More Pieces to the Puzzle: Endeavor Expands its Pursuit of Precision Medicines Attacking the Genetic Causes of Cancer and Fibrosis

@EndeavorBiomedicines has dramatically evolved since @MigueldelosRios, our Co-Founder & Chief Scientific Officer, and I first talked about the molecule that led us to start the company while blacksmithing on his front lawn more than two years ago. The symbol that Mig stamped into the bottle opener I made that day, a weird little constellation squished spider thing, became the logo for Endeavor.

When we launched 12 months ago, we were focused on a Hedgehog inhibitor program, ENV-101 (taladegib), targeting the underlying cause of idiopathic pulmonary fibrosis (#IPF). It turns out that the PTCH1 driver mutations that ENV-101 is very active against in basal cell carcinoma patients are much more common in other cancer types than previously realized and we’re now developing the molecule as a precision oncology agent as well. Last fall we in-licensed ENV-201, an exciting ULK1/2 inhibitor program targeting LKB1- and RAS-mutated cancers. One year from founding, Endeavor has a Phase 2 study of ENV-101 already enrolling in IPF, ENV-101 initiating Phase 2 clinical trials and ENV-201 set to enter clinical studies in various cancer indications within a year. Just recently we raised $101M in a Series B financing, bringing total funding since inception to $163M to fund these programs and continue our rapid trajectory.

A lot of people approach me with ideas, but what Mig had that lured me is his local network who knew about different molecules that had already reached the clinic and that could potentially make a difference in patient lives. It wasn’t just a biological thesis or a scientific idea, it was a biological idea that also had the right tool to test the hypothesis. The molecule that he was talking about, that we formed Endeavor around, was a Hedgehog inhibitor from @EliLilly and he knew the clinical lead who had worked on it at Lilly. It wasn’t just a matter of seeing the publications, I could talk to the one that oversaw the clinical experience who could say firsthand what this drug does, why it’s different than other Hedgehog inhibitors and why we think it could succeed if you put it into the correct trial. Based on that I had a lot of conviction that this will be an approved drug in multiple indications.

Three Hedgehog inhibitors are currently on the market. Two are approved for basal cell carcinoma, and one for acute myeloid leukemia. We believe that our molecule has the potential to be a #best-in-class molecule in terms of both safety and efficacy. In an epiphany we had last year, we realized all the current diagnostics that are doing solid and liquid biopsies on cancer patients to identify the mutations now include components of the Hedgehog pathway. That wasn’t true when the Hedgehog molecules were first introduced in clinic between 2010 and 2015. Now is the right time to deliver the right drug to the right patients, and we have that drug. It couldn’t have been done three or four years ago.

Cancer is still the No. 2 killer in the nation behind only heart disease, and the unmet need in this area is high. We are all personally touched by people who died due to cancer. Both my mom and one of my brothers passed away from lung cancer, and so this is a disease area I have always wanted to work on and that’s why I was particularly inspired by the evidence to expand our programs into oncology in addition to IPF.

We believe the biggest improvement in patient outcomes occurs when you can attack the cause of the pathology, which is what we’re doing with all our programs. In our #IPF program, we are attacking the cellular cause which is driven by a cell type called myofibroblasts responsible for tissue remodeling that is regulated by the #Hedgehog pathway.?Hedgehog is a developmental pathway sparsely active in adults outside of tissue remodeling and oncogenesis.?Activating mutations in the pathway are well known as the cause for ~25% of medulloblastoma and 75+% of basal cell carcinoma. We realized that the same mutations present in these cancers are present in a little over 2% of all cancers across all cell types or tissue histologies. That’s 30,000-40,000 patients a year just in the United States who have Hedgehog pathway mutations driving their cancer, whom we could potentially help by attacking the #genetic cause of their disease.

Our most recently added program, ENV-201, an ULK1 kinase inhibitor we in-licensed from @The Salk Institute and @Sanford Burnham Prebys, regulates autophagy, which is a cellular recycling program that is often linked to drug resistance in RAS- and LKB1-mutated cancers. If you’re one of the unfortunate few to have mutations in both, there’s essentially nothing that can treat you, so the unmet need is very, very high. These mutations are found in about 15% of all people with #non-small cell lung cancer and a significant number of individuals with other cancers, so it’s a big population of patients that have dire outcomes and we believe this molecule can help.

My interest in going after the genetic driver of disease originated when I was a post doc and one of my personal heroes, Brian Druker, discovered Gleevec for chronic myelogenous leukemia (CML) thereby showing that you could give patients full lives who previously had dire prognoses. Before Gleevec, these patients only had about a year to live, but now these patients are out 30+ years and riding motorcycles at 90, rarely dying of CML anymore. Being able to dramatically change lives like that, identify the driver that’s causing the disease and take a patient who had a poor prognosis and give them a full life – if that’s not what we dream of in this industry, it should be. I know that’s what I dream of. Meeting patients who are alive because your drug worked is the greatest reward.

I talked before about solving a puzzle with Endeavor. By bringing in the right compound that has phenomenal efficacy, great safety, good pharmaceutical properties, you solve a lot of the parts of the puzzle early. Then it becomes a matter of using the other tools in the industry’s tool belt to identify the right patients for the right agent, and this involves multi-parametric problem solving. Genomic sequencing has opened the window for oncology. Right now, genetic diagnostics companies are screening for 500-600 potential mutations, but there are at most a couple dozen different targeted agents they could potentially use. We want to introduce another tool into the tool belt for the #oncologist by going after the underlying cause of the disease.

I couldn't help but think about the irony in the logo we forged with iron and a centuries-old anvil. The ability to take something rigid and shape it into something precise and purposeful – that’s what we do at Endeavor. We are targeting the underlying drivers of disease to develop precision medicines that help patients feel better and live longer. It’s a fulfilling endeavor.