LIVING CELL TECHNOLOGIES LIMITED Audio Webcast

LIVING CELL TECHNOLOGIES LIMITED (LCT)

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LIVING CELL TECHNOLOGIES LIMITED (LCT) Events

Company (Stock Code)	Date/Time	Event	Timezone: Australia/NSW
LIVING CELL TECHNOLOGIES LIMITED (LCT) Cell Therapy to Generate New Functioning Tissue	Thu, 31 Jul 2008 12:30PM	LCT - Australian Biotechnology Summit Presentation - Dr Paul Tan, Chief Operating Officer
LIVING CELL TECHNOLOGIES LIMITED (LCT) LCT Appoints New CEO	Thu, 31 Jul 2008 10:30AM	LCT - LCT Expands Management Team - Dr Robert Caspari, CEO
LIVING CELL TECHNOLOGIES LIMITED (LCT)	Fri, 7 Jul 2006 02:00PM	LCT - Living Cell Technologies Granted Diabetes Patent in the US - Mr David Collinson, CEO & Executive Director
LIVING CELL TECHNOLOGIES LIMITED (LCT)	Thu, 6 Nov 2008 01:30PM 01:30PM Australia/SA-NT	Annual General Meeting Clare Room, Stamford Plaza Hotel, 150 North Terrace, Adelaide, SA
LIVING CELL TECHNOLOGIES LIMITED (LCT)	Tue, 7 Oct 2008	Full Year Results
LIVING CELL TECHNOLOGIES LIMITED (LCT)	Fri, 29 Feb 2008	Interim Results
LIVING CELL TECHNOLOGIES LIMITED (LCT)	Wed, 28 Nov 2007	Annual General Meeting Level 47, MLC Centre, 19 Martin Place Sydney NSW 2000
LIVING CELL TECHNOLOGIES LIMITED (LCT)	Fri, 31 Aug 2007	Full Year Results
LIVING CELL TECHNOLOGIES LIMITED (LCT)	Wed, 28 Feb 2007	Interim Results
LIVING CELL TECHNOLOGIES LIMITED (LCT)	Wed, 13 Sep 2006	Full Year Results
LIVING CELL TECHNOLOGIES LIMITED (LCT)	Thu, 16 Mar 2006	Interim Results
LIVING CELL TECHNOLOGIES LIMITED (LCT)	Wed, 16 Nov 2005 04:30PM	Annual General Meeting
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LIVING CELL TECHNOLOGIES LIMITED (LCT)

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PRESENTATION BY PAUL TAN, CHIEF OPERATING OFFICER OF LIVING CELL TECHNOLOGIES LIMITED (LCT)

“Cell Therapy to Generate New Functioning Tissue”

http://www.brr.com.au/event/48820

 

THURSDAY, JULY 31, 2008, 12:30 PM.

 

            LCT     I thank the organizers for the invitation not only for myself but also for Robert Caspari who is as obvious today the chief executive of the entire group of

10                    LCT. Robert comes from Boulder, Colorado. The significance of his appointment will be clearer as we move forward in this presentation. I’ve been asked to talk about cell therapy and the use of cells derived from pigs as a source of tissue mainly because of the lack of human donor cells or human donor organs. LCT has been in this business for many years developing the

15                    research that came out of the University of Auckland and progressed by Professor Bob Elliot for at least the last 20 years. I will focus on two of our products. The first is a product for Type 1 diabetes and the second is in the field of neurology. The first use is porcine cells that I encapsulated and used for the treatment of Type 1 diabetes and that product is currently in Phase I/II

20                    Clinical Trials and I will speak mainly about the current status and the recent results that we released this month. The strategy for diabetes really is to replace cells that have been lost by disease, by this autoimmune disease wherein Type 1 diabetes the cells that produce insulin are missing. And so the rationale was to replace the islet cells that are not there. With the

25                    neurology product, the strategy is quite different because the cells that we implant are cells that produce neurotrophins, essentially brain reproductive hormones. The cells themselves do not naturally replace cells that are lost, but in releasing neurotrophins, the intention is to recruit progenitor cells endogenous stem cell-like cells to the site of the lesion and repair the injury

30                    caused by disease and potentially also in cases of trauma.

 

                        To talk about the DiabeCell, the product for diabetes, the cells taken from neonatal piglets, the pancreas is removed, and the cells are then prepared and put into microspheres. These microspheres, as you see in the top

35                    diagram, are tiny little spheres of capsules that are about .6 of a millimetre and diameter, the size of a pinhead and in each capsules we have encapsulated a pancreatic islet that produces insulin as well as other factors such as glucagon and also vascular endothelial growth factor. The capsules are engineered such that the cells are maintained alive because of the

40                    diffusion inwards of nutrients and oxygen and it allows the insulin that is produced by these cells to permeate out. The purpose of the encapsulation is to isolate the cells from the immune system such that they are not seen and therefore one does not see an inflammatory response or an immune anti-rejection response. And this is what it looks like when it is implanted. The idea

45                    is to implant it into the peritoneum, into the abdomen. And these photographs are from animal studies where it shows clearly that these bead-like structures are attached to the organs. They are attached as a single sheet at the liver surface or for that matter also to the surface of the gut and on to the augmentum. And because they do release vascular endothelial growth factor, we see that in animals over a period of weeks, three weeks, and certainly by six weeks, the appearance of vascularization and we believe that this is important in maintaining the long-term viability of islets.

 

5                      The current product is in Phase I Clinical Trials according to current regulatory requirements. In fact, Bob Elliot has done work with a prototype product going back 10 years ago, and last year, we published this data and what this shows are – the photographs on the slide shows the top shows the capsule as it was placed in the abdomen of the patient 10 years ago. The

10                    current product will look very much the same except they are much smaller. And 10 years later, these capsules are still there as shown in the lower photograph, embedded into the augmentum with evidence of vascularization. And as reported we have stated that it is possible to retrieve these capsules and demonstrate that they are alive, that they contain insulin-producing cells

15                    as well as glucagon-producing cells. We have reported the presence of insulin and glucagon in histological sections of these capsules, but more importantly, in this particular patient it was possible to submit the person to a glucose tolerance test and then withdraw blood samples during the test and demonstrate the presence of porcine insulin present in very small amounts

20                    but nevertheless present indicating that the cells were still viable after nine‑and‑a‑half years and have repeated again in 10 years. So that these cells are alive, viable, producing insulin, and doing so in a regulated manner. So with the current product and because the prototype product while the cells were viable, the amount of insulin produced was not sufficient to make a

25                    significant difference to the amount of insulin he was taking, and although the control of glucose was significantly better after the implant for many years as reflected by the glycated hemoglobin levels, the company went on to develop the product further and change the method of encapsulation to produce these smaller capsules. With smaller capsules, you would expect that the diffusion

30                    distance for oxygen and for the travel – the insulin leaving would be much less.

 

                        The first clinical studies were done in Russia using regulatory approvals that were available then. These included firstly approval from the New Zealand

35                    government to manufacture DiabeCell on the GMP conditions for use in human trials and also an internationally accredited capability to test for potential infections that might potentially be transferred from animals to humans, although this has never occurred in the entire history of xenotransplantation over the last 200 years. The ethics approval for the

40                    clinical trial program, we are still waiting an approval to conduct the trial in New Zealand later this year or early next year. But with those approvals, the Russian institution gave us the ethics and the scientific approval to proceed with this study starting with the lowest dose of DiabeCell that would answer two questions, the first question being the safety of the product and the

45                    procedure, and secondly to collect initial preliminary efficacy data. To date we have implanted five patients with the lowest dose. This dose is calculated to demonstrate some effect and obviously not the optimal dose or the optimal clinical efficacy would be expected. In all five patients, the procedure has gone on very smoothly. There were certainly no significant adverse events to report. The clinical effect of the implant of the lowest dose surprised us as we have seen clinical benefit in all five patients and I would just go through this very quickly.

 

5                      In the control of diabetes, there are two major parameters to consider. The first is the overall control of blood glucose and as you’re aware, your blood glucose level and mine would vary throughout the day. Every diabetic knows that the best indication of whether the diabetes is well controlled is the level of glycated hemoglobin. It’s a reflection of how good the blood glucose has been

10                    over the past two months. When we look at all these five patients, in all of them, the first clinical measure to look at is whether there has been an improvement in glycated hemoglobin and we see that this is so in four of the five patients who have been followed up for varying periods since this trial started. The group mean showed a drop which was more impressive than we

15                    could have expected at the beginning of the study from the group being of 8.5% to 6.8%.

 

                        Secondly, are you able to maintain good or achieved better blood glucose control with a lower requirement of daily insulin dosing. We had expected that

20                    with the 5,000 islet equivalent per kilogram dose that we might see possibly a 25% reduction. What we see is that for the group, there was about a 40% reduction on an average. For the individual patients, we have seen maximum reductions from a minimum of 10% to a patient who went off insulin altogether for a period of four, five months again followed up for various periods. This,

25                    as we have expressed and commented on, was something that was certainly beyond our expectations taking into account that this is the lowest dose. Two of the patients have in fact been given a second dose, a second implant. The implant is given quite simply through a laparoscope as shown in the figure there. The advantage of doing a second implant is that one is able to retrieve

30                    capsules that were implanted six months ago and it was possible to check these capsules demonstrate that the capsules are in tact, there was no inflammatory reaction, there’s no breakdown of these capsules, and that the cells in there were still viable.

 

35                    The second additional thing to do of course is to be absolutely sure that the clinical effects one observe is indeed due to the release of porcine insulin from a viable graft. While it might be difficult to believe that someone who has diabetes for 15 years would suddenly go off on insulin altogether. Nevertheless it was important to demonstrate it was possible to detect

40                    porcine insulin. For the first two patients, this has been possible. The one taken at about six months after the first implant and the second patient 11 months after the second implant, so that at this still very preliminary stage our interim observations are that there has been no significant adverse effects/events, that the clinical benefit has been seen in all five patients either

45                    in better control of diabetes as reflected by their glycated hemoglobin levels improving or by reduction by the daily dosage of insulin. Given the fact that there are no adverse events the program has moved forth to the next stage to test the next level which is 10,000 islets equivalence per kilogram body weight. We think that the optimum dose is probably around 10,000 to 15,000 islets equivalence based on comparisons broadly speaking with the human islet transplant program. That has started so that one patient in fact was implanted with a high dose in July and we look forward to reporting positively on you. The company is very pleased with this result obviously. The response

5                      of patients with diabetes as reflected in diabetes websites are also very clear that this safety has been maintained and that the response has been as dramatic as this with the lowest dose.

 

                        I would like to move on to our second product. The picture on your left is a

10                    section of a brain which shows a tissue called the choroid plexus. The choroid plexus is an epithelial tissue responsible or producing cerebrospinal fluid, and in the CSF, a number of neurotrophins brain-derived growth factor, BDNF, GDNF, including some IGF as well. These cells from the choroid plexus have been processed in very much the same way. They’ve been digested and then

15                    formed in tiny little clusters and have been encapsulated as shown in photograph on the right in not too different manner as we have encapsulated islets. These neurotrophin-producing cells have been implanted in animal models of stroke and in animal models of Huntington’s, and the data has been published.

20

                        I’ll just go very quickly through the published data in the Huntington’s model in the rat. Here, the disease is induced by the injection of a toxin quinolinic acid. These encapsulated cells are implanted into the brain, and following that, the toxin is injected and the animal is then assessed after six weeks later.

25                    Essentially what we’re looking for are firstly the size of the lesion; secondly functional improvement; and thirdly whether we’re able to retrieve the capsules and show that the cells remain viable and are functioning. What you see in the graft in the bar chart on the left are a number of groups of animals. The controls are either sham operation or given blank capsules and the

30                    treatment groups are given the encapsulated porcine or rat choroid plexus cells that produce neurotrophins and the size of the lesion is significantly reduced with the implant. The H&E section on the right side shows the capsule wall as well as the cells that appear viable and certainly the capsules can be retrieved from the brains of these animals and shown to be viable.

35                    Reduction in the size of lesion is not sufficient for the FDA. One has to show a functional improvement and our neurologists, neuroscientists conduct a number of functional tests. This is one called the placement test where the normal limb is able to place – be placed appropriately when given a stimulus whereas the affected side, the side of the lesion, where the limb is poorly

40                    used, paralysed, and what you’re looking for is a recovery in the function of limbs on the affected side and we see a significant difference in those given either blank capsule where there’s no improvement, a little improvement, and an improvement almost to normal in animals that have been given the capsules containing choroid plexus cells.

45

                        Studies have also been done in non-human primates, in cynomolgous monkeys, and there you see in the top two photographs on the left in A is the lesion that is caused by quinolinic acid in the striated part of the brain that is affected in Huntington’s disease. On the right, the capsules have been placed there. The volume of the lesion is significantly less and naturally when histological studies are done on these areas, one sees that there’s a significant loss of neurons when blank capsules are implanted and neuronal cells being present in the brains of animals that have been treated. As I sort

5                      of mentioned earlier on, the strategy here is to implant cells that produce neurotrophins, not to replace the cells that are lost with the implanted cells. There have been a number of studies with this model to suggest what the mechanism here should be. We do know that in brain disease or injury caused to the brain that there are natural endogenous progenitor cells that

10                    proliferate and that these do try to repair the injury. However, in disease this repair mechanism is inadequate. What is done when neurotrophins are delivered to the site of the lesion either by injecting recombinant neurotrophins or preferably by placing cells that produce neurotrophins one is able to detect a migration of progenital like cells towards the site of the lesion

15                    so that the recruitment of progenitor cells as well as some direct effect, protective effects, of neurotrophins, of neuronal cells to various stimuli, chemical stimuli or injury.

 

                        So we are at the stage where we have one product in Phase I/II Clinical Trials

20                    and moving on to higher doses whereas the neurotrophins cell is very much still in research and at very early clinical development. The company at the moment is based essentially in Auckland for its operations. You’re aware that we are listed on the ASX and we have a corporate office here. Our pigs, high health status pigs, which we use as a source of tissue are derived originally

25                    from the Auckland islands right down towards the South Pole and they are a very unique breed and we believe they are the cleanest herd of pigs to use as a source of tissue for xeno-implants and we keep them in isolation in two herds in New Zealand. Now while those operations are there we do have associations with laboratories at Rhode Island and in Perugia and more

30                    recently as I said with the announcement of appointment of the new CEO based in Colorado, I think it would be clear to most of you that we see ourselves as moving from Australia and New Zealand and taking more of an international role and that this product is ultimately not just for Australia and New Zealand but is a product for global consumption and that we need

35                    someone with the expertise, deep experience of Robert Caspari who comes from the biopharmaceutical industry. Currently, the shareholding of the company is about one-third in Australia, one-third in New Zealand, and about one-third in the rest of the world, mostly US and Moscow. We also this year listed our ADRs onto the OTCQX.

40

                        Finally, I have been asked to say something about our intellectual property. We do need to protect the interest of that shareholding that you’ve just seen. We have a family of about 12 families of patents and 19 issued patents in Australia, New Zealand, and US and Europe, and the patents cover the use

45                    of high health status pigs particularly neonatal pigs as a source of tissue and also the method of encapsulation. While the use of alginate to form capsules has been in the literature for some years we believe that the reason why we have succeeded where others have not is because of the attention to details and the selection of the materials, there’s alginate and there’s alginate. Our patents cover chemical compositions, the very fine physical characteristics of alginate, and also the methods of encapsulation, the way we have made the layer by layer of fabrication of the capsules to ensure that the pulse size is of the appropriate nano scale that would allow molecules of less than 50 nano

5                      meters to move in and out and to keep immune complexes and certainly cytotoxic cells also away from the cells. The patents obviously cover the use of cells for specific diseases. So Living Cell Technologies is in a very interesting phase that we have a product for Type 1 diabetes, the early results of a promising. We see ourselves as being in a growth phase and it is

10                    for that reason that we have made major commitment to a new seal to take this company from the research and the Phase I Trial to the next important phase of the growth of this company. Thank you very much. Yes, Kevin.

 

            Q         Paul, you see a deterioration in the effect in the autotransplant as I guess

15                    you’d expect, what’s the duration you’re aiming for to make this a commercial product?

 

            LCT     We would want to see a duration of at least a year or more and I think we are not able to make any definitive comments right now on the duration of the

20                    effects until we follow the patients for at least a year or more. Again what you’ve seen is the implant with the lowest dose and we believe that the dose has an effect on the longevity of the implant as well because we take a normal pancreas into a section not all the islets are working. Some islets will contain insulin-producing cells, others will not contain stored insulin. So they

25                    do need to go through a cycle of activity and risk. No conclusions can actually be made with the lowest dose presently.

 

            Q         You inject the cells intraperitoneally I assume to get the hepatic part.

 

30        LCT     Yes, correct. Yes.

 

            Q         But is that essential? Have you tried at least in animals to do this just subcutaneously?

 

35        LCT     It’s possible to do that but physiologically we do want to implant these capsules in the upper part of the abdomen. We make a point of putting it under the liver and into the lesser sac mainly to deliver insulin into the portal system, insulin and glucagon because I think that we believe that – based under the physiology that they would be more effective. You will see an effect

40                    if you were to place capsules subcutaneously but this may reflect – this may affect the ultimate dosage that you would want to implant, the number of cells and the number of capsules and the amount of the islets.

 

            Q         I’m sure you’ve considered this but, so if you can allow some of the cells that

45                    you implant, the molecules to get out and regulate, as those cells die by natural turnover, there may be other proteins that get out even the small peptides which could sensitize the patient in this case. So do you – have you monitored any the serum of these people over the period of a year or more to see if there’s any antibodies at all against the porcine product. If so would that be – is there a risk of sensitization?

 

            LCT     Yes. If you look at the capsules and the dose that we’re putting in, you – if we

5                      put in 300,000 islet equivalents we’re putting in roughly about 300,000 of these capsules, a proportion of them might die, 1%, and our studies with antibodies to pick sort of tissue with antigal antibodies, there’s no correlation with the functioning of the graft. So that’s why ultimately the longevity of the implant is demonstrated by whether you can continue to detect regulated

10                    release of insulin at six months, one year, and beyond. And the fact that there is a clinical effect beyond a year.

 

            Q         It is impressive. I’m just guessing taking to the next stage as people after a year (inaudible) (00:28:14) implant because the disease will still be there. So

15                    it’s a question of whether over a period of time will you risk that sensitization I suppose.

 

            LCT     In animals studies it’s possible to put in more than one implant and if you look at the antigal response, there is no increase in the antigal antigen response,

20                    the xeno antigen response, and that response has no correlation with the function of the graft, again probably because those capsules that remain intact remain functioning. The ones that break down will probably be destroyed.

 

25                    Okay. Thank you very much indeed.

 

INTERVIEW CONCLUDED

 

 

 

 

Contact brr@brr.com.au for more information

 

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