Verastem, Inc. Study result

All right. Good morning, everyone. For those that don't know me, I am Julissa Viana, the Senior Vice President of Corporate Communications, Investor Relations, and Patient Advocacy. We are really excited to have you here today, and thank you for those that are listening via the live stream. Please note that this event is being recorded and will be available on our website afterwards. This morning, we are very excited to discuss VS-7375, our best-in-class, highly selective oral KRAS G12D on/off inhibitor, which is being evaluated in multiple clinical trials. Today, we will share new clinical data from our TARGET-D 101 trial, including, for the first time, U.S. efficacy data and updated safety and tolerability results in KRAS G12D mutated pancreatic, colorectal, and lung cancers. This morning, we issued a very long press release detailing these results, along with a slide presentation that we will reference today. Both are available on our website.

Go to the next slide. Let's see. All right. I will not be reading this slide, but I do need to point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. We encourage you to consult the risk factors discussed in our SEC filings for additional details. Joining me today to present the data are Dan Paterson, President and CEO, Dr. Michael G. Kauffman, President of Development, Dr. Ting Wu, Vice President of Clinical Development, and Dr. Manuel Hidalgo, who is the Director of Gastrointestinal Cancer at NYU Langone Health and Professor of Medicine at NYU Grossman School of Medicine. As many as you know, he is a leading medical oncologist, and he is currently also an investigator on ongoing trials.

Along with our presenters, Dr. Jonathan Pachter, our CSO, will also join us for Q&A. I will now turn the presentation over to Dan.

Well, good morning and welcome. We are very excited. This is, in many ways, the beginning of really a new journey for us now as we accelerate the development here and really the end of what has been a four-year journey where we set out and made a conscious decision working with GenFleet to have a G12D selective agent. Everyone has been talking about pan-RAS versus G12D, and I think within the last month or so, I think folks have come to realize Revolution Medicines did an amazing thing as a drug that is a leap forward for patients. But when you look at things like quality of life and tolerability, having a selective molecule matters. In order to have a selective molecule, there were a couple of key things that we really needed. We wanted it to be potent, very selective, on/off inhibition.

One of the more important things, if we go back a year or so ago and you looked at as this area was evolving, I would say Mirati BMS is probably a good example where these molecules didn't have good oral bioavailability, that's really the starting point. We have a molecule here that we can give orally. We get dose-proportional exposure. One of the things that's amazing, hopefully, you will take this away from looking at the data, is the consistency around what we saw in vivo, what they reported out of China, and now what we are seeing in the U.S. I think what differentiates this molecule from a lot of others in the space is you give more drug, you get higher blood levels, and you get better efficacy.

We will walk through that, I would say PDAC is probably our best example of that so far today, where you can clearly see that, and we expect the same thing with lung. We will be showing data on PDAC, CRC, and non-small cell lung cancer. I think we have set a new benchmark in PDAC, efficacious and safe, and we will go through that. CRC is a little earlier, but we have shown we can combine with EGFR inhibitors and are seeing early anti-tumor activity. The data set that you will see today in lung is at the 600 milligram dose. Our go-forward dose is 900 milligrams, and we expect to see the same dose response as that data comes out. I think lastly, the favorable safety profile. What you are seeing now, it's largely grade 1 and 2 gastric AEs, and it's the pill in the gut.

There is no systemic cause here, down the road, we will do things like different formulations and stuff to even make that better. Even where we are today, we are able to deliver 97% dose intensity at the 900 milligram level, and it's very combinable with the standard of care agents that will be critical to combine with in frontline. With that, I will turn it over to Michael to take us through the clinical data. Again, the picture that's emerging is what we had dreamed of four years ago.

Michael Thanks, Dan. As some of you know, I was sitting on the sidelines on the board for over a decade with this company, watching it go through various excellent lives.

Back in December, as the data started to emerge with this molecule, I just kept running onto the field and getting penalties. Finally, I just said I better join the team, and Dan let me. It has been an absolute pleasure working with him. We are going to continue to work together, and I am looking forward to working with Michael Bailey going forward. Let's switch gears now to talk about this.

I have to say, in a career that I left practicing medicine in 1995, I have never been involved in a program that could squash solid tumors this way, with the kinds of side effects that we are seeing and keeping in mind, this is a once-a-day oral pill. We dreamed of this. If you had told me when I graduated med school or left my residency, that we would ever be able to treat pancreatic cancer with a single agent, I would have laughed at you, and so would every one of my colleagues. It is absolutely thrilling, honestly, to be up here and present these data. We all know that the current therapies are very limited. Chemotherapy, we say FOLFIRINOX, it is brutal. It is like being run over by a truck.

Even Gem/Nab, which is chemo light, is not pleasant at all, and everybody gets neuropathy within months. We will talk about that towards the end, that chemotherapy is okay at the beginning. It is very unpleasant, to put it nicely. But nobody stays on the therapy because they are really toxic, and that means that nobody's tumor remains under good disease control. We have a different molecule here that so far can be given indefinitely. So the durability of our molecule is what is emerging, and we will be able to update you in the future. The other issue, as we talked about, is the toxicity burdens of all of these therapies are very high and very difficult. Even a pan-RAS inhibitor, which is a breakthrough for sure, and wonderful, doubling lifespan and second-line disease, even that is difficult. People have rashes. These are very tough-to-treat rashes.

People do get rashes from other drugs in oncology and other diseases, but the cetuximab, panitumumab rashes are generally much easier to treat and take care of than some of the pan-RAS rashes. Mucositis and stomatitis are big deals with chemotherapy or a pan-RAS inhibitor because you want people to be able to eat, especially with pancreatic and colorectal cancers. The other G12D inhibitors, as Dan alluded to, just have limited absorption, and they have limited ability to get into the tumor at levels that kill the tumor. The first thing you learn in Cancer 101 drug development is you have got to achieve a dose that hits the cancer cell. Not the bloodstream, the cancer cell. You will see evidence today that we are the best in class in that area. Okay. The goal in the program, the sort of holy grail here is, of course, to cure the disease.

The best chance for at least prolonged disease control with a good life for patients is to get into the frontline setting as quickly as possible. I am happy to let you know, and you have seen from the press release, that our FDA has approved our phase III trial design for frontline pancreatic cancer. It is a beautiful design, has some new elements in it that I think FDA has recognized the unique qualities of this drug. We will talk about that. That trial should open by the end of the year. But while we have that frontline potential, I just want to focus everybody now where we are. Today, we are talking to you about single-agent and combination potential across three of the worst G12D tumors we have.

Remember that G12D is a bad prognostic factor for all of these. We are treating the worst of the worst. We already have three potential accelerated approval trials ongoing in each of these diseases that are accruing today. We expect to accrue for pancreatic and colorectal to finish by year-end, and lung cancer in the first half of next year. Our intention is to establish a beachhead in the second line. But as we say, frontline is where we all want to get to because that will address the most patients at the time when their disease is most susceptible to impact. The pancreas study, as you heard, will start by the end of this year, and we expect the lung and the colorectal phase IIIs, pardon me, frontline studies to start in the first half of next year.