This Italian Academic-turned-CEO also Launched 7 Cancer Drugs at GSK

Paolo Paoletti GammaDelta

Paolo Paoletti might have been forced to reconsider his career as a professor in medicine, but academia’s loss was biopharma’s gain!

Before becoming CEO of one of London’s most exciting biotechs, GammaDelta Therapeutics, Paolo Paoletti had a long run through the corporate ranks of pharma. He was coaxed out of academic medicine to join Eli Lilly’s oncology unit, of which he eventually became Vice President.

He then moved to GSK, where he took on the role of Head of Oncology R&D and then President of Oncology. With Paoletti at the helm, Bloomberg remarks that the unit enjoyed “an almost unprecedented level of success” as he brought Arranon/Atriance, Tykerb/Tyverb, Promacta/Revolade, Arzerra, Votrient, Mekinist and Tafinlart to American and European markets.

Paoletti made his first foray into biotech in 2014, when he joined the board of Psioxus Therapeutics; then in 2015, he joined Kesios Therapeutics as CEO where he drove for a rapid closure of the company for lack of reproducibility of the pre-clinical data. After GammaDelta was launched last fall with the support of Abingworth, Paoletti joined the start-up as CEO in March this year. He remains on the Board of Directors of Psioxus Therapeutics, Genmab, Forma Therapeutics and NuCana.

I caught up with him to hear about how he transitioned from academia to biopharma and what makes GammaDelta’s tech so exciting to him and Takeda following their $ 100M deal last month.

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Why did you go from academia to pharma and then from pharma to biotech?

There are two reasons I left academia. One was geography: academic careers in Italy are politically driven, so they’re very strict. It was a traumatic event when I lost what should’ve been my tenured position in an unfair competition…but good things can still happen from a bad thing.

I met the general manager of Eli Lilly in Italy, who was also a physician who had quit an academic career — he offered me the Medical Directorship for the company’s Italian branch. While I was in academia, I had worked with a pharmaceutical company, and I realized that science can be extremely interesting in industry as well as academia. I shared with my wife the doubts about going, leaving my day-to-day relationship with patients…However, I thought it was an interesting challenge to dive straight into understanding the development of a medicine; she agreed and supported me.

So I decided to join Lilly and learned what it means to develop a medicine, execute large clinical trials, understand marketing needs, the manufacturing process, etc. The company asked me to move from Florence, Italy to Indianapolis in USA, which was a significant change, for me as well as for my family.

The edge of a tumour where the levels of different proteins has been probed for using antibodies labelled with fluorophores

It has been a fantastic experience, getting all this training in drug development, which ended with the approval of my first medicine ALIMTA, currently the standard of care in NSCLC and selling for more than $2B annually. After Lilly, I was lucky enough to move to GSK and be directly involved in the approval of several medicines. When you succeed like this, you become addicted to drug development.

The satisfaction of putting a medicine on the market that will be used by hundreds of thousands of people is immense. That’s the second reason I moved to pharma…If I could turn back time, I would make the move earlier. But in the last years, I would say the bureaucracy in big pharma has become unbearable: the decision-making process was slow and repetitive.

Research is increasingly externalized as people are more entrepreneurial to make decisions more quickly. But to make good decisions, you need a team of a few good people. Hence, in the small biotech environment, we sit down, and in two hours we decide what to do without going through many committees that may not have the necessary experience to make the decision. Working in biotech has been a liberation.

I could have worked in venture capital or as an advisor, but as I said, I’m addicted to drug development, and the entire fascinating journey of discovering a target, validating the target, the pre-clinical phase, translating the science from the lab to the clinic and, finally agreeing with regulators the path for the registration of a new medicine. I like to be hands-on with a team to put another medicine on the market to change the way we treat cancer. At this point in my career, I have a lot of experience that I’d like to transmit to younger people and groom them to raise the next generation of drug developers.

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What is it about cancer that intrigues you more than any other disease?

When I was practicing medicine, and dealing with lung cancer patients, there was no hope, frankly. The first chemotherapy was a major improvement, but we only had minor success with it. Therefore, my attention became devoted to what we could do to improve the outcome.

I was part of the transformation from chemotherapy to targeted therapies; the understanding of the genetic and biology of cancer was exploding in an area with high unmet clinical needs. When I started in lung cancer, the median survival time was eight months and only chemotherapy was offered to patients…Today, the median survival is doubled and in addition to chemotherapy, patients may be treated with specific targeted agents based on the presence of specific mutations and more recently with immunotherapy.

The last twenty years have seen a transformation on the modality to treat cancer due to the progress of understanding the biology of cancer in its multifaceted aspects — tumour microenvironment, angiogenesis, signal transduction, epigenetics, cancer metabolism… Recently, a new chapter has been open with immuno-oncology and we are just at the beginning of a new era. I think the next transformation will be related to additional progress on understanding how to use our immune system to fight cancer and on gene therapy, cell therapy and oncolytic viruses.

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What was it about GammaDelta’s technology that convinced you to join the company?

The possibility to transform the treatment of cancer — any kind of cancer. A small number of researchers, including Professor Adrian Hayday, the scientific founder of our company, recently discovered gamma delta T cells, and they have demonstrated many sharp distinctions from conventional alpha beta T cells.

Although the journey to fully understand them is still ongoing, they can play important roles in orchestrating immunological responses to infections, tissue damage and the presence of cancer cells.

Among their distinctive features, they are not limited to recognizing antigens presented by personalised MHC (Major Histocompatibility Complex), and hence it is theoretically possible that any person’s gamma delta T cells could work equally well in another person. These cells represent 5-6% of circulating lymphocytes.

Professor Hayday found a way to isolate these cells from tissues — the skin, in this case – and cultivate them. We can use these cells for autologous cell therapy and explore the possible allogenic use. In addition, we can investigate the biology of these cells in cancer patients and understand possible differences when compared to those derived from tissues of normal subjects. Moreover, we can expand the research in patients with auto-inflammatory disease, where gamma delta T cells appear to have an important role.

Takeda immediately understood the potential of this platform, and since we had the right chemistry and a common interest with them, we completed the agreement to receive €100M in funding together with our seed investors. The money will allow us to develop various parallel lines of research in cancer, and Takeda is also offering us their expertise in GI and inflammatory disease, so we’ll explore that direction as well.

A tumour sample where the levels of different proteins in cell populations have been identified using a fluorescently labelled antibody

A tumour sample where the levels of different proteins in cell populations have been identified using a fluorescently labelled antibody

Do you have any competition in this arena?

There are some companies working on gamma delta T-cells derived from the blood, but we are the only ones working on those supplied from tissues. Of course, there are many companies working with alpha beta T cells in the field of cell therapy. The field is evolving and we’re in the process of learning; but I do believe that cell therapy is becoming a reality, and a lot of progress has been achieved after the first attempts with CAR-T cell therapy. A significant improvement in managing side effects has been achieved, though, as usual in drug development, the appropriate risk to benefit must be assessed.

Pioneering novel treatments is important, however the safety of the patients always come first. In cell therapy, it is extremely important to have an optimized process to isolate and expand cells to reduce the risk for patient.

In just five or six years, immuno-oncology has evolved dramatically: after many years of failures with vaccines, the first check point inhibitors have brought about a transformation in the way cancer is treated…A new chapter of research has been opened.

I’m optimistic thinking of the progress we have achieved overall today, offering different treatment options to patients, based on the specific knowledge of the different aspects of the biology of cancer. This amazing progress will be further enhanced in the coming years by the optimization of immune therapy based on new medicines, their combinations, cell therapy and the use of oncolytic viruses. We will find additional new aspects of biology that will lead to new modalities of treatment and I hope to continue to contribute.


Images via Christoph Burgstedt, CI Photo, toonishwarhead, vanzittoo, Carl Dupont / shutterstock.com

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