Standard Template for a Candidate Demonstration Project

Transcription

1 Standard Template for a Candidate Demonstration Project Note: the questions with asterisk should be filled. 1.* Title of the project: HepSeeVax- A Vaccine to prevent Hepatitis C 2.* Submitted by: 3.* Target disease or health condition: (Focus on type II and III diseases and special R&D needs of developing countries in type I diseases where there is an identified health technology gap.) Prevention of chronic hepatitis C infection 4.* The suggested health technology that project seeks to develop: (e.g. medicine; diagnostic test; medical device; vaccine etc.) Vaccine

2 5.* Project summary: There is no vaccine available to prevent Hepatitis C (HCV) HCV chronically infects ~3 % of the human population causing recurring, progressively worsening liver disease, cirrhosis and hepatocellular carcinoma. After infection with HCV, ~70% of individuals become chronically infected of whom 10-20% develop cirrhosis and 1-5% develop liver cancer. With around 5% of the global population having been infected with HCV, ~ 3 % of the population have chronic HCV and are subject to progressively worsening liver disease, cirrhosis and hepatocellular carcinoma. HCV testing is not routinely performed and so the true incidence and prevalence of HCV is not known and likely underestimated. Compounding this, it is thought up to 75% of chronically infected HCV patients are unaware of their infection status. While there is new hope in treating the disease, with new antiviral drugs approved and in development, they are extremely expensive (~$40,000/person). It is unlikely that the countries with the highest burden of disease, including countries in Asia, Africa and the Middle East, will be able to support costs of such treatment. Indeed, the number of HCV infected people in China has been estimated to be between million people or 2-8% of its population. In Egypt, this figure rises to 14%, >11 million people. Antiviral therapy for the treatment of HCV in the developing world will be unaffordable, and in the developed world the high costs will put pressure on health care systems making it difficult to provide subsidised treatment for all. Antiviral drugs are not a complete solution for controlling the global HCV epidemic. There is a clear need for a prophylactic vaccine to reduce the burden of HCV, preventing new infections worldwide. A study performed on the cost effectiveness of an HCV vaccine in Canada confirmed that even a vaccine with modest (80%) efficacy would reduce the lifetime risk of HCV by 35-50% and reduce HCV-related deaths by 32-45% bringing a cost saving of $18,000/QALY. In developing countries where current treatment options are limited due to costs, vaccines will likely have high acceptance rates. This has been the case for the highly efficacious Hepatitis B vaccine which is recommended for universal use with 179 World Health Organisation (WHO) member states vaccinating infants as part of their vaccination schedules in 2011.The roll out of a HCV vaccine can utilise existing vaccine distribution channels working with AID organisations, local governments and the WHO to reach the target population. We now have an exciting opportunity to eradicate HCV through a combination of vaccination to prevent new infections, and antiviral therapy to eliminate HCV coupled with vaccination to prevent re-infection.

3 6.* Public health need that the proposed project aims to address: (Explain the public health need in terms of burden of disease; prevalence; incidence; fatality rate; geographical spread; current interventions and their limitations; and what proposed new technology would change in terms of disease prevention, control, diagnosis, treatment etc. If detailed information is not possible at present then please provide some basic level information) An estimated million people world-wide are infected with Hepatitis C Virus and 350,000 people die each year of HCV related disease. Initial infection with HCV is often asymptomatic but progresses to a chronic life-long infection in 50-70% of cases. Of those chronic carriers 20% will develop chronic liver chirrosis and 5% will develop liver cancer. HCV is a highly variable virus and is classified into 7 different geographically distinct genotypes, HCV genotypes 1, 2, and 3 are most common in the Western world and Australia. Genotype 6 is most prevalent in South East Asia and genotype 4 is most commonly found in North Africa (predominately in Egypt). Prevalence and more particularly incidence data is difficult to come by due to the large geographical distribution and the fact that acute infection is often asymptomatic. It has been suggested that up to 85% of infected individuals are unaware of their infectious status, which implies that epidemiological data available are likely to be severely underestimated. The highest burden of disease however is seen in emerging countries and in poor and disadvantaged communities. (see Table 1). Risk factors vary by country with injecting drug use being the main risk factor for HCV transmission in countries with screening programs of blood products. In countries with a high prevalence of HCV the most common risk factors include the re-use of syringes and needles, unsterilized equipment for various medical procedures (Pakistan; Egypt; Taiwan; India; Romania) and blood transfusions with contaminated blood products (China; Japan; Korea; Saudi Arabia; Russia). TABLE 1- HCV DISEASE STATISTICS Country Prevalence DALY s average number** US 1-2% EUROPE 1-3% AUSTRALIA 1-2% 4775 CHINA 8% TAIWAN 4.4% 8223 PAKISTAN 4.7% EGYPT 15% INDIA 1-8% AFRICA ** Data derived from total Hepatitis Burden from healthmetricsandevaluation.org assumption that 20% of viral hepatitis is cause by HCV

4 Until 2012, the standard treatment of choice for those suffering chronic HCV infection was combination therapy with pegylated interferon alpha and ribavarin (pegifn-a/rbv). A major disadvantage of this therapy is the associated side effects and the high cost of treatment at approximately US $32,700 for a standard course of 48 weeks. A recent WHO survey of member states on clinical practices for Hepatitis suggested that only 58.6% included pegylated interferon in their treatment regimen for HCV. New drugs are looking promising, however, they are mainly focusing on genotype 1 (which is mainly prevalent in western countries) and the anticipated costs (up to $100K)will make these drugs unattainable in the developing world. There is no vaccine currently for HCV 7.* Explain which new and innovative approaches and mechanisms to supporting financing and coordination of R&D this project would demonstrate? (This is a very important part to be filled. The idea of these demonstrations projects is to address identified gaps that disproportionately affect developing countries, particularly the poor, and for which immediate action can be taken (WHA66.22). 66 th WHA considered these demonstration projects as part of the efforts to take forward action in relation to monitoring, coordination and financing for health research and development. The assembly decided to identify such projects that: (a) address identified research and development gaps related to discovery, development and/or delivery, including promising product pipelines, for diseases that disproportionally affect developing countries, particularly the poor, and for which immediate action can be taken; (b) utilize collaborative approaches, including openknowledge approaches, for research and development coordination; (c) promote the de-linkage of the cost of research and development from product price; and (d) propose and foster financing mechanisms including innovative, sustainable and pooled funding; (2) The demonstration projects should provide evidence for long-term sustainable solutions. ) HCV is a disease that disproportionately affects individuals living in poor and disadvantages communities. It is these communities that are less likely able to access the new treatments that are becoming available due to cost and access to health care. The new drugs becoming available are mainly focused on genotypes affecting the western world targeted at the ageing baby boomer market segment. More importantly they do not prevent re-infection and therefore will have little impact on the epidemic in emerging countries where transmission is mainly related to contaminated blood products and unsafe medical practices. It is unlikely that countries with the highest burden of disease will be able to roll out access to these new drugs, given difficulties in providing access to the current gold standard. There is a clear unmet need for a vaccine to PREVENT HCV. The main difficulty in the development of preventative HCV vaccines has been due to its genetic variability and the challenge of producing one vaccine capable of protecting across the multiple genotypes. Researchers at the Burnet Institute have overcome this challenge and developed a novel vaccine candidate with the potential of becoming a universal vaccine for HCV. The vaccine candidate Delta3 TM contains only the conserved elements of

5 the major viral surface protein E2 which works to focus the immune response to generate specific and potent antibodies capable of preventing infection. The vaccine has been shown to elicit high titre, potent, neutralising antibodies able to prevent infection with both similar and distantly related strains of HCV in vitro. These results provide proof of concept for the development of a vaccine capable of protecting individuals against a broad range of HCV strains and the world s first preventative HCV vaccine. We are seeking funding over 2 years to progress Delta3 into Phase I clinical trials with the aim to determine whether the vaccine is safe and able to induce appropriate neutralising antibody responses. 8.* Evidence of market failure/research landscape: (Explain why there has been no investment in this technology or why investment has not resulted in access to the health care product.) The market dynamics in the HCV field have changed due to the increased emphasis on the development of new drugs. The problem is that these drugs are mainly targeted for the developed world given their focus on gentotype 1 and high anticipated costs of treatment. There is a prevailing view therefore in the developed world that HCV will no longer be a problem and that HCV will be curable in these markets. Even though this may be the case in the western world, although some argue those at risk will be unable to access these treatments even in these markets, it is evident that these drugs will not filter to those in the developing world and countries with the highest burden of disease. Another problem is the difficulty in accessing accurate incidence and prevalence data for HCV, particularly in the developing world, which makes it difficult to articulate the scale of the problem in these markets. As discussed earlier given the asymptomatic nature of the disease it is likely that current estimates are highly under- estimated. These market failures have made it a difficult proposition to raise funding by venture capital and private investment means. Another main barrier for the development of a HCV vaccine is access to funding at early stages of development. It is likely that in order to successfully attract partnerships we will have to leverage funding from different means in order to affray the risk to potential partners and investors. Feedback we have received from potential partners suggest we will have to progress development of the vaccine into humans before they are likely to engage. 9. The scientific and technical feasibility: (Describe the scientific and technical basis for the proposed technology in terms of the state of the art e.g. candidate molecules; biomarkers; pipeline; previous efforts, if any, to develop same or similar technology etc. Include some risk analysis) One of the challenges in developing an effective preventative vaccine for HCV is its genetic variability making it difficult to generate one vaccine that is protective for the various HCV genotypes. Researchers at the Burnet Institute have developed a HCV Vaccine candidate that aims to overcome these challenges and prevent HCV infection using a novel antigen based on modifying the key viral surface protein E2. The Burnet s vaccine candidate Delta3

6 does not contain the highly variable (hypervariable) regions normally present in E2 and allows the immune system the opportunity to produce cross neutralizing antibodies capable of preventing HCV infection in in vitro systems (see Figure below). This strategy overcomes the problems seen in previous HCV vaccines, Novartis and Chiron, where the focus was the inclusion of the full E2 region including the highly variable domains. Their vaccine approach failed to induce antibodies that were able to neutralize different strains. DELTA 3 Schematic diagram of the construction of Delta3 containing deletions of 1, 2 and 3 variable regions to form Delta3. Delta3 has undergone substantial preclinical studies in mice and guinea pigs and elicits high titres of cross neutralizing antibodies reactive to genetically diverse strains of HCV and prevent infection in vitro. These results provide proof of concept for the development of an effective prophylactic vaccine able to protect individuals from different strains of circulating HCV. Preclinical studies in mice and guinea pigs have shown that vaccination with the Delta3 elicits high titres of neutralising antibodies to similar and distantly related strains of HCV (Figure below). The antibody response generated was focused on conserved epitopes that block the interaction between E2 and the cellular receptor CD81 (the HCV virus infects human liver cells by attaching to the CD81 receptor on host cells). This was the first time that cross neutralising antibodies against HCV E2 had been generated at such high levels. Immune response induced by conventional recombinant E2 (left) and Delta3 (right). Average IC80 titres from 10 guinea pigs vaccinated with E2 protein and tested for the ability to inhibit G1a or G2a virus entry and the ability to inhibit the interaction between 1a or 2a E2 and cellular receptor CD81.

7 There is only one HCV prophylactic vaccine being developed commercially by European based biotechnology company Okairos. Okairos technology is focused on the development of genetic vaccines based on their novel chimpanzee derived adenovirus vector platform. The focus of their approach is to generate T cell responses, it is widely recognized that the successful element of every marketed infectious disease vaccine is the generation of high levels of neutralizing antibodies. Another difficulty with Okairos s approach is the need for a prime boost regimen which adds cost and complexity of vaccination regimens. Additionally there currently results on completion of Phase I have not shown the capacity to generate responses for different genotypes apart from genotype 1, which will limit its potential in developing markets. Our approach is novel and is potentially addressing the holy grail in the HCV field of being able to generate broad and specific cross neutralizing antibodies to a number of strains. The key risks of our approach is whether we will be able to achieve the same responses in humans as in animals. Safety is unlikey to be an issue given E1E2 vaccine has already been administered into humans and in a number of chimpanzees. 10. Reasons for proposing: (Provide details if any priority setting and/or selection criteria that has underpinned the consideration to take up this area of technology for development.) There are no current vaccines available for HCV. The reason for this is likely to be due to the technical challenges of addressing the multiple genotypes worldwide but also due to the fact that majority of the disease burden exists in the developing world. Researchers at the Burnet have for the first time developed a vaccine candidate that may overcome the challenges of genetic diversity of the virus and as a potential UNIVERSAL vaccine. Vaccines are recognised as the best high value low cost means for preventing infection. This can be seen in the relatively successful roll out of the hepatitis B vaccine worldwide, which has now been recommended for universal roll out by the WHO. Strong support from agencies including the WHO has ensured that vaccine distribution channels are established and improving in the developing world which will positively impact on the future success of our vaccine. Our vaccine could easily be adopted into the current vaccination regimen and opens the possibliy of the production of a combined hepatitis A, B, C vaccine. The availability of a vaccine that prevents HCV will have a large impact on the epidemic and prevent the devastating effects due to the chronicity of the disease- liver cirrhosis and cancer. 11. Who could potentially develop the technology/carry out the research? (Provide known details: individual researcher? Group of researchers? Research/coordination organization including PDPs? Group of research organizations working together? Combination of these; What would be the process of selection of developers?)

8 The next stage of development of the vaccine will require the engagement of a number of contract research organizations for the scale up, manufacture, toxicity testing and finally clinical trials. For the manufacture of the protein it is important we engage groups that have capabilities in the area of mammalian cell culture and protein production. In addition we need to ensure that the vaccine is produced to a standard that is safe to be able to introduce in humans. We are also engaging with potential consultants to advise on the regulatory and clinical aspects of the program. The process of selection will depend on cost and previous experience in vaccine development. 12. Who could potentially manufacture the final product? Multinational company? Local production? Joint venture? How the decision will be made about the producer? We have corresponded with potential vaccine manufacturers who have all indicated that they would like to re-connect once we have first in human data (Pfizer, GSK, Sanofi Pasteur, Astellas). It is at this stage where we expect that we will be able to partner with one of these groups for the further development of the vaccine. There is a precedent for this being possible with Okairos recently announcing a deal with GSK earlier this year for the further development of their vaccine platform- where HCV is their lead product having just completed Phase I clinical trials. 13. What could be the role of WHO, if any, in this demonstration project to bring this venture to fruition? It will be essential to engage with groups like WHO and other AID agencies to ensure that a HCV vaccine will become available in developing countries. As a registered NGO as well as medical research Institute the Burnet has established links with AID agencies which position us to be able to begin the engagement process early as well as having capability of conducting and facilitating in country field trials. Burnet have been successful in adopting this strategy for other interventions for the developing world such as our recent point of care test for measuring CD4 (Visitect CD4). Visitect was licensed to UK diagnostic manufacturer Omega Diagnostics PLC in 2012 and since then Burnet has been involved in managing coordinating the conduction of field trials in India and South Africa through support from AID agencies. With WHO support along with Burnet capabilities the ability to help fast track acceptability in emerging countries by engaging with local clinicians and government is essential to the eventual successful roll out in developing world. 14. Please outline a timeframe and projected milestones for the project covering the first 5 years. This should also highlight the immediate actions that need to be taken? The next immediate stage of development is to move Delta3 into phase I clinical trials. The key milestones will be to manufacture the vaccine at GMP standards, undertake

9 animal safety and toxicology studies and finally the completion of a Phase I clinical trial determining safety and immunogenicity. Q1 14 Q2 14 Q3 14 Q4 14 Q1 15 Q2 15 Q3 15 Q4 15 GMP Manufacture Toxicology Studies Phase I Clinical Trial * On completion of Phase I trials we anticipate that we will collaborate with a vaccine manufacturer to assist us in conducting Phase II clinical trials to determine efficacy (over 3 years). The Burnet Institute has a unique competitive advantage as it has access established cohorts of subjects (1000 individuals) with high incidence rates of HCV infection, together with infectious disease experts and facilities to conduct complex immunological monitoring in accredited facilities. This will allow significant cost savings and the ability to fast-track timelines to determine vaccine efficacy. 15. What is the intellectual property (IP) landscape relative to this project? Is there any IP, e.g. patents that need to be licensed in to be able to develop and market the product in developing countries? How would IP and related intellectual assets, including knowhow, proposed to be managed in this project? There is an extensive patent portfolio covering the HCV Vaccine technology. Primarily our applications are focused on the methodology of removing the variable regions of E2 to form novel vaccine candidates; the modification of the antigen to focus expression of the vaccine candidate to monomeric forms and a composition comprised of a multimeric species of our vaccine candidate. We have experience in managing IP to commercialisation, having licensed technologies that are now on the market and engage patent attorneys at the renowned Davies Collison Cave to assist in patent strategy. International PCT Application No PCT/AU2007/ Recombinant HCV E2 Glycoprotein recently granted in the US and AUS International PCT Application No PCT/AU2011/ Compositions and Methods International PCT Application No PCT/AU2011/ Modified Hepatitis C Virus Proteins. 16.* What would be the strategy to ensure access to the product once it is developed? (Access is an important dimension of these demonstration projects, it is important for the projects to begin with the end in mind, explain how this project would deliver the technologies to the needy patients i.e. price and affordability; modes of supply; storage;

10 prescription; dispensing; and compliance; WHO will develop guiding principles for ensuring access to any products coming out of the demonstration projects) This strategy will be developed with the vaccine manufacturer and will likely rely on differential pricing as adopted with other vaccine and drugs in emerging markets. Another approach will be to potentially set up low cost manufacture in emerging markets, i.e. in China for distribution to other developing countries. The Burnet has recently set up a company in Nanjing China, Nanjing BioPoint Diagnostics, to adopt this strategy for the development of low cost point of care diagnostics. WHO recently announced the prequalification of a Chinese manufactured Japenese Encephalitis vaccine, this will have a huge impact on the uptake of the vaccine in China and emerging countries. We anticipate that a similar strategy can be adopted for our HCV vaccine, particularly given that China has the highest burden of disease currently with approximately 200 million carriers. 17. How could the project be financed paying particular attention to the need to demonstrate new and innovative forms of financing? Also provide an estimated cost of the project. The cost for the completion of Phase I clinical trials is anticipated to be approximately AU$2-4M. We are looking to leverage funding from other sources including local government grants (NHMRC development grant) and international funding agencies (Wellcome trust). There is also the potential to spin this technology out into a company vehicle which will open us to a 45% tax incentive scheme that provides 45cents back in the dollar for eligible R&D activity. In addition we are speaking to NIH to see whether we are able to leverage their capabilities in preclinical development. 18. How could the project be governed and coordinated paying particular attention to the need to demonstrate better way of coordination? Should we be successful in attaining funding it will be necessary to engage a project manager that will be responsible for managing the day to day aspects of project. In addition we will engage consultants with experience in regulatory affairs and clinical trials. The principal investigator will be responsible for making decisions on the technical aspects of the program. The Office for Business development Innovation and Research will be responsible for maintaining the IP around the project in conjunction with our patent attorneys DCC as well as engagement with Industry about potential collaboration. A suggested reporting chart is shown below.

11 Burnet Office for Business Development and innovation Professor David Anderson Head Ms Serina Cucuzza -Industry engagement, coordinate stakeholders Dr Alison Greenway Manage IP GMP Manufacture- provider to be engaged Project Manager to be enaged Principal Investigator- Professor Heidi Drummer Regulatory Advisor-Dr Jim Ackland- Global biosolutions Ltd Toxicology Studies- provider to be engaged Project Manager- to be engaged Principal Investigator - Professor Heidi Drummer Regulatory Advisor-Dr Jim Ackland- Global biosolutions Ltd Clinical Trial provider to be engaged Project Manager to be engaged Principal Investigator- Professor Heidi Drummer Clinical advisor/ data management to be engaged 19. Have any donor agencies/governments already indicated interest in supporting the project? Given that we are at a relatively early stage of development we have not yet engaged with donor agencies about this project. We have had some interest through our links with local CDCs in China who recognise HCV as a major problem in China. We believe that we will be at a stage to engage on a more serious level on successful completion of Phase I trials. It is at this stage we hope we will be able to explore conduct trials in country to ensure that on successful completion of Phase III trials there will be no impediments to the uptake and registration of the vaccine.