Patients have been clamoring for the drug that cured Jimmy Carter’s cancer. The inventors told us their story, from Keytruda to Aduro.
The checkpoint inhibitor, Keytruda, continues to make headlines as one of the top cancer treatments, approved for melanoma, head and neck cancer and lung cancer and under investigation for use in combinations. Keytruda is outperforming its competitor from BMS, Opdivo, though its sales lag behind. The gap could be a consequence of the necessary PD-L1 testing before the prescription of Keytruda; its sales are nevertheless accelerating towards €1B this year and could reach €7.3B in 2025.
While America claims this commercial success, a team of Dutch scientists conceived the PD-L1 inhibitor and were just awarded Inventors of the Year for its success. Winners Hans van Eenennam, John Dulos and their colleague, Andrea van Elsas told us their drug’s history and how they rode the triumph to the C-suite of one of biotech’s unicorns, Aduro. What is Keytruda’s role in today’s efforts to combat cancer?
How did Keytruda begin and where has it taken you?
We started the work in 2003 at a company called Organon, a Dutch pharmaceutical company with a tradition in women’s health and neurological diseases. In those days, immunology thought about how to develop antibody technology into a novel therapeutic agent. Keytruda was one of the avenues that we embarked upon, and it was eventually picked up by Merck & Co.
We were one of four companies that broke through in immuno-oncology 125 years after the discovery that the immune system could be used to fight cancer. In 2011, we founded BioNovion in Oss, the Netherlands to further develop the antibody technology from Organon; we improved and enhanced it to become the B-select platform that is now one of the pillars of Aduro.
Some of the compounds of the B-select platform date back to PD1 and CD27 agonists, for which Merck partnered with us as advisors. Our lead program targets APRIL, a key driver in multiple myeloma and other tumors. Additionally, we are currently developing a PD1 and CTLA4 platform that are also slated for this year or 2018. These programs were all very productive for BioNovion, which led to Aduro’s interest in acquiring the company about 16 months ago.
During that transition, Hans and Andrea kept their roles at BioNovion as COO and CSO, respectively, after the move to Aduro; John transitioned as a Principal Scientist. Could you elaborate on how your programs from BioNovion mesh with Aduro’s?
Aduro saw BioNovion’s programs as complementary to the company’s other platforms. Aduro saw the opportunity to do rational combinations of small and large molecules and whole cells: we believe these are essential to expanding the benefit of immunotherapy to more patients. The most advanced program is based on listeria, a bacteria is known by immunologists as a highly immunogenic vehicle to drive immune responses.
Listeria changes the microenvironment and allows the potential rejection of tumors. In combination with a PD1 drug, this could be a very strong combination as a second-line treatment for mesothelioma: there is strong evidence supporting synergy between two platforms. Aduro has engineered a strain of Live, Attenuated Double-Deleted (LADD) listeria to vaccinate people for particular tumor antigens — the lead candidate, CRS207, targets mesothelin, the antigen of mesothelioma. This year, we hope to start Phase II of this for mesothelioma, which is caused by asbestos and whose patients don’t have a lot of options.
There’s a personalized version of LADD (pLADD) in which neoantigens are sequenced out of a patient’s own tumor and then engineered into a personalized strain of listeria for vaccination. Then there’s the small molecule approach — STING, a first in class program cyclic dinucleotide structure — that is now progressing to Phase I in partnership with Novartis. The core premise is that it will activate inflammatory responses in the injected tumor and induce an immune response to reject distant tumors and lead to durable long-term immunity.
You don’t see small molecules as outdated then?
All of us made our careers in big pharma, and our view of the trends is that you should select an approach based on where biology is bringing you. So if you can only or preferably do it with a small molecule, that should be the driver. We are in a unique position as a biotech with three completely different technologies under one roof, so we can select the right technology for the challenge. All approaches equally feasible, it’s just a matter of finding the right targets.
As some of the founders of immuno-oncology, can you comment on the hype?
It reflects the initial success with immunotherapy, which was achieved mostly with antibodies. By blocking the brakes on the immune response, we can accelerate it and provide long-term clinical benefit. CTLA4 was the first to show the potential for immunotherapy. Nowadays, you’ll see that a lot is being done to educate physicians on activity and safety issues, but we believe that the benefits of our programs outweigh potential side effects. We have observed a very manageable safety profile with listeria to date; it’s too early to say with the other programs. But of course, we will be very mindful of monitoring these as it is always an important consideration.
Everyone has been very excited about the breakthroughs in immunotherapy. We are proud to be part of the group that opened up the field and started the buzz.
Why did you move to the US?
That’s not entirely correct — the B-select platform is solely driven in Oss. A little over a year ago, the founders and shareholders of BioNovion decided to merge with Aduro, located in Berkeley. The STING and LADD programs are driven there, but B-select remains in the Netherlands, where our CD27 antibody originated as well.
Moreover, we have doubled the headcount of our research team in the Netherlands, reflecting a further investment in our people, structure and antibodies, which we are pushing to IND this year. This underscores the commitment that we have to invest in the European franchise, and our collaboration with Merck is great news for European biotech and research in immuno-oncology: it has placed its biotech squarely in the limelight.
Thanks to Hans, John and Andrea for taking the time to tell us about their history! Keep an eye on Aduro as it combines its LADD platform with Keytruda for gastric cancer.
Images via Nagel Photography, Andrei Tudoran, Sebastian Kaulitzki / shutterstock.com ; Aduro