Public Funding for Phion Therapeutics Ltd

mRNA vaccines have the potential to transform healthcare interventions as evidenced by the approval of 2 products in the last 2 years for Covid-19\. The mRNA codes for an antigen for a disease that can either be administered to healthy patients to prevent infective diseases or can treat diseases such as cancer. Vaccines that prevent disease are typically administered via intramuscular or intradermal routes and those that treat disease are delivered intravenously. According to Clinical Trials.gov there are currently 287 ongoing mRNA vaccine clinical trials. However, the key to a successful vaccine is the delivery inside the cell and for this a 'trojan horse' is required. For the approved vaccines, lipid nanoparticles (LNPs) have been used but the cells recognise the LNPs as foreign which provokes an immune response that is unrelated to the mRNA. Additionally, LNPs require cold chain storage, are solvent based, are restricted by the size of mRNA they can deliver with suboptimal endosomal escape. pHion (Belfast SME) have developed a solution for mRNA delivery that is safe, does not further exacerbate the immune system, and readily enters antigen presenting cells with full escape of the mRNA to the cytoplasm of the cell. The innovation centres around the use of a peptide termed RALA that is designed to condense mRNA into nanoparticles (NPs) irrespective of size or number. The NPs have the properties necessary to enter cells, escape endosomes and deliver the cargo to the cytoplasm with high efficiency. pHion has shown that these vaccines are highly efficient in vivo because of this intracellular entry. However, as a platform technology, we need to address some key questions to realise the potential for global manufacture. With clear alignment to the theme of this call, the aim is to develop both a liquid and powdered formulation of the RALA/mRNA vaccine platform that can be given either intravenously for therapeutic vaccines and intramuscularly or intradermally for prophylactic vaccines. Specific goals are to understand i) where the mRNA goes following injection via these routes; ii) how to formulate a stable liquid formulation; iii) how to freeze-dry large enough RALA/mRNA batches that can be scaled up; iv) how to ensure we make the NPs on multiple different types of microfluidics machines; v) how to produce a full package of critical key quality attributes and vi) an analysis of the cost of goods. This will make us and the UK future ready.

Prostate cancer (PCa) accounts for 7.3% (1.4 Million) of all cancers worldwide and ~20% become Castrate Resistant Prostate Cancer (CRPC) which is highly aggressive. In the UK the incidence of PCa accounts for 27.8% of all new cancer cases in males. The 5-year survival rates are only 28.9% when metastases arise in CRPC. The incidence in the UK is set to rise by a further 12% by 2035\. Worldwide, the Globocan study predicts a 60% increase to ~2.3 Million new cases and 740,000 deaths by 2040\. There is a need to create a vaccine that can treat CRPC and reduce the mortality and that is the main focus of this project. To make a vaccine therapeutic a particular type of immunity is required known as a CD8+ response. pHion Therapeutics have created a vaccine that produces a CD8+ response. We get this response because we can deliver the vaccine into the correct cells using a cell penetrating peptide as a delivery vehicle. We are the only company to have this peptide to deliver the vaccine. The vaccine is mRNAs designed to code for tumour associated antigens in CRPC. This project is designed to understand the immune response from our multi antigen vaccine, determine the best dose and administration regime to regress CRPC. The vision is that by the end of this project we are ready to commence large-scale toxicology studies. This is a highly innovative project as the first of its kind peptide/mRNA vaccine that can be used to treat CRPC. The development of the technology in this project could be the catalyst for a new generation of vaccines. In addition, this investment represents a significant commercial opportunity for pHion, further strengthening the UK's position in the gene therapy market with potential for global exploitation.

The Crimean-Congo Haemorrhagic Fever (CCHF) is transmitted to humans via infected ticks and through animal reservoirs that carry the virus. CCHF is also transmitted to humans through close contact and bodily fluids and has a fatality rate of 10-40%. CCHF is restricted to primarily warmer countries so any vaccine needs to withstand extreme temperatures. The CCHF virus has been found in ticks in Africa, Asia, the Middle East, Eastern Europe and South Western Europe, the widest geographic region of any tick virus which is a potential threat to human health. With continued global warming, the migration of ticks coupled with large animal transmission, places CCHF on the high priority for vaccine development. With a rapid onset of symptoms which progress from typical viral infections into haemorrhaging from several tracts to uncontrolled bleeding, there is a need for a vaccine that not only prevents CCHF but also treats those with CCHF. pHion Therapeutics have developed a peptide termed RALA that can deliver messenger RNA (mRNA) to antigen producing cells to produce a prophylactic T-Cell memory and a therapeutic CD8+ vaccine response. The vision for this project is to apply pHion's technology to develop a vaccine using RALA to deliver mRNA encoding 3 CCHF antigens that will not only prevent patients contracting CCHF but will also treat those that are infected with CCHF. pHion is the only company that has this RALA peptide which can condense multiple mRNA antigenic sequences into nanoparticles which are lyophilised into a product that is stable for \>18 months at room temperature. As our mRNA vaccines do not require cold-chain storage, this enables wide-spread distribution. The pre-clinical objectives are designed over 12 months to formulate and assess the CCHF vaccine in challenge models so that the optimal dose and injection regimen is known. This places pHion ready to progress to toxicology, IND filing and into the clinic with the optimal product. There are also manufacturing and scalability advantages of our RALA/mRNA vaccines which include a fully automated cost -effective process that only requires sterile filtration post-production. The development of this platform technology in this project could be the catalyst for a new generation of room-temperature mRNA vaccines. In addition, this investment represents a further validation of pHion's platform technology, further strengthening the UK's position in the vaccine market with potential for global impact.

Epithelial ovarian cancer accounts for 90% of all ovarian cancer cases and of these \>50% are the High Grade Serious Carcinomas (HGSC) which is highly aggressive. With no symptoms, most patients are diagnosed at stage 3 or 4 where the 5-year survival rates are only 15%. Given that worldwide, there are 600,000 women living within 5 years with ovarian cancer and that the Globocan study predicts that there will be a 55% increase in annual incidence to \>370,000 and deaths to 67% by 2035, there is a need to create a vaccine that can treat the disease and reduce the mortality and that is the main focus of this project. To make a vaccine therapeutic a particular type of immunity is required known as a CD8+ response. Phion Therapeutics have created a vaccine that produces a CD8+ response. We get this response because we can deliver the vaccine into the correct cells using a cell penetrating peptide as a delivery vehicle. We are the only company to have this peptide to deliver the vaccine. The vaccine itself is a genetic cargo (mRNA) designed to code for two tumour associated antigens in HGSC. To date, we have produced and published data proving our prototype vaccine can eradicate target infected cells in vivo. This project is designed to understand the immune response from our dual antigen vaccine, determine the best dose and administration regime to regress HGSC in recommended pre-clinical animal models. The vision is to take our technology along the development pipeline so that by the end of the 18 months we are ready to commence large-scale toxicology studies. The data pack achieved from this project is essential for us to raise further funds for these toxicology studies and this is also critical for the success of phion's internal pipeline of projects. This is a highly innovative project as the first of its kind peptide/mRNA vaccine that can be used to treat HGSC. Additionally, key information from this project can be applied to build therapeutic vaccines for other tumours such as pancreatic, triple negative breast and castrate resistant prostate cancers. The development of the technology in this project could be the catalyst for a new generation of vaccines based upon specific cancer antigens. In addition, this investment represents a significant commercial opportunity for pHion, further strengthening the UK's position in the gene therapy market with potential for global exploitation.

As infections with SARS-CoV-2 continue to rise with associated healthcare and economic implications, there is a race on to develop a vaccine to prevent the disease. RNA vaccines are designed to encode the genetic sequences of antigens of a disease, in this instance SARS-CoV-2 and evoke an appropriate immune response. There are several pipeline mRNA vaccines for SARS-CoV-2 that are designed to evoke a prophylactic response but as yet there is no therapeutic vaccine in development. To make a vaccine therapeutic, a particular type of immunity is required known as a CD8+ response. Phion Therapeutics (Belfast SME) have a technology that when added to mRNA, creates a vaccine that produces a CD8+ response. We get this response because we can deliver the vaccine into the correct cells (antigen presenting cells) using a cell penetrating peptide (RALA) as a delivery vehicle which is not recognised as foreign and bypasses the innate response. RALA is designed to cross cellular membranes and fuse with endosomal membranes when the pH lowers which facilitates the release of the mRNA antigens into the cytosol without any associated toxicity. We are the only company to have this peptide to deliver the vaccine. The vaccine itself is a genetic cargo (mRNA) designed to code for the antigens in a particular disease, in this instance multiple immunogenic proteins from SARS-CoV-2\. RALA is adept at condensing all three mRNA into nanoparticles which are lyophilised and uniquely stable at room temperature without losing functionality. Studies are designed to create a RALA/mRNA vaccine, validate baseline characteristics in humanised mice expressing the ACE-2 receptor, followed by determining the response in hamsters and then ferrets through outsourced challenge studies with SARS-CoV-2\. Finally, we will develop a regulatory framework to ensure progression to the clinic. Outputs from this project are designed to provide definitive evidence of a robust prophylactic and therapeutic response using in vivo models. With a comprehensive data package, by the end of this 18 month project we will have the candidate vaccine to progress to toxicology studies. We believe that the RALA/mRNA technology marks the advent of a new generation of therapeutic vaccines that could clear viral infections on a global scale. Most importantly, this platform technology for therapeutic vaccination will be made readily available to other industries and academics across the UK. With validation of automated scalability by the Centre for Process Innovation, pHion is confident of the supply chain.

RNAi therapeutics have the potential to transform healthcare interventions as evidenced by the approval of 2 products in the last 2 years for life threatening diseases. RNAi therapy is designed to transiently reduce a defective gene for therapeutic purposes. It is a rapidly growing market with 109 RNAi based therapeutics in clinical trials (July 2018) \[Wu X. and Turnball A.P. 2018\]. However, there are still issues that surround the RNAi therapeutics which include getting to the appropriate tissue and then ensuring intracellular delivery to the destination site. Recent studies have also indicated that those with underlying health conditions such as diabetes, high-blood pressure or smokers have an increased number of ACE-2 receptors in the lung epithelium \[Leung J.M, 2020\]. Studies have revealed that COVID-19 uses the ACE-2 receptor to enter cells in order to produce more viral particles that can infect more ACE-2 receptor positive cells \[Kuba K. 2005\]. The ACE-2 receptor plays a role for many biological functions but if expression could be lowered for a short period of time it could reduce the infectivity of the virus and help tip the balance towards healthy recovery. RNAi could be used to transiently reduce expression of this ACE-2 receptor but only if there is an appropriate delivery system. pHion (Belfast SME) have developed a solution for RNAi delivery that is safe, does not further exacerbate the immune system, preferentially delivers the therapeutic to the lung and is cost-effective, ultimately enabling widespread adoption of the RNAi therapy. The innovation centres around the use of a peptide termed RALA that is designed to condense RNAi into nanoparticles (NPs) that have the properties necessary to cross cell membranes, escape endosomes delivering the cargo to the cytoplasm with high efficiency. The NPs formed between the RNAi which is designed to reduce ACE-2 expression and the RALA peptide NPs do not require cold chain storage and can be stored for many months without losing functionality. However, we do not as yet have a methodology in place to support the large-scale production of these NPs. Indeed, for the nucleic acid industry, one of the greatest hurdles will be the manufacture of novel therapeutics. Therefore with clear alignment to the specific theme of challenges as a result of COVID-19, this project is designed to accelerate and optimise the scale-up of the RALA/RNAi therapeutic to patient doses in order to be 'future ready'. The proposed 9 month project is designed to develop the optimal conditions for the automated production of functional NPs using microfluidics that can be readily transferred to clinical doses. We will also develop the optimal lyophilisation process to ensure a highly stable functional product. Finally, with regulatory framework in place and proof that we can transfer our process externally to scale up to clinical doses, we will be well positioned to take this therapy to the clinic and to position RALA as the go-to delivery system for RNAi therapeutics to the lung.

RNAi therapeutics have the potential to transform healthcare interventions as evidenced by the approval of 2 products in the last 2 years for life threatening diseases. RNAi therapy is designed to transiently reduce a defective gene for therapeutic purposes. It is a rapidly growing market with 109 RNAi based therapeutics in clinical trials (July 2018) \[Turnbull 2020\]. However, there are still issues that surround the RNAi therapeutics which include getting to the appropriate tissue and then ensuring intracellular delivery to the destination site. Recent studies have also indicated that those with underlying health conditions such as diabetes, high-blood pressure or smokers have an increased number of ACE-2 receptors in the lung epithelium \[Leung 2020\]. Studies have revealed that COVID-19 uses the ACE-2 receptor to enter cells in order to produce more viral particles that can infect more ACE-2 receptor positive cells \[Kuba 2005\]. The ACE-2 receptor plays a role for many biological functions but if expression could be lowered for a short period of time it could reduce the infectivity of the virus and help tip the balance towards healthy recovery. RNAi could be used to transiently reduce expression of this ACE-2 receptor but only if there is an appropriate delivery system. Therefore with clear alignment to the specific theme of healthcare in this COVID-19 grant call, pHion have developed a solution for RNAi delivery that is safe, does not further exacerbate the immune system, preferentially delivers the therapeutic to the lung and is cost-effective, ultimately enabling widespread adoption of the RNAi therapy. The innovation centres around the use of a peptide termed RALA that is designed to condense RNAi into nanoparticles (NPs) that have the properties necessary to cross cell membranes, escape endosomes delivering the cargo to the cytoplasm with high efficiency. The NPs formed between the RNAi which is designed to reduce ACE-2 expression and the RALA peptide do not require cold chain storage can be stored for many months without losing functionality. The proposed 6 month pilot study is designed to demonstrate that the RALA/RNAi NPs can reduce ACE-2 receptor expression in human lung cells and then in vivo for a short period of time. The extension for impact funding builds upon the initial project by interrogating the safety profile of the RALA/RNAi NPs in vivo. This 3 month extension is designed to complete a study that measures both the toxicological and immunological response following single and multiple injections of the RALA/RNAi NPs in vivo. The outputs from this additional study will result in a commercially valuable data pack that demonstrates how safe the RALA technology is. The original project and the further impact study will provide evidence which is critical to secure future investment for the development of this therapeutic towards a Phase I trial. This short-acting RNAi therapy holds potential for any coronavirus outbreak that targets the ACE-2 receptor.

no public description

Advancements in the development of genome editing technologies have significantly improved our ability to make precise changes to the DNA of eukaryotic cells, with the potential to truly transform healthcare interventions from the targeting of faulty genomes of cancer cells through to correcting genetic errors of inherited disorders. Despite this potential, current genome editing techniques such as CRISPR - which have originated as research tools - have to date failed to fully translate into therapeutic application due to unresolved challenges in accuracy (high risk in mis-editing DNA and off target effects), tolerance (potential for an immunological reaction) and ultimately safety and while these problems are acceptable in research or _ex vivo_ applications, they represent critical barriers preventing the full potential for human therapeutic genome editing to be realised.With the potential to truly disrupt the global genome editing market (forecast to reach $8.1 billion by 2025), Mote have developed a solution with significantly higher precision and safety than current genome editing technologies, and better suited to therapeutic use. Having proven the ability to effectively target a defined DNA sequence in cultured human cells and in collaboration with the Belfast based pHion who offer a unique platform drug delivery system suited for therapeutic applications, the proposed 18 month industrial research project will seek to advance the concept to Phase 1 trial based around two initial targets -- EBV and Cystic fibrosis (CF) with R&D activity around alternate targeting approaches, the design of a delivery system for integrase and therapeutic payload and animal modelling.As a fundamental technology the approach offers the potential to be translated into therapeutic agents for a range of genetic diseases, retroviral diseases and cancers, with the promise to replace costly and lengthy drug treatments with improved efficacy and patient outcomes. At a time when significant investment is being made in the genome editing market -- investment that centres largely around the use of CRISPR which has known limitations (it is a great tool but wrong for the job), the development also offers a significant commercial opportunity for both partners also helping strengthen the UK's dominant position in the cell and gene therapy market with global exploitation potentialAwaiting Public Project Summary

Infection with the human papilloma virus (HPV) leads to genital warts, pre-cancerous lesions and cancer. HPV is the most common sexually transmitted disease, yet all current vaccines are designed to prevent the disease and there is no effective treatment for those currently infected. Given that worldwide there are 200 million currently infected with HPV there is a clear need to create a vaccine that can treat the disease and clear the infection and that is the main focus of this project. To make a vaccine therapeutic a particular type of immunity is required known as a CD8+ response. Phion Therapeutics have created a vaccine that produces a CD8+ response. We get this response because we can deliver the vaccine into the correct cells using a cell penetrating peptide as a delivery vehicle. We are the only company to have this peptide to deliver the vaccine. The vaccine itself is a genetic cargo (mRNA) designed to code for the antigens in a particular disease. To date, we have produced and published data proving our prototype vaccine can eradicate target infected cells in vivo. This project is designed to build a vaccine specifically for HPV using genetic mRNA antigens termed E6/E7. We aim to clear HPV infections from small and large animal models of disease. We will also gather key information on the best dose and when to give the vaccine to get the best therapeutic response. The vision is to take our technology along the pipeline so that by the end we are ready to commence large-scale toxicology studies. The data pack achieved from this project is essential for us to raise further funds for these toxicology studies and this is also critical for the success of Phion's internal pipeline of projects. This is a highly innovative project as the first of its kind peptide/mRNA vaccine that can be used to treat HPV. Additionally, key information from this project can be applied to build therapeutic vaccines for viral infections such as Herpes Simplex Virus (HSV) and Human Immunodeficiency Virus (HIV). The development of the technology in this project could be the catalyst for a new generation of vaccines designed to clear viral infections on a global scale.

Tumour Targeted Small Molecule Therapeutic (RALgem)