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Az akadémiai-ipari együttműködések szerepe a gyógyszerfejlesztésben pandémia idején

Drug development collaborations between Academia and Industry in Pandemia

Scientia et Securitas
Author: György Miklós Keserű

Összefoglaló. Egészen az ezredfordulóig a gyógyszeripari kutatás-fejlesztés világszerte hagyományosan nagyvállalati keretek között folyt. Az elmúlt évtizedekben azonban ebben a szegmensben jelentős átrendeződések tapasztalhatók, ugyanis a korai kutatási és fejlesztési projektek sok esetben már az egyetemi-akadémiai, illetve kkv-szektorból indulnak. A szervezeti keretek mellett a fejlesztések szakmai tartalma is változott, a hagyományos kismolekulás gyógyszerek mellett egyre meghatározóbb szerep jut a biológiai terápiáknak, valamint a hatóanyagok fejlesztése mára összekapcsolódott a releváns diagnosztikumok fejlesztésével. A projektek finanszírozásában is fontos változások történtek, egyre jelentősebb szerep jut az állami KFI finanszírozásnak és a (kockázati) tőkebefektetéseknek. A gyógyszeripari K+F szakmai, szervezeti és finanszírozási kereteinek változása jelentősen felértékelte és szélesítette a korábban is meglévő akadémiai-ipari kapcsolatokat. Az együttműködések fontos szerepet játszanak a COVID–19 járványra adott válaszokban is, amit a magyar egyetemek, kutatóintézetek, kis- és középvállalatok, valamint gyógyszeripari nagyvállalatok részvételével indult kutatások igazolnak.

Summary. Until the turn of the millennium, pharmaceutical research and development worldwide had traditionally taken place in pharmaceutical companies. In recent decades, however, significant rearrangements have been witnessed, as early-stage research and development projects often start at the universities or the academic and SME sectors. In addition to the organizational framework, the professional content has also changed: in addition to traditional small molecule drugs, biological therapies are playing an increasingly important role, and the development of active ingredients is now linked to the development of relevant diagnostics. Important changes have also taken place in the financing of projects, with public RDI financing and (venture) capital investments playing an increasing role. Changes in the professional, organizational and funding frameworks for pharmaceutical R&D have significantly enhanced and broadened existing academic-industrial relations. Collaborations also play an important role in the responses to the COVID-19 epidemic, as evidenced by research involving Hungarian universities, research institutes, small and medium-sized enterprises, and large pharmaceutical companies. The first example is a collaboration of an academic research group and a spin-off company formed from this environment. Researchers of the Eötvös University (ELTE) and others working at the Research Centre for Natural Sciences (RCNS) applied phage display technology to discover new protease inhibitors. They established EvolVeritas Ltd, a spin-off company developing high affinity and high specificity inhibitors of the TMPRSS2 protease that is involved in the SARS-CoV-2 viral entry to host cells. In a parallel research program, the same consortium is working on new inhibitors of the MASP2 protease contributing to the coronavirus mediated activation of innate immunity, particularly the complement system. This latter approach would result in the effective control of microthrombosis events associated with serious COVID-19 infections. Both of the approaches are in the early preclinical phase and further investment would be needed to push these projects into clinical testing. The second example is a collaboration between an academic research group and an SME to reposition of azelastine, an approved antihistamine drug that was found to be effective in blocking SARS-CoV-2 mediated pathogenesis. After successful preclinical studies, the partners have now initiated clinical trials to demonstrate the efficacy of azelastine nasal drops in the prevention and treatment of COVID-19 infections. The third example is a collaboration of academic research groups, a SME and a pharmaceutical company. This consortium develops an antibody-like fusion protein therapeutics that can neutralize the SARS-CoV-2 virus. One component of the ACE2-Fc fusion protein is the relevant portion of angiotensin-converting enzyme 2 (ACE2) produced by recombinant technologies, which binds to the spike protein of the pathogen. The virus thus binds to the fusion protein instead of the ACE2 receptors in human cells. Another component is responsible for the long half-life of IgG, the so-called Fc region. The consortium confirmed that the ACE2-Fc fusion protein inhibits SARS-CoV-2 infection in cell culture, and prevents disease in experimental animals. Preclinical development and the preparation of the core documentation is ongoing, which will soon be submitted to the European Medicines Agency (EMA) to initiate clinical trials. The final example is a joint development project that involved a research group, an SME and two pharmaceutical companies. The objective of this program is process development and pharmaceutical formulation of favipiravir, a broad-spectrum antiviral with a treatment potential against COVID-19. The consortium completed the process development of the active pharmaceutical ingredient (API) and developed finished dosage formulations available for clinical testing. Clinical trials are ongoing that aim investigating safety and efficacy of favipiravir in COVID-19 infected patients. All of the examples described here demonstrate the power of collaborations that helped the participants to give diverse and effective responses to the unprecedented pandemic challenge of COVID-19. We believe that these experiences would encourage the members of the academic and industry community to formulate further collaborations to tackle the unmet medical need in our societies.

Open access
Scientia et Securitas
Author: György Miklós Keserű

Összefoglaló. A COVID–19-járvány egyre növekvő számú fertőzött betegének ellátása érdekében rövid időn belül szükség mutatkozott vírusellenes terápiás lehetőségekre. A gyors reagálás szempontját figyelembe véve erre a célra elsősorban más vírusok ellen már kifejlesztett vírusellenes szerek jöhetnek szóba. A magyar betegek ellátásbiztonsága szempontjából különösen fontos a hatóanyagok és gyógyszerkészítmények hazai gyártása. Ezt a cél tűzte ki a favipiravir, egy széles spektrumú antivirális hatóanyag hazai fejlesztése, amely sikeresen befejeződött, a gyógyszerkészítmény klinikai vizsgálata folyamatban van.

Summary. Increasing impact of COVID-19 on the healthcare system prompted the identification of potential antiviral therapies. Due to the immediate demand, known drugs were subjected to repositioning attempts. These drugs include agents inhibiting the viral entry into the host cells, drugs potentially blocking the release of the viral RNA from the endosomes, antivirals inhibiting the replication of the viral RNA and finally compounds that might prevent the assembly of the new virion. Since there is less experience with camostat and nafamostat, the entry inhibitors tested in Japan, and due to the ambiguous data collected with the endosome blocking chloroquine and hydroxyl-chloroquine, we focused on the actual antiviral treatment options for COVID-19 infections. In addition to favipiravir and remdesivir that were used early, at the onset of the pandemic, we discuss novel candidates including molnupiravir, a promising antiviral actually investigated in clinical trials. Considering the needs of Hungarian COVID patients and the security of supply as first priority, we selected favipiravir and developed a convenient process for the industry-scale production of the active pharmaceutical ingredient (API). At the end of this review we summarize the development and clinical investigation of favipiravir, a wide spectrum antiviral drug used for the treatment of mild and moderate COVID patients in Hungary in both ambulant and clinical settings. The Hungarian COVID Task Force set up two consortia, one for the development and the other for the clinical investigations of favipiravir. The objective of the favipiravir development consortium was to develop processes for the production of Favipiravir API and dosage forms. The consortium completed the pilot plant scale industrial production of the API and produced clinical samples for the upcoming trials. The selection and laboratory scale optimization of the synthesis route was performed at the Medicinal Chemistry Research Group of the Research Center for Natural Sciences. The laboratory scale synthesis was scaled up for pilot plant production at EVI plc and Gedeon Richter plc. GMP production was realized at the facilities of Gedeon Richter plc. Finished dosage forms were developed at Meditop Ltd who produced the clinical samples under GMP conditions. The clinical consortium is headed by the Hungarian section of the European Clinical Research Infrastructure Network (ECRIN) and organized two trials. One of these trials investigates favipiravir produced in Hungary while the other trial is performed with favipiravir produced in Japan. Both studies were approved by the Hungarian regulatory agency (OGYÉI) and are ongoing.

Open access