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Publicly Available Published by De Gruyter February 13, 2019

From academic research to founding a company: the story of AiCuris

  • Helga Rübsamen-Schaeff EMAIL logo

Abstract

This contribution describes the experiences with three careers: leading and building an academic research institute, heading a research area in a multinational pharma company and founding and leading a biotech company, which saw its first drug successfully enter the market in its 11th year of existence. The three positions had very different challenges, the common denominator for success was good and innovative science. However, research in a commercial environment, in addition to scientific excellence, also means to demonstrate the likely commercial success of the particular research. The most challenging, but at the same time the most interesting mission was the foundation of a new company, securing the financial means and developing the drugs, which had been discovered, in the clinics.

Introduction

With this contribution, I am sharing my experiences as I was moving from an academic institution to a major, multinational pharmaceutical company and then founded a new company in order to continue research and development of novel drugs. I had started to develop tests for drug discovery, while still in academia. However, the decision to move from an academic institute to a big pharmaceutical company allowed this work to proceed at a much different level, but also required and at the same time allowed a lot of learning. Finally, in the newly founded company, decisions could be made more quickly and there was a seamless transition of the molecules from discovery through late-stage development with all experts on board – a very positive experience and different from big companies, where silos and department structures may hinder the flow of information. On the other hand, the knowledge gained in a large pharmaceutical company about the drug discovery and development processes has certainly been a very good basis for me when I needed to structure and run the new company. Last but not least, in all three environments, scientific work at the highest standards was of utmost importance to lay the ground for the discovery of novel modes of actions, which eventually would lead to drugs that make a real difference for patients. Looking back, I am glad I went that way. The goal to help patients and the convictions that our drug candidates were very innovative, was my compass when I made the difficult decisions moving from academia to “Big Pharma” and from “Big Pharma” to founding and running a new biotech company.

The start

I had studied chemistry and this was an excellent foundation for developing my career. Once I received my PhD, I decided to learn more about biochemistry and joined the Department of Biochemistry at Cornell University NY. While working on signal transduction in nerve membranes in the laboratory of G. P. Hess [1], I heard at a conference about a virus causing malignant tumors. So, I decided to leave Cornell after 2 years and to join the University of Gießen to take up work with this virus, the Rous Sarcoma Virus.

It was known at that time that the virus had a single gene, called “src”, which was necessary and sufficient for transforming normal cells within 16 h into malignant tumor cells. I therefore felt that this virus was an excellent system to study the biochemical events of malignant transformation. In addition, work was published by the group of Raymond Erikson [2] that src was coding for an enzyme, a protein kinase. I confirmed this work and with our mutant strains of Rous Sarcoma Virus at the Gießen Institute of Virology and demonstrated that mutants, which were temperature-sensitive for transformation, had a temperature-sensitive src-kinase [3], implying that the kinase activity was involved in the process of malignant transformation.

AIDS and cancer research and re-building a historical institute

After having moved to the University of Cologne, I started my own research group with further work on the viral src gene but also looking for alterations in the human src gene in human tumors [4]. When receiving an offer to join the Chemotherapeutical Research Institute Georg-Speyer-Haus in Frankfurt as Head of the Department of Immune Therapy, I transferred my group to Frankfurt. A few years later, when I spent a research fellowship at Harvard University (US) with J. Mullins, cloning a human tumor virus HTLV [5], I heard rumors about a strange disease mainly afflicting gay men and i.v. drug users. In 1983, the virus causing this disease, now called HIV, was discovered [6].

It turned out that this virus was a retrovirus like the Rous Sarcoma Virus, with which I was very familiar. Therefore, when the first AIDS cases were treated at the University Clinics in Frankfurt (next door to my institute), I decided to take another look at the virus causing AIDS and our group was the first in Germany with own isolates of HIV (Fig. 1 AIDS Laboratory). However, when we grew the first cultures from different patients, we were staggered: the infected cells looked different and died at different times, depending on the patient from whom the virus had been derived [7], revealing a highly divergent biology of HIV. In line with this observation, the first genetic sequences of our strains showed an over 10% divergence from the strain first discovered by Barre-Sinoussi and her group at the Insitut Pasteur [6] and they were each at least 10% divergent from each other [7].

Fig. 1: Work in the AIDS laboratory at the Georg-Speyer-Haus in Frankfurt, 1986.
Fig. 1:

Work in the AIDS laboratory at the Georg-Speyer-Haus in Frankfurt, 1986.

In addition, we saw that patients developed neurological symptoms. We were able to isolate a number of HIV-1 strains from cerebrospinal fluid [7], [9], demonstrating that the virus also existed in the nervous system. Interestingly, most of these strains grew very well on macrophages and not so well on lymphocytes. So, the macrophage had to be another important viral host cell, but also a reservoir and responsible for inflammatory responses [8], [9], [10].

As could have been expected based on the high variability of HIV-1, a second major family, HIV-2, was discovered and we also found macrophage-tropic viruses in this family [11]. Furthermore, we detected a very divergent HIV-2 isolate [12], which must have split off in the evolutionary tree at much earlier times.

After we had demonstrated that HIV was a highly variable pathogen, I concluded that it would be very difficult to make a vaccine, which would reliably protect people from an infection by HIV or from developing the disease, once infected. I therefore decided that we should develop assays to find drugs against HIV as well as diagnostic tests to detect the infection in patients.

However, in 1986, a major reorganisation happened with the institute, which at the same time meant major management challenges for me: the Georg-Speyer-Haus had been founded in 1906 by Paul-Ehrlich (Fig. 2) and being a Jewish foundation, it had hardly survived the times of the Nazi regime and the 2nd world war. After the war, with not much original research going on, it was used as an institute, which mainly worked for the Paul-Ehrlich-Institute, a state authority licensing sera and vaccines in Germany. Both institutes were housed in the center of Frankfurt next to each other and next to the University Clinics. In order to give the Paul-Ehrlich-Institute better working conditions, the decision was made in the 1970s to erect a new building for the Paul-Ehrlich-Institute, which meant that it would move out of Frankfurt. When the Paul-Ehrlich-Institute had moved to its new building in 1986, the Georg-Speyer-Haus was split from it, so that it could now concentrate on basic research again and would no longer have responsibility for the tasks of the Paul-Ehrlich-Institute.

Fig. 2: The Chemotherapeutical Research Institute Georg-Speyer-Haus in Frankfurt at the begin of the 20th century and Paul-Ehrlich in his laboratory (top left and right). Source: Georg-Speyer-Haus.
Fig. 2:

The Chemotherapeutical Research Institute Georg-Speyer-Haus in Frankfurt at the begin of the 20th century and Paul-Ehrlich in his laboratory (top left and right). Source: Georg-Speyer-Haus.

In 1987, I was appointed as the managing and scientific director of the new, stand-alone Georg-Speyer-Haus. However, the budget and the positions for staff had been transferred to nearly 100% to the Paul-Ehrlich-Institute in order to ensure that it could continue to fulfil its responsibility for licensing vaccines and other biologicals. So, we started the “new” Georg-Speyer-Haus with three staff positions and a very limited budget. While I was happy to have been elected to direct this historical institute, I was, at the same time, very much aware of the enormous task ahead of me.

However, at that time, we already had the first very valuable strains of HIV. This allowed to apply for substantial public research funding and to start cooperations with industry, through which I was able to hire additional staff. Another challenge was the building: the location was excellent for basic research on medical problems: we were located right next to the University Clinics of Frankfurt and after the Paul-Ehrlich-Institute had moved out, we had a lot of space, about 6000 m2. However, the building stemmed from 1906 and while some repair had been done over the years, it was in a very bad condition and urgently needed a general renovation.

After having become independent, we continued our work on oncogenic kinases and discovered a number of human kinase genes [13], [14], [15], [16], [17], [18], [19]. In parallel, a big effort also went into HIV. We isolated strains from all over the world, detected HIV-1 and HIV-2 in India [20], [21], [22], [23], demonstrated that the Indian HIV-1 strains were quite divergent from the HIV-1 subtypes found in the US and Europe, but highly related to a strain from South Africa ([21], [23]; later, these strains were called HIV-1 subtype C). We also established a network with the World Health Organization, WHO, for the isolation and characterization of HIV worldwide (e.g. [24]). We worked on diagnostic tests and licensed one of our strains to a major company, which developed an HIV test for the simultaneous detection of HIV-1 and HIV-2. In parallel, we set up a screen for antiviral compounds using our most aggressive viral strain for a quick read-out.

This work on test systems for drugs against HIV attracted pharma companies: Hoechst and Bayer decided to join forces in AIDS research and they formed a collaboration with us at the Georg-Speyer-Haus as the academic partner. This collaboration resulted in two drug candidates for clinical development against HIV (HBY 097 and HBY 1293, both non-nucleosidic inhibitors of the reverse transcriptase).

From academic research to “Big Pharma”

In 1993, I got a call from Bayer, inquiring whether I was interested to join Bayer as VP and Head of Virological Research. I was hesitant, because by that time, I had achieved a lot for the “new” Georg-Speyer-Haus: it meanwhile had a staff of about 100, we had built a modern P3 facility for the work with HIV, I had re-newed the contract with the city of Frankfurt (which owned the building) so that the city would guarantee the future use of the building for the work of the Georg-Speyer-Haus, I had signed license contracts for our HIV-strains, which gave the institute a significant income for the years to come and I had secured money from the state for a full renovation of the whole premises.

However, finally, I did decide to leave what I had built up in Frankfurt (Fig. 3) as I was intrigued to learn more about drug development and to see the development candidates, which had been created in the collaboration with Hoechst and Bayer, enter testing in humans.

I joined Bayer in 1994 (Fig. 4). The first drug candidate against HIV was given up due to insufficient metabolic properties in spite of good antiviral activity [25], [26], [27], [28], the second was a very stable molecule with interesting phase I results and Bayer decided to license it to GSK. With this molecule (HBY1293 or GW 420867), we were able to demonstrate in monkeys that very early treatment after infection allows the host to mount a strong immune response, which controls viral loads without further therapy and leads to a “long-term nonprogressor” status [29]. This effect was seen when the drug was given in monotherapy only.

Fig. 3: The chemotherapeutical research institute Georg-Speyer Haus around 1993. Source: Georg-Speyer-Haus.
Fig. 3:

The chemotherapeutical research institute Georg-Speyer Haus around 1993. Source: Georg-Speyer-Haus.

In the next years at Bayer, we took up work on Herpes, Hepatitis B and C and on the Human Cytomegalovirus. From 2002 onwards, when it had become clear that drug combinations would be needed for HIV, we resumed work on HIV as well. A review of HIV drug development can be found under [30].

Entering the discovery of novel drugs against hepatitis B virus, Herpes and Cytomegalovirus required some decisions: the first was that we would not use the viral polymerase as a target, which so far had been the target for nearly drugs in the market against these particular viruses. One reason was the potential of interactions of inhibitors of the viral polymerase with human polymerases, which could lead to side-effects and was well-documented for several of the drugs in the market at that time (e.g. [31]). The second decision – coupled with the decision not to work on polymerase as the target was not to work on nucleoside-analogs, because these are prodrugs and require phosphorylation by a viral kinase. This made it very likely that antiviral protection by nucleoside-analogs would be leaky in uninfected cells. A third reason to avoid the viral polymerase as target was the fact that resistance was building up against polymerase-inhibitors and by addressing a different target, our drugs would be resistance-breaking a priori.

Several experts from academic laboratories working with these viruses joined our group and we generated a number of development candidates. These included a very innovative herpes compound [32], [33] and a very innovative compound against Hepatitis B [34], [35]. This compound was the first inhibitor of the viral core protein and in later years this work led to very active research for HBV inhibitors in a number of laboratories addressing this target [36]. In addition to the Herpes compound and the Hepatitis B compound, two compounds against Cytomegalovirus were generated [37], [38], [39], [40].

All of these compounds against Herpes, Hepatitis B and the Cytomegalovirus were very innovative as they addressed novel targets of the viruses with novel chemistry. According to our strategy, they were all non-nucleosidic. In 2001, I was appointed SVP and Head of Infectious Disease Research at Bayer, which meant that I was also responsible for bacteriological research. In the following years, in virology, three additional development candidates were generated against the cytomegalo virus CMC. Furthermore, an immune modulator was discovered with antiviral potential against a number of viruses (review in [41]). In bacteriology, we did research on resistance-breaking drugs against Gram-positive bacteria and generated several projects stemming from natural products – again, with innovative chemistry and modes of action [42], [43], [44], [45].

Late in 2004, I was informed that Bayer had decided to increase investment in oncology and to stop the work on infectious diseases. I was told that the company was willing to transfer the projects from our portfolio to a new company, if I wanted to found a new company and if I was able to find the investors for it. By that time, we had generated a pipeline of 13 highly innovative projects, mostly development candidates, from bacteriology and virology, but founding a company had not been on my mind before....

From “Big Pharma” to founding a new company

When I decided to take up this great challenge and to found a new company, it was due to my firm conviction that our projects were very innovative, scientifically sound and worth to be developed further. Also, I was convinced that work on combating infectious diseases was needed in a globalized world, now and in the future and that the know how in infectious diseases, which Bayer was willing to transfer to the new company, was to be saved.

However, considering the failure rates in clinical development in pharma, it was clear to me that I should have all 13 projects transferred to the new company. The statistics about the attrition rates in pharmaceutical development mean that 10 projects need to enter phase I testing in humans, for one of them to gain market approval. Therefore, I needed to find the money to develop all of the projects until phase I. Developing this very young pipeline to a stage, where the promising projects for further development could be distinguished, consequently, meant that we needed to invest double digit million Euros per year over at least 5 years.

But how to find this large amount of money? No public grants would match that requirement. It was equally clear that venture capital investments generally would be too low and run for too short terms to be of any help. We needed investors with a long-term perspective, who were able and willing to invest a large amount of money over a long period of time. One possibility would be other companies interested in entering the field of infectious diseases and we had discussions with such companies. Another possibility were large funds, aiming at long-term investments. Finally, we were able to attract the interest of the two twin brothers, the Drs. Strüngmann, who had owned a major generics company, Hexal, and had just sold it to Novartis. By financing our new company after having produced generic drugs, they now became pharma innovators together with us!

After the financing contract was signed, a huge amount of decisions and work was to be dealt with. The new company was founded March 1st 2006, we decided to name it AiCuris for “Anti-Infective Cures” – our mission (Fig. 5). The team which had left Bayer with me and which before had never been involved in clinical development had to learn a lot, including myself, about pharmakokinetics, toxicology, formulation of drugs, synthesis under GMP conditions, writing the respective SOPs, interaction with the authorities, etc. At the same time, we had to remodel the building, which we rented from Bayer, and to build up and organize the new company. But there was also a strong cultural change: everyone had to take much more responsibility than when at Bayer, but everyone also had the feeling that he or she could contribute much more than before to reach our goal of making the company become a reality and moving our precious drug candidates forward.

Fig. 4: The new home for my research: the pharma research center of Bayer in Wuppertal. Source: Bayer AG.
Fig. 4:

The new home for my research: the pharma research center of Bayer in Wuppertal. Source: Bayer AG.

I hired experts in clinical development from other companies to expand our know how, the first GMP batches of drugs were synthesized and at the end of 2006, we had first positive results from a phase I study with our drug Letermovir (AIC246) against the Human Cytomegalovirus. Other drugs from our pipeline were in preclinical testing, but a very innovative antibiotic derived from a natural product, unfortunately, had failed in preclinical testing by that time.

In the following years, we were successful in developing the herpes drug Pritelivir from our pipeline until and including phase II [46] and in a side by side comparison it beat the “gold standard” ValtrexR [47]. Letermovir also had a very successful development and first showed proof of concept in phase II in a small group of patients, who had received a kidney transplant – our first proof of activity in humans [48]. We then were ready to conduct a dose-finding study in our target population with Letermovir, i.e. in patients, who had received a stem cell transplantation and were carriers of the Cytomegalovirus, CMV. In parallel, we were asked to supply the drug for a patient who had been lung transplanted, had reactivated CMV, and had become resistant to all CMV-drugs then in the market. The virus had already caused disease in several organs. Treating this patient under an emergency IND demonstrated a high efficacy of our terminase inhibitor Letermovir against his resistant virus, leading to healing of all afflicted organs [49].

In addition, we received excellent data from phase II testing in the stem cell recipients, which showed a dose-dependent inhibition of CMV-reactivation in these patients [50]. Based on this, a number of major pharma companies became interested in the drug and asked for a license for Letermovir. At the same time, the authorities had signaled to us that if we did one phase III study, which would confirm the results of phase II, we might get market approval for Letermovir. With this scenario, it was thinkable to continue development on our own, provided our investors would fund the phase III work as well.

The decision finally was made to license the drug to MSD, as we felt a very good scientific fit between the two companies combined with attractive contract conditions involving a downpayment upon signature of € 110 million, milestone payments of up to € 332.5 million and significant worldwide royalties on sales. MSD then conducted the phase III study and was able to confirm our results from phase II and to also demonstrate that letermovir-treated patients had a survival benefit [51]. Letermovir was licensed in the US in November 2017 (Fig. 6) and in the EU in January 2018 – a great success for a young company!

Fig. 5: AiCuris anti-infective cures GmbH in Wuppertal, Germany. Source: AiCuris Anti-Infective Cures GmbH.
Fig. 5:

AiCuris anti-infective cures GmbH in Wuppertal, Germany. Source: AiCuris Anti-Infective Cures GmbH.

It should be noted that parallel to the development of Letermovir, there were four approaches from other companies trying to protect stem cell recipients after transplantation from CMV. All of these attempts failed (e.g. [52]), underscoring the scientific difficulty of protecting patients, who carry this virus, but do not have any immune protection.

In the meantime, Letermovir (with the trade name Prevymis™) has entered and is entering many additional markets worldwide. I am convinced that it will also be a very valuable drug for many other patients, who need protection from CMV, such as HIV/AIDS patients, patients in intensive care, certain cancer patients or newborns.

In summary, our research strategy at Bayer payed off: we wanted to address novel targets and avoid the problems of many nucleosidic antiviral drugs: (a) the need to become activated by a viral enzyme and (b) the potential interaction with human polymerases, which for some of them causes significant sides effects. And we wanted to generate resistance-breaking drugs by addressing different targets to begin with.

Looking back, all three stages of my professional life were exciting and very worth while. Bringing the Georg-Speyer-Haus back to life, while at the same time working at the forefront of AIDS research and cancer research, establishing a broad virological research at Bayer and adding new approaches in bacteriology to it, was challenging, but also allowed a lot of creativity.

Founding AiCuris, building the company and developing its projects unto late stage clinical testing, was the greatest challenge, but also very exciting and very rewarding. As AiCuris has now reached the market with Letermovir it is in a position, where it can grow, continue development of the additional assets and establish itself as a new, highly innovative pharma company. It is a very rare event that a young biopharma company reaches the market and this makes me as the founder and long-term CEO very proud. At the same time, seeing that the research strategy and the many years of work in the laboratory now bear fruit and have led to unique new treatment options improving the survival of very sick patients, is a high point in my scientific career. The successful generation of Letermovir with its unique properties was recently awarded the German Future Prize for Technology and Innovation by the President of State, Frank Walter Steinmeier (Fig. 7). The path towards this success obviously was not always easy, but I am glad that I went that way. What has helped me to continue in difficult times was the firm wish that our research should make a real difference for patients in coping with their disease.

Fig. 6: H. Ruebsamen-Schaeff with the plaque commemorating the market authorisation of Letermovir, marketed as Prevymis™. Source: Picture People.
Fig. 6:

H. Ruebsamen-Schaeff with the plaque commemorating the market authorisation of Letermovir, marketed as Prevymis™. Source: Picture People.

Fig. 7: H. Ruebsamen-Schaeff, member of the National Academy of Sciences and Honorary Member of the German Chemical Society is awarded the German Future Prize for Technology and Innovation by the President of State, Frank Walter Steinmeier together with Dr. Holger Zimmermann November 28th, 2018. Source: Dt Zukunftspreis.
Fig. 7:

H. Ruebsamen-Schaeff, member of the National Academy of Sciences and Honorary Member of the German Chemical Society is awarded the German Future Prize for Technology and Innovation by the President of State, Frank Walter Steinmeier together with Dr. Holger Zimmermann November 28th, 2018. Source: Dt Zukunftspreis.

Reflections and recommendations on founding and establishing a company

When asked what the success factors for founding and establishing AiCuris were, I would say: most important was to first create a well-defined vision of the mission of the company (e.g. why is it needed? Why should it be founded? What will it do differently?) and then, it was important to gain a clear understanding, how we would achieve our goals, e.g. a clear understanding of the financial requirements, the timelines and milestones and the time and money needed to reach each of the milestones. The third factor of success was the begin with a small but dedicated team of scientists and technicians allowing to transfer all biological know how into the new unit and to carry the work further. Adding additional experts to the team – as needed – from other companies (including legal, financial, drug development, quality assurance, chemistry and other expertises) was very important as well, while trying to leave the company as lean as possible. This means that rather than establishing everything in house, we collaborated with many external service providers and partners, but these were steered by us and by those additional highly qualified experts in house. This rather “virtual structure”, means that a very good system of contracts and a very systematic follow up of activities needs to be built up, but it keeps the burn rate low and flexibility high. This is very important for a company, which is at an early stage and dependent on investor money. Last but not least, I would like to reiterate that very good and innovative science is needed, when starting pharma projects, because they have a very long way to go until reaching the market.

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Article note

A special collection of invited papers by recipients of the IUPAC Distinguished Women in Chemistry and Chemical Engineering Awards.


Published Online: 2019-02-13
Published in Print: 2019-04-24

©2019 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/

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