticals are ramping up for phase two clinical trials which they hope to begin in April and they will take about two years. And then if they get through those, the drug will go into phase three clinical trials, where a much larger number of patients with different pain conditions will be given the opportunity to trial the drug and it will be done probably in a double blind fashion so the person doesn't know whether they're receiving the pain killer or on a placebo. Although, current thinking is that it's unfair to give a patient a placebo if they're in pain. So more people actually, receive the pain killer than receive the placebo. And some of those trials will be open so they'll know which they're on.

And that trial may not occur in Australia, because to my knowledge, no pharmaceutical company has been able to mount a phase three trial in Australia, because they cost about 60 million dollars US for the trial, so that means that Metabolic Pharmaceuticals will probably be looking to on-licence this to a larger international pharmaceutical company--a Pfizer or Glaxo or somebody like that.

Then once it gets through those phase three trials, it has to get FDA approval, Federal Drug Administration approval, and that takes about another year. So we're probably looking at another seven or eight years before the drug would be on the market.

BLANCH : That's worth waiting for by the sound of things though, the way it's going?

DR LIVETT : It certainly is and if you look at the pile of letters that I've received and emails that I've received over the period I've been working, there is a great unmet need out there and there's so many people in pain and they've tried everything, they're desperate and they just can't wait for this drug to come on the market.

BLANCH : Dr Bruce Livett, from Bio21 Molecular Science and Biotechnology Institute , at the University of Melbourne, and whose research has found pain relief drugs from the beautiful, but dangerous cone shell.


Date: Sun, 11 Mar 2007 09:03:31 -0400
Reply-To: Conchologists List
Sender: Conchologists List
From: Livett Family
Subject: Update on Conus victoriae analgesic "ACV1"
Clincal trials (Phase 2A) of conotoxin Vc1.1 (ACV1) from Conus victoriae
were begun by Metabolic Pharmaceuticals, Melbourne

ACV1 is a synthetic 16 amino acid peptide drug designed from a component
of the venom of the Australian marine cone snail, Conus victoriae, a
mollusc hunting cone shell.

In laboratory animals, ACV1 has profound, direct effects on pain sensing
nerves in the peripheral nervous system called C-fibres, which are
hypersensitive in neuropathic pain. It blocks a subtype of a broad class
of receptors called neuronal nicotinic acetylcholine receptors (nAChR)
which reside on the C-fibres. ACV1 has been shown to directly reduce the
sensitivity of sensitised C-fibres. It is the first drug to utilise this
biochemical mechanism.

ACV1 has been tested in several well-established animal pain models and
shows efficacy in relieving the characteristic pain symptoms of
neuropathy, allodynia and hyperalgesia, following subcutaneous or
intramuscular dosing. In addition, evidence suggests that ACV1 accelerates
the recovery of injured nerves and tissues.

On 24 November 2006, Metabolic Pharmaceuticals announced that the Phase 2A programme for ACV1, for neuropathic pain is progressing well. This
programme involves two human clinical trials targeting specific
neuropathies. The first group of patients (with painful sciatica) in the
first of two trials in this Phase 2A programme have been treated and the
second trial (involving patients with painful shingles and others with
painful diabetic neuropathy) is due to commence in Q107. Additionally, a
separate trial to test safety of a higher dose level of ACV1 commenced in
Q406.


Enjoy !

Bruce Livett

__________________________________________________ _______________

As you can see from Dr Livett email....results are due soon for the phase trial 2 that started in Nov 2006. Little exclusive here where Dr Levitt reports that this trial is progressing well (this is a March email).
Also the mention of a major Pharma company taking a role in developing ACV1 is very real possibility when successful trial results are released.