N4 Pharma Plc (LON:N4P), the specialist pharmaceutical company developing Nuvec®, a novel delivery system for cancer treatments and vaccines, has announced its audited results for the year ended 31 December 2022.
• Nuvec® as a delivery system has consistently been shown to deliver DNA and RNA payloads into the cell where the compound is able to escape the endosome and be released into the cell
• Strategic review highlighted that Nuvec® was best suited to applications where intra cellular delivery by itself was a key element of product development
• The Company has designed an experimental plan to develop, formulate and deliver a double loaded Nuvec with siRNA against EGFR and BCL-2 and test this in a xenograft cancer model
• The Company to start business development outreach of its siRNA data working alongside a US company, Partner International, who have extensive biotech business development experience
• The Company has filed its own patent on using Nuvec® to enhance the performance of viral vectors which is now entering the national phases of patent execution
• Operating loss for the year was reduced to £1,029,261 (2021: £1,843,290)
• Cash balance at period end of approximately £1.9m (2021: £1.8m)
Nigel Theobald, Chief Executive Officer of the Company, commented:
“It is important that the Company is able to react to the fast changing nature of the vaccines and oncology treamtment markets and, by focusing our internal development work on the significant opportunity for siRNA delivery, this will allow us to be best placed to do this.
“The work we have done with monodisperse formulations of Nuvec® show how well suited it is to the intracellular delivery of siRNA and our longer term R&D on oral delivery and the use of Nuvec® to enhance viral vector delivery shows the wide potential of its application in this space.“
N4 Pharma Plc, is the holding company and Parent Company for N4 Pharma UK Limited, and together form the Group.
N4 UK is a specialist pharmaceutical company engaged in the development of silica nanoparticle delivery systems to improve the cellular delivery of cancer treatments and vaccines.
Review of operations for the financial year ended 31 December 2022
During the year to 31 December 2022 no revenue was generated by the Group (31 December 2021: £nil).
The operating loss for the year was reduced to £1,029,261 (31 December 2021: £1,843,290 loss). Expenditure was broadly in line with budget and decreased as less work was undertaken on in vivo vaccine and oncology studies in 2022 compared to 2021.
Cash at the year-end stood at £1,919,529 (31 December 2021: £1,784,024) having raised £1,054,000 towards the end of 2022. Our cash position remains good and leaves us well positioned to complete our current work streams for the year ahead.
Key Operational Events and Opportunities
2022 saw further significant changes in the field of vaccine and oncology product. The success of the mRNA lipid nanoparticle covid vaccines from Pfizer and Moderna firmly established RNA products in this field however their success also led others such as Astra Zeneca to reassess their approach in this area. Having launched covid vaccines the key players in this area turned their attention to launching new vaccines addressing other illnesses such as influenza using their existing lipid delivery systems, meaning opportunities for novel delivery systems other than lipid nanoparticles in the vaccine space would be in less demand. However there remains significant opportunities for novel delivery system in earlier stage development using RNA in oncology, especially siRNA products of which there are over 200 in clinical development and delivery is often cited as a major issue in product development in this field.
The Company therefore undertook a strategic review of all the findings from the Nuvec® proof of concept in vivo and in vitro work including its vaccine work, the successful intravenous tumour reduction study and a series of in vitro experiments looking at the ability to bind Nuvec® with multiple siRNA compounds for gene silencing to determine the most appropriate commercial area where it is most likely to be able to secure a commercial licensing deal.
Strategic review of Nuvec® as a delivery system
Nuvec® has consistently been shown to deliver DNA and RNA payloads into the cell where the compound is able to escape the endosome and be released into the cell. Its unique structure allows strong binding and protection of RNA/DNA leading to good stability for the formulated product. It is also able to be formulated into a monodisperse formulation making it suitable for intravenous injection as well as sub-cutaneous or intra muscular injection. It is also much cheaper to make and formulate than lipid nanoparticles.
The field of vaccine development is complex and delivery of RNA into the cell is just the first step on the medical pathway of a successful product. Once inside the cell, for a successful vaccine sufficient RNA needs to produce the right amount of protein which in turn needs to attract the right amount and type of antibodies to teach the body to ultimately fight an invading virus. The review clearly highlighted that as well as being able to deliver RNA/DNA into a cell Nuvec® would require optimisation with a partner’s payload in order to achieve these downstream effects and the studies to do this are extremely expensive.
The review highlighted that Nuvec® was best suited to applications where intra cellular delivery by itself was a key element of product development. The tumour suppression work also showed that monodisperse Nuvec® could be delivered intravenously and be safe and effective. The Company therefore decided to focus its internal development work on loading and delivering siRNA intra cellularly for applications in the field of oncology treatments and gene therapy since once inside the cell, the payload needs to silence a gene inside the cell and a successful product is not dependent on multiple downstream pathways.
The Company’s work also highlighted that Nuvec® can load multiple siRNA onto each particle and deliver each into the cell allowing a product to work intra cellularly on different pathways within the same cell. This is a novel and highly differentiated aspect of Nuvec® as a delivery system.
In September 2022, the Company announced a research programme looking to extend its work with siRNA and load two clinically relevant siRNAs onto Nuvec® with the goal to test in vivo the ability for tumour regression.
After several discussions with opinion leaders in oncology, lung cancer was identified as the most appropriate target cancer type for this test. Most of these cancers are characterised by overexpressing a receptor called the Epidermal growth factor receptor (EGFR), which prevents apoptosis. Apoptosis is a type of cell death which the body uses to get rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells which are then prevented from naturally dying and this can lead to uncontrolled growth. Silencing this mutated receptor would lead to re-establishing apoptosis in the tumor cells and could potentially restore sensitivity to other treatments.
This work has been researched extensively however often the body develops a resistance to such single siRNA treatments. To strengthen the effect, the Company identified another target protein BCL-2, which it would simultaneously load onto the same Nuvec® particle alongside EGFR to give a second line of defence against the cancer cells growing.
The Company chose BCL-2 which belongs to the family of proteins that regulate apoptosis. This mechanism is controlled by the ratio between the anti-apoptotic BCL-2 and the pro-apoptotic protein BH3-only. When silencing BCL-2, BH3-only proteins will not be blocked and are therefore more likely to induce apoptosis.
By targeting both EGFR and BCL-2 a double loaded Nuvec® can combat both the mechanism that causes uncontrolled cell growth and the mechanism that prevents cell death which it believes will give a greater chance to push the tumor cell into apoptosis and lead to tumour regression.
The Company has designed an experimental plan to develop, formulate and deliver a double loaded Nuvec with siRNA against EGFR and BCL-2 and test this in a xenograft cancer model. This work will provide relevant clinical proof of concept data which the Company believes will greatly showcase Nuvec®’s potential in this space and lead to a better chance of establishing a commercial license deal with one of the many companies operating in this space. The programme of work is as follows:
Step 1: Loading, characterisation and formulation of Nuvec with EGFR and BCL-2 siRNA.
Step 2: In vitro testing of delivery and ratios of the siRNAs
Step 3: Biodistribution and preliminary toxicology in both tumour and non-tumour models
Step 4: In vivo efficacy model of tumour regression
Globally, there is a shortage and delays in acquiring research grade materials and the Company suffered delays towards the end of 2022 in getting the materials to start the work. These materials have now arrived and the work is underway. Full results are expected by the end of Q2 2023.
Material Transfer Agreements (“MTAs”)
MTAs are seen by the Company as a good means of establishing relationships with potential partners but are totally dependent on the speed and ability of the partner to prioritise the research and subject to strict confidentiality which means the Company is limited in any meaningful information it can divulge. The Company still has one active MTA and the pursuit of MTAs remains a key strategy as a means to see how Nuvec® may work with a potential partner’s proprietary technology. However, the field of siRNA gives the Company greater ability to undertake its own clinically relevant work to establish how Nuvec® behaves in this space, hence its decision to operate both elements together so it is not overly exposed to one particular MTA partner.
The Company has the exclusive worldwide rights for therapeutic uses in humans and animals for technology developed by The University of Queensland (“UQ”). 2022 now sees this technology having patents granted in Europe, Australia, Japan, China and the US.
The Company has also filed its own patent on using Nuvec® to enhance the performance of viral vectors which is now entering the national phases of patent execution.
The Company is well funded to deliver its siRNA programme and will now start business development outreach of its siRNA data working alongside a US company, Partner International, who have extensive biotech business development experience.
Alongside the siRNA programme the Company, in conjunction with UQ, is continuing to research the application of Nuvec® as an oral delivery system. Recent work has shown how Nuvec® can be loaded with DNA and encapsulated by a pH-controlled polymer to deliver the DNA and transfect cells locally in the intestine. The work will continue to test the ability to produce a localised intestinal effect in vivo which could have applications either in the vaccine field or more likely as a locally delivered intestinal medicine.
The Company also announced in 2022 work to support its patent for viral vector improvements whereby loading a lentivirus or adenovirus onto Nuvec® could reduce the amount of vector required to deliver an enhance effect. Importantly, Adeno-Associated Virus (AAV) is seen as a key improvement on other viral vectors and products have been developed to treat various conditions, including hepatitis. However, due to the nature of the AAV, these products are very expensive and can have toxicity issues. The Company intends to continue working in collaboration with Brunel University to investigate improving Associated-Adeno Virus (AAV) as AAVs are at the forefront of approved products in this area.
On behalf of the Board, I would like to thank all of our shareholders for their continued patient support and look forward to providing further updates on our progress.
By order of the Board
8 March 2023