Operational Review
Kindly note: The following text is drawn from the Annual Report & Accounts for 2009, which were published on 3rd June 2010. It is reproduced here for information purposes only. Current information on the individual areas of operation is available in other areas of this website:-
Introduction
ReGen Therapeutics Plc is commercialising its lead product Colostrinin™ on a world wide basis. Originally ReGen was formed to develop Colostrinin™ as a pharmaceutical compound for the treatment of Alzheimer’s disease. For a number of reasons Colostrinin™ was finally assessed to be more suitable for development as a nutraceutical.
ReGen, however, has not lost its interest in pharmaceuticals. It is looking for development partners for Colostrinin™ peptides for the treatment of Alzheimer’s disease and obesity and for zolpidem. ReGen continues to maintain the patents for these products.
To provide capital for the original programme the Company was floated on the Ofex market in December 1998 and on the Alternative Investment Market (AIM) of the London Stock Exchange in March 2000. In its public offerings and subsequent offerings the Company has raised approximately £22 million. We regard our ability to raise capital under difficult market conditions as crucial as it has enabled us to continue to carry out our programmes without interruption.
Objectives
ReGen’s core objective is to commercialise Colostrinin™ so that revenue from sales of this product will make ReGen profitable. Subsidiary objectives are to find development partners for the Colostrinin™ peptides and zolpidem.
Key Historical Milestones
Colostrinin™ World wide Commercial Roll out July 2007 to present day
Turkey – April 2010
Eczacibasi Ilac Pazarlama A.S. – a leading Turkish industrials group launched Colostrinin™ in the Republic of Turkey under the brand name ‘Dyna’ in April 2010.
This generated immediate cash for ReGen as Eczacibasi paid ReGen a $50,000 milestone payment on full approval being granted. Net Revenues to ReGen from Eczacibasi pursuant to the minimum annual purchase commitments in the distribution agreement are estimated to be $52,000 in the first year after regulatory approval is obtained and $104,000 in the second year.
UK – October 2009
PRG Nutraceuticals Limited launched Colostrinin™ under the brand name ‘MemoryAid’ in the UK over the internet on the 1st October 2009.
Poland – April 2009
In April 2009 Tagerr gained approval to import and market Colostrinin™. Tagerr is a professional services and trading company established in Cologne, Germany. In operation since 1995, it has enjoyed a number of successes in the marketing and distribution of consumer products including food supplements in Central Europe and Germany.
Cyprus – October 2008
Golgi Pharmaceuticals Ltd of Cyprus launched Colostrinin™ under the brand name of ‘Cognase’ in October 2008. This was the first launch in the European Union of the nutraceutical product.
North America – October 2007
Metagenics Inc, a leading developer, manufacturer and marketeer of nutraceuticals, headquartered in San Clemente, California launched Colostrinin™ branded as ‘Cognisure’ in the North American market. This was a key launch for ReGen as the USA alone accounts for around one third of the world nutraceutical market.
Australia - July 2007
Healthworld Limited (a subsidiary of Metagenics Inc.) launched Colostrinin™ in the Australian market.
Major Scientific Milestones
Colostrinin™
2009
In March 2009 the Company reported that it had successfully completed the first stage of an evaluation of several Colostrinin™ derived peptides to modulate the expression of genes associated with obesity and Alzheimer’s disease. This work was performed under a Sponsored Research Agreement with the University of Texas Medical Branch at Galveston.
Alzheimer’s disease:
In an in-vitro study using neuronal cells two synthetic peptides (RG-01 and RG-018) showed significant impact on expression of genes involved in beta-amyloid generation and degradation pathways. Controlling beta-amyloid generation could have important implications in Alzheimer’s disease:
Anti-obesity:
In an in-vivo study on obesity Colostrinin™, as well as three peptides in combination, significantly reduced body weight gain in mice fed a high fat diet (HFD).
The obesity data could be used to create another nutraceutical product.
2008
In September of 2008 Dr. Marian Kruzel, the Company’s Chief Scientific Advisor presented a paper at the 1st Clinical Trials in Alzheimer’s Disease Conference, held in Montpellier, France. The paper provided a transcriptomal network analysis of gene expression in cells after exposure to Colostrinin™. Colostrinin™ favourably modulated the expression of several molecules involved in the pathology of Alzheimer’s disease (upregulation of bleomycin hydrolase, downregulation of APP and effects on Tau phosphorylation). For the first time we were able to demonstrate how a low dose of Colostrinin™ could produce significant medical benefits in AD patients. The presentation was published in the Journal of Nutrition Health and Aging (Szaniszlo P, German P, Hajas G, Saenz DN, Kruzel ML, Boldogh I. New insights into clinical trial for Colostrinin in Alzheimer’s Disease. J Nutr Health Aging. 2009 Mar;13(3):235-41).
In June of 2008 ReGen completed its work on gene expression in epithelial cell culture using both Colostrinin™ and specific synthetic peptides. This was published in the Journal of International Immunopharmacology in February 2009 (Szaniszlo P, German P, Hajas G, Saenz DN, Woodberry MW, Kruzel ML, Boldogh I. Effects of Colostrinin on Gene Expression – Transcriptomal Network Analysis. International Immunopharmacology. 2009;9(2):181-193).
In April of 2008 a review paper on Colostrinin™ and its constitutive peptides was published by Dr. Kruzel and Dr. Boldogh in the prestigious Journal of Alzheimer’s Disease. It is considered to be the most comprehensive review regarding the potential utility of Colostrinin™ in neurodegenerative disorders. The paper also reviewed the novel mechanisms of action involved in neuroprotection and clearly demonstrates Colostrinin'sTM biodiversity.
2007
In December 2007 ReGen announced that preliminary results of a study of Colostrinin™ in the treatment of dementia in ageing dogs looked encouraging. The dosing phase of the study had been completed and a preliminary report based on 22/23 subjects showed that Colostrinin™ was well tolerated and that ‘40% of owners felt that there had been signs of improvement’ throughout the trial.
Also in December 2007 ReGen announced that several Colostrinin™-derived peptides had been identified for further development. Two such synthetic peptides may have a potential utility in Alzheimer’s disease and a further candidate potential utility in the management of obesity.
Further evidence of the diverse scientific potential of Colostrinin™ was presented in February 2007 when ReGen announced the results of an in vivo study that showed Colostrinin™ increases the lifespan of inbred mice predisposed to premature ageing.
2006
In August an in vitro study published in the peer-reviewed Journal of Experimental Therapeutics and Oncology showed that Colostrinin™ reduced the spontaneous or induced mutation frequency in the DNA of cells. This would suggest an impact on both the ageing process and the development of cancer.
In May 2006 formal safety studies started with the commercial form of Colostrinin™.
In January the full results of an in vitro study which showed that Colostrinin™ could cause precursor nerve cells to differentiate and proliferate was published in the peer-reviewed journal Cell and Molecular Neurobiology.
2005
In October 2005 ReGen presented an important paper regarding the effects of Colostrinin™ on life span in mice at the 21st International Conference of Alzheimer’s Disease International in Istanbul.
In June 2005 the peer-reviewed journal ‘Neuropeptides’ published an article showing that Colostrinin™ can prevent the aggregation of beta amyloid – a toxic protein that builds up in the brains of Alzheimer’s disease sufferers.
Also in June 2005 ReGen achieved production scale-up of Colostrinin™ using a proprietary industrial process.
In April 2005 ReGen announced that Colostrinin™ and a nine amino-acid synthetic homolog of a Colostrinin™-derived peptide showed neuroprotection in a cell line model of Parkinson’s disease.
In February 2005 the United States Patent and Trademark Office granted US Patent No. 6,852,700 for the use of Colostrinin™ as a medicament, particularly in the treatment of chronic disorders of the central nervous system and the immune system.
2004
October 2004 at The Society for Neuroscience meeting, scientists at the Open University, showed that pre-treatment with Colostrinin™ in a chick model can limit the memory impairment induced by beta amyloid, a toxic protein involved in the pathology of Alzheimer’s disease. Bovine-sourced Colostrinin™ made by ReGen’s new production process was shown to have the same activity profile as the ovine-sourced material used in the clinical studies.
In July 2004 at the 9th International Conference on Alzheimer’s Disease and Related Disorders scientists reported that the neuroprotective effects of Colostrinin™ can be due, in part, to a decrease in beta amyloid-induced apoptosis.
Also in July, at the Federation of European Neurological Societies meeting it was reported that Colostrinin™ was able to enhance memory when compared with control saline injections in young chicks.
In May 2004 at the 14th Alzheimer Europe Conference scientists presented two papers. In one they showed that Colostrinin™ could prevent the aggregation of beta amyloid and reduce its toxic effect on neuroblastoma cells and in the other they showed that Colostrinin™ could block the proliferation and promote the differentiation of primary cells into neuronal cells.
In February 2004 ReGen’s placebo-controlled clinical trial of Colostrinin™ given over 30 weeks (RG-010) to 106 Alzheimer’s sufferers was published in the peer-reviewed Journal of Alzheimer’s Disease. This study reached statistical significance in its main clinical end-point of cognitive efficacy and its main secondary endpoint of Independent Activities of Daily Living (IADL).
Zolpidem
2009
A study confirming the zolpidem effect in brain damage was presented at the 4th International Congress on Brain and Behaviour on 3 – 6 December 2009 in Thessaloniki, Greece by Dr Ralf Clauss. 23 of 41 consecutive adult patients, at least 6 months after brain damage were selected as neurologically disabled patients after scoring less than 100/100 on the Barthel Index. Causes of brain damage included stroke (12 subjects), traumatic brain injury (7 subjects), anaphylaxis (2 subjects), drug overdoes (1 subject) and birth injury (1 subject). The selected 23 patients had a baseline SPECT scan before starting daily zolpidem therapy and a second within two weeks of therapy, performed 1 hour after receiving 10 mg oral zolpidem. Scans were designated as improved when at least two of three independent assessors detected improvement after zolpidem. The rest were designated non-improved.
After four months of daily zolpidem therapy, the clinical condition of subjects was rated on the Tinetti Falls Efficacy Scale (TFES) before and after zolpidem. The TFES ratings of all subjects and scan improvers and non-improvers were compared statistically.
Mean overall improvement after zolpidem on TFES was 11.3% from 73.4/100 (SD 25.4) to 62.1/100 (SD 28.8) (p=0.0006). 10/23 (43%) improved on SPECT scan after zolpidem. Their mean TFES improvement was 19.4% (SD 16.75) compared with 5.17% (SD 5.167) in 13/23 non improvers (p=0.0081).
2008
In November, 2008, the preliminary findings from a study at the University of Pretoria, examining the use of zolpidem to reverse neurodormancy after brain damage were presented at the Asia Oceania Congress of Nuclear Medicine and Biology, Delhi, India.
In this prospective study, 40 patients with clinical and neurologically-confirmed brain damage due to various causes (mainly stroke and traumatic brain injury) were investigated by brain SPECT imaging before and after zolpidem. All patients underwent non-attenuation corrected Ceretec rest/zolpidem imaging. All testing was completed within a maximum period of a week. Three neuroimaging experts not directly involved in the study reviewed all of the images for each subject blinded to the treatment received. Concordance / discordance of brain SPECT and neurological assessment was determined. The results show that 72.5% of patients demonstrated an improvement in cerebral perfusion after zolpidem, which is significantly higher than the response rate based on clinical measurements only.
In June 2008, the Company announced that collaborators at Aston University, Birmingham UK had discovered new evidence of zolpidem’s unique mode of action using pharmaco-magneto-encephalography (MEG) brain imaging. They found that non-functioning areas of the brain within the stroke damaged area of a patient were being kept in a dormant state by excessive slow wave activity that zolpidem reversed. This effect could not be reproduced with either a placebo or another sedative with a similar pharmacological action (zopiclone). ReGen has filed a new patent application around this important discovery.
In 2008 further analysis of data from ReGen's first clinical study in patients with long-standing brain damage established that the sublingual route of dosing is more consistent, faster in onset and more potent than existing tablets. Such characteristics will greatly help patients to control the effect of dosing when they need to avoid sedation. More importantly, the trial also demonstrated that 2.5 mg sublingually was non-sedative even when repeated. Since published reports have shown 2.5mg to be an effective dose in this new indication, this finding established a clear demarcation between ReGen's new indication and generic sedative formulations.
2007
In August 2007 the Company announced the successful completion of a Phase II trial in South Africa where it was established that a 2.5mg dose of a novel sublingual formulation of zolpidem is non-sedating. Two television documentaries on the effects of zolpidem in the treatment of brain trauma were screened in 2007. The most important one in scientific terms was screened in March on the Discovery Channel. This programme gave full prominence to ReGen’s work in this area.
2006
Zolpidem was acquired in February 2006 as in a number of ‘open’ clinical case observations zolpidem had been shown to normalise areas of brain dormancy secondary to a primary lesion in brain damaged conditions.
Our Market Place, Principal Risks and Uncertainties, Outlook
In summary the principal risks for ReGen are that:
- It will not be able to fund its development.
- It will not be able to do further licensing deals.
- Revenues from licensing deals may not be sufficient to sustain the Company.
- It is a very small player in an international market.
ReGen is now primarily active in the commercial development of its nutraceutical product Colostrinin™. It is however seeking to capitalise on previous research done in the pharmaceutical field with the Colostrinin™ derived peptides and zolpidem.
The nutraceutical business is a different proposition in terms of risk/reward than pharmaceuticals, as generally it is easier to get a product to market because there the regulatory hurdles are less, but the returns will usually be lower. In terms of structure, the similarities are that ReGen is dependent on a marketeer to sell its end product, but it is able to get the product sufficiently developed so that it is ready to be marketed, unlike in pharmaceuticals. Although there are global nutraceutical marketeers such as Nestlé and Unilever there are a number of individual national or regional companies who are able to sell ReGen’s product, which lowers its risk and this is shown by the number of deals it has done. We would, however, admit that there are still major deals to be done and the prime risk at this stage is not doing a licensing deal in the remaining key markets. We would also point out that we need to achieve the sales revenue necessary to sustain the Company once the product is launched.
ReGen has tried to guard against the licensing risk by initially employing an international licensing consultancy to introduce it to prospective licensees and advise it on the terms of appropriate licensing deals. ReGen now believes it has sufficient internal expertise built up to negotiate the licensing deals itself. To date, the efforts of the licensing consultancy and ourselves have resulted in the Company achieving licensing arrangements in North America, Australasia, parts of Europe, Turkey and India.
With regard to the problems of funding, ReGen has a long history of raising working capital and has now been on the AIM market since March 2000, having joined Ofex in December 1998.
The prime risk for ReGen is that we will not be able to do further deals or that we will not do particularly attractive deals. There is also a significant risk, before ReGen has done a deal, that we will run out of money, as we may not be able to attract further funding. Other risks are that, given the size of the company, its competitive intelligence may both overestimate its opportunities and underestimate its difficulties. Essentially one must remember that ReGen is a very ‘small fish in the nutraceutical and pharmaceutical sea’.
American Depositary Receipt (ADR) Programme
Looking to the future development of the Company, we established an ADR programme in the US in March 2005. On the financial side, the US is by far the largest capital market, particularly for biotech. In consequence we believe that shareholder value could be enhanced by having a US-based share trading facility as in time it could be used for capital raising and in the long term for acquisition.
Last updated: 7th June 2010
