The IZB company Atriva Therapeutics is working on minimizing the global threat posed by RNA viruses that cause epidemics and pandemics. The lead candidate Zapnometinib has generated relevant Phase 2 data and will now be tested in a proof-of-concept study in patients hospitalized with severe influenza. A conversation with CEO Christian Pangratz about a potential broad spectrum antiviral agent, current fundraising, and the dangers of a future flu epidemic.

Christian, you have been in biotech and pharmaceutical Industries for 25 years, since the begining of 2023 as CEO of Atriva. What is special for your about this company?
What is special about Atriva is the unique nature of the technology that this company has developed, in combination with the expertise at the personnel and professional level, which I was happy to inhertit from my predecessor. Of special importance are the scientific founders, who continue to support the company with their know-how, and are extremely valuable to Atriva for both internal development and partner and financing discussions.

Atriva develops therapies for severe viral respiratory infections, including influenza or Covid-19. How does your approach work?
We are targeting a signaling pathway in the host cell that is simultaneously responsible for two things. Firstly, it prevents the replicated viral material from exiting the host cell and spreading the infection. At the same time, however, this signaling pathway is also responsible for downregulating the immune response, which tends to massively over react in the case of a severe viral infection, meaning that it remains at a reasonable level.

Through this combination of an indirect antiviral effect and immune modulation, we achieve an optimal therapeutic result, especially in severely ill patients. These patients no longer suffer from a high viral load, since this goes down again as the disease progresses, but they do suffer from severe symptoms due to an excessive immune response. It is therefore important to be able to address both aspects well: the antiviral aspect and the immunomodulatory aspect by arresting excessive immune reactions.

How does this approach differ from other antiviral therapies?
The largest difference is that most current therapies directly target the virus, i.e. are direct antivirus agents. These have the potential disadvantage that viral resistance can arise, because due to the changed structure of a mutated virus the drug can no longer function. We on the other hand are the first to have a project in advanced clinical development that uses a so-called host cell mechanism and is therefore completely independent of virus mutations. We downregulate a signaling pathway that RNA viruses depend on to replicate in the host cell. This means we can treat a whole range of RNA viruses because they all need the same replication and immunomodulatory signaling pathway. I would call it a kind of penicillin of antivirals, only without the potential of selection pressure for developing resistance. The novelty is thus the unrestricted spectrum of application with RNA virus infections. This “pipeline in a molecule” that Atriva has here, is unique.

Atriva’s lead program Zapnometinib was clinically tested in a phase 2a trial in severely ill COVID-19 patients. What can you tell me about the data from this study?
The data from this proof-of-concept study are very promising, even though we were unable to complete the study due to the ongoing pandemic. This is related to the fact that we want to use our therapy to treat those patients for whom there are no, or only very limited effective therapeutic measures ­– i.e. moderately to severely ill patients who are in hospital. In our study of patients who were hospitalized with a Covid-19 infection, we saw a good therapeutic effect with good safety and tolerability. This also led to a shortened length of stay in hospital, which is extremely relevant for costs in the healthcare system. In other words, the patients not only benefited from a strong therapeutic effect, but due to the good efficacy, were also able to leave the hospital earlier. In principle, this is a dream combination.

Due to the ongoing pandemic we could not fully recruit for this study, but had to stop half way through. With the 100 out of 220 patients that were included, of whom about half were on placebo and half on medication, we have a very substantial database from which we can extrapolate and see exactly that the therapy works and is safe. So, as the technical jargon goes, we have collected highly medically relevant data, but it is not statistically significant.

What further steps are you planning for your lead program?
Now that the pandemic is over and Covid-19 is no longer financially viable as an indication, we have decided to go back to our roots. Atriva was founded in 2015 as an influenza company, but when we were ready to go into the clinic, the pandemic had started and we were motivated by financial support from the German government and the European Investment Bank to test our lead program Zapnometinib in Covid-19 – which is what we did. Now, we are going to conduct a phase 2 proof-of-concept study in patients hospitalized with a severe influenza infection. There is currently no approved therapy for these patients because direct antiviral agents are no longer effective in severe cases of the disease. When you talk to doctors in hospitals, they are often desperate because there is not much they can do for these patients other than provide them with oxygen and stabilize them as best as possible in intensive care. This means there is a huge unmet market need.

In Germany, in a good year, a maximum of approximately 50% of the population are vaccinated against influenza, which means that a large part of the population remains completely unprotected. In addition, there is a very high number of breakthrough infections with influenza, especially in older patients, even though the patients are vaccinated. This means that the volume of patients we are dealing with here is very large, especially when it comes to severe influenza. Patients who are hospitalized with a severe influenza infection usually stay there for a long time, which costs the health system a lot of money. In addition, the mortality rate of these patients is 10%. That is a lot – and the next wave of flu is always just around the corner.

Another possible indication for zapnometinib is RSV. Why is this indication so important?
Respiratory syncytial virus (RSV) represents a huge indication; we are talking about dimensions in the range of influenza virus. This virus appears primarily in the weakest patients in the community – either young patients, whose immune system is not yet fully developed, or patients aged over 60, who often have a less effective immune system. Infection rates in RSV are very high and also the associated mortality rates.

How is Atriva financed and what further steps do you plan to finance the next study?
To date, Atriva has been financed by venture capital. The capital comes from different sources, private individuals and institutions. Meneldor is a lead investor, a Dutch fund that pools capital and invests in biotech companies. High-Tech Gründerfonds is also one of our investors. In addition, we received research funding from the German government as part of the development of corona medications and a so-called venture loan from the European Investment Bank. In total, a high double-digit million sum has flowed into the company. We have handled the money very carefully and have already achieved a lot. We have successfully completed the preclinical phase and conducted two phase 1 studies where we were able to determine the safety as well as the pharmacokinetic and pharmacodynamic profile of Zapnometinib and the optimal dose strength for subsequent clinical studies. And we have conducted the phase 2a proof-of-concept study described above in moderately to severely ill COVID-19 patients. The bottom line is that we were very capital efficient and have been able to generate a maximum amount of data with the money we have raised so far.

The next step is a financing round in excess of 15 million Euro, for which we are currently carrying out fundraising activities. With these funds, we want to conclude our previously planed phase 2 proof-of-concept study in patients hospitalized with severe influenza, and confirm the broad spectrum antivirus aspect that  Zapnometinib possesses due its action in the host cell, with clinical data.

You moved into the IZB in the fall of 2022. What was the reason for for this new location and what is special for you at the IZB?
We came to the IZB because we developed from a strongly research-oriented company into a clinical development company. The infrastructure that we find here in the greater Munich area and at the IZB is ideal for a project development company, as Atriva is today. A large part of Atriva’s management team was already based in the greater Munich area, so it made sense in terms of organization and content to stop operating at the Tübingen research site and to move the Frankfurt administrative site with all its responsibilities to the IZB. The IZB is the ideal hub for us. We work together with many other biotech companies here, can share our know-how with other companies and of course benefit from them too. There is a very lively exchange here, which is supported by the IZB through numerous events.

Based on your long years of experience what advice would you give to young founders of biotech start-ups, who are just at the start of their careers, to take with them?
I think the most important aspect is not to fall in love with science, but at the same time to always ask yourself: is there actually a commercial application for the scientific aspects and inventions that you have made and that you want to spin off from academia? The hurdles for financing young companies have become very high, competition is intense. There is no shortage of good ideas and great opportunities, but capital has become very selective. Therefore, it is the combination of commercial attractiveness and exciting science that will lead to success.