Takis

Publication January 11, 2023 Takis and Rottapharm Biotech announce the advance publication of the article “A first-in-human trial on the safety and immunogenicity of COVID-eVax, a cellular response-skewed DNA vaccine against COVID-19” by L. Aurisicchio et al in Molecular Therapy, the leading journal for research in the areas of gene transfer, vector development, stem cell manipulation, gene- and cell-based therapeutics, and vaccine development. COVID-eVax is a DNA vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. It is the first COVID-19 vaccine based on the DNA platform to reach clinical development in Europe and it was developed in synergy with an innovative technology called “electroporation”, which thanks to short electrical stimuli mediates the passage of DNA inside the cells and activates the immune system. Among the important advantages, DNA is cheap, does not need complex formulations and does not need the cold chain. The study is the result of a fruitful collaboration within a 100% Italian network: the two companies developing COVID-eVax (Takis and Rottapharm Biotech); the leader in the electroporation technology (IGEA); important academic institutions and clinical centers (San Gerardo Hospital in Monza with the University of Milan-Bicocca, the National Cancer Institute IRCCS Pascale in Naples and the Clinical Research Center in Verona); the VisMederi laboratories in Siena, worldwide expert in viral and immune assays. COVID-eVax was well tolerated and induced an immune response (binding antibodies and/or T cells) in up to 90% of the volunteers at the highest dose. However, the vaccine did not induce neutralizing antibodies, while particularly relevant was the T cell-mediated immunity, with a robust Th1 response. This T cell-skewed immunological response adds significant information to the DNA vaccine platform and should be assessed in further studies for its protective capacity and potential usefulness also in other therapeutic areas, such as Oncology. Takis Takis is a biotechnology company created by a group of scientists formerly from Merck Research Laboratories (MRL) and it is located in Rome (Italy). The group has more than 15 years of experience and proven expertise in drug discovery in Oncology and is recognized for the design and implementation of a number of innovative technologies, including that of DNA gene therapy. One of Takis’s core assets is its experience with electroporation, a technology that can be used for a variety of clinically useful applications, from vaccine development to somatic gene therapy. Takis’ pipeline includes four cancer vaccine candidates based on this technology. Takis is also actively involved in the generation of humanized monoclonal antibodies for use in oncology and infectious diseases, including COVID-19. For more information on the company, visit www.takisbiotech.it Takis contact Dr. Luigi Aurisicchio (CEO/CSO) aurisicchio@takisbiotech.it Rottapharm Biotech Rottapharm Biotech is a research company dedicated to the discovery and development of innovative drugs. It is located in Monza (Italy) The company expertise in research and development includes medicinal / computational chemistry for small molecules, a proprietary platform for the generation and selection of new monoclonal antibodies and the development of other biological drugs and advanced therapies, the validation of new molecular targets, the pharmacological, pharmacokinetic, toxicological and pharmaceutical characterization of new drug candidates; the design and conduct of innovative clinical trials. The company strategy is to develop its own pipeline independently and then seek partnerships with pharmaceutical companies, as well as investing in alliances on innovative projects of other biotech companies or university spin-offs. Rottapharm Biotech contact Dr. Federica Girolami (Business Development, Scientific Liaison and Drug Safety Director) federica.girolami@rottapharmbiotech.com

November 29, 2021 Monza and Roma (Italy) – The biotech Takis today announced its strategy to address variant B.1.1.529 (Omicron) and SARS-CoV-2 variants of concern. The Omicron variant includes a number of mutations in the Spike protein and other regions already observed in the Delta variant that are believed to increase the transmissibility of the virus, as well as mutations in other variants that are thought to promote escape from the immune system. The combination of these mutations represents a significant potential risk for accelerating the decline of natural and vaccine-induced immunity. COVID-eVax vaccine, developed together with Rottapharm Biotech, generated very promising preclinical data and completed phase 1 in humans, where over 90% of volunteers developed a specific immune response against the Spike protein. The vaccine is based on an innovative system that uses the “electroporation” of DNA, which favors its entry into cells and increases the immune response. “As we seek to defeat the pandemic, it is imperative to be proactive while the virus evolves. In recent months, we have generated almost in real time modifications of COVID-eVax against the Alpha, Beta, Gamma, Delta and many other variants, demonstrating their immunogenicity in animal models. Unlike the previous variants, Omicron has a high number of new mutations and it is difficult to predict whether the current vaccines are still protective: for this reason we are moving as fast as possible to adapt our vaccine also against this variant”, said Luigi Aurisicchio, CEO and scientific director of Takis. “Like messenger RNA, the DNA platform has the characteristic of being extremely flexible, administrable several times and being easily adapted to virus mutations. But compared to RNA, DNA is easily produced in bacteria, is stable at room temperature and has a simple formulation. This allows for shorter production times, less expensive processes, easier transport and storage and potentially a better safety profile” says Fabio Palombo, Director of the Cancer Vaccines Area at Takis. “Due to these characteristics, DNA technology is ideal for developing countries where the percentage of vaccinated is still too low and maintaining the cold chain is the real critical factor. Furthermore, it could be used in many other areas of prevention and treatment of other infectious diseases, such as malaria and tuberculosis” said Emanuele Marra, Director of the Infectious Diseases department at Takis. Antonella Conforti, Director at Evvivax, the veterinary spinoff of Takis, says: “Being a zoonotic virus, SARS-CoV-2 is capable of infecting various animal species. On this basis, we must be ready to protect even the species in closest contact with humans and also prevent any variants from the animal world, as happened in the case of mink last year. ” In addition to vaccines, Takis is also generating therapeutic antibodies for COVID-19. “In the past few months, we have generated over 2,000 antibodies capable of neutralizing SARS-CoV-2 and its variants of concern. We intend to also evaluate them against the Omicron variant as soon as possible and bring them into clinical development” comments Giuseppe Roscilli, Director of the generation and production department of Monoclonal Antibodies, of Takis. “The efforts of the scientific community in the last two years have been extraordinary and the resources made available by some states immense, but also amply rewarded by the results obtained. We all hope that current vaccines and therapies are equally effective against the Omicron variant” declares Lucio Rovati, President and Scientific Director of Rottapharm Biotech. “However, it is essential to have more vaccine technology platforms available such as COVID-eVax, which are readily adaptable to any new variants such as booster of the immune response previously induced by other vaccines, or for use in countries where there is currently no vaccine availability. Given the impact of the pandemic on our lives and on the world economy, Italy can do its part and make its experience available to everybody.” Finally, Dr. Aurisicchio concluded: “Thanks to what we have learned since the beginning of the pandemic, we designed the COVID-eVax vaccine – Omicron version – in a few hours and in a few weeks we will be able to test it in preclinical models. The fact remains that the lack of funding currently prevents us from continuing clinical trials to carry out the development of this Italian vaccine. We hope that Italy with the resources of the PNRR can make strategic investments and encourage Italian research to make the Country more competitive”. Takis Takis is a biotechnology company created by a group of scientists formerly from Merck Research Laboratories (MRL) and it is located in Rome (Italy). The group has more than 15 years of experience and proven expertise in drug discovery in Oncology and is recognized for the design and implementation of a number of innovative technologies, including that of DNA gene therapy. One of Takis’s core assets is its experience with electroporation, a technology that can be used for a variety of clinically useful applications, from vaccine development to somatic gene therapy. Takis’ pipeline includes four cancer vaccine candidates based on this technology. Takis is also actively involved in the generation of humanized monoclonal antibodies for use in oncology and infectious diseases, including COVID-19. For more information on the company, visit www.takisbiotech.it Rottapharm Biotech Rottapharm Biotech is a research company dedicated to the discovery and development of innovative drugs. It is located in Monza (Italy) The company expertise in research and development includes medicinal / computational chemistry for small molecules, a proprietary platform for the generation and selection of new monoclonal antibodies and the development of other biological drugs and advanced therapies, the validation of new molecular targets, the pharmacological, pharmacokinetic, toxicological and pharmaceutical characterization of new drug candidates; the design and conduct of innovative clinical trials. The company strategy is to develop its own pipeline independently and then seek partnerships with pharmaceutical companies, as well as investing in alliances on innovative projects of other biotech companies or university spin-offs. Rottapharm Biotech contacts Federica Girolami (Scientific Liaisons and Business Development Director) federica.girolami@rottapharmbiotech.com

September 7, 2021 Monza (Italy) – Takis and Rottapharm Biotech today announced preliminary results from the phase I clinical study conducted in Italy with COVID-eVax (the first DNA vaccine candidate against COVID-19 to reach the clinical development stage in Europe). COVID-eVax was well tolerated and induced an immune response (humoral and/or cell-mediated response) with all tested doses (0.5 mg, 1 mg and 2 mg, administered as prime-boost regimen). The best response was observed in the group treated at the highest dose, with the induction of an immune response in up to 90% of the volunteers. Particularly relevant was the cell-mediated immune response (i.e. the immune response generated by T lymphocytes, which complements the response induced by antibodies and prevents the replication of the virus in infected human cells). “The preliminary results are favourable,” said Dr. Lucio Rovati, President and Chief Scientific Officer at Rottapharm Biotech. “We believe that the data generated in this study are a validation of the efficiency of the new technology platform of DNA vaccines, which is different from those already available, i.e. mRNA or viral vector vaccines, and potentially useful also in other therapeutic areas, such as oncology.” However, Dr. Rovati added that it will be difficult to carry out the second part of the study (the phase II) as initially planned, due to the current high number of vaccinated people thanks to the vaccination campaigns. “We are thinking about possible alternatives: the immunogenicity profile of the vaccine, with a strong cellular immune response, is such that Covid-eVax should be tested as a third dose when the antibody response from available vaccines decreases, and in order to provide a strong boost to the immune system memory.” “We would like to express our sincere gratitude to the volunteers who participated in the study, for making themselves available to research: a great act of generosity, especially at this time when there are other vaccines available”, underlines Dr. Luigi Aurisicchio, CEO and Scientific Director of Takis, hoping that the Green pass not yet granted to the volunteers will arrive in the next few days. “Special thanks also to the investigators who conducted the study, for the praiseworthy work done in the recent months: Prof. Marina Cazzaniga and Prof. Paolo Bonfanti of the San Gerardo Hospital in Monza together with the University of Milano-Bicocca for having enrolled the largest number of volunteers, Prof. Paolo Ascierto of the Pascale Institute in Naples for believing in this project since its inception, and Dr. Stefano Milleri of the Clinical Research Center in Verona for readily accepting to support the study when an acceleration was necessary; in addition thanks to Prof. Emanuele Montomoli for the exceptional openness and expertise in carrying out the immunological investigations at the VisMederi laboratories.” Dr. Aurisicchio concluded: “For the continuation of the clinical development, the funding that we have not been able to obtain so far would be necessary: ​​after all, even the existing vaccines, despite being developed by large companies, have required important interventions by their own countries, as it is logical for vaccines against a global pandemic.” Takis Takis is a biotechnology company created by a group of scientists formerly from Merck Research Laboratories (MRL) and it is located in Rome (Italy). The group has more than 15 years of experience and proven expertise in drug discovery in Oncology and is recognized for the design and implementation of a number of innovative technologies, including that of DNA gene therapy. One of Takis’s core assets is its experience with electroporation, a technology that can be used for a variety of clinically useful applications, from vaccine development to somatic gene therapy. Takis’ pipeline includes four cancer vaccine candidates based on this technology. Takis is also actively involved in the generation of humanized monoclonal antibodies for use in oncology and infectious diseases, including COVID-19. For more information on the company, visit www.takisbiotech.it Rottapharm Biotech Rottapharm Biotech is a research company dedicated to the discovery and development of innovative drugs. It is located in Monza (Italy) The company expertise in research and development includes medicinal / computational chemistry for small molecules, a proprietary platform for the generation and selection of new monoclonal antibodies and the development of other biological drugs and advanced therapies, the validation of new molecular targets, the pharmacological, pharmacokinetic, toxicological and pharmaceutical characterization of new drug candidates; the design and conduct of innovative clinical trials. The company strategy is to develop its own pipeline independently and then seek partnerships with pharmaceutical companies, as well as investing in alliances on innovative projects of other biotech companies or university spin-offs. Rottapharm Biotech contacts Federica Girolami (Scientific Liaisons and Business Development Director) federica.girolami@rottapharmbiotech.com