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Dr. Gregory Stein From Curtana

Dr. Gregory Stein is the President and CEO of Curtana, a biopharmaceutical company developing targeted treatments for brain cancer. They are currently working on a therapy that targets Olig2, a transcription factor contributing to tumor growth. Read our interview with him below!

Tell me a little bit about yourself. What is your job?

I am a physician by training and did a residency in emergency medicine. I worked in and ran a large ER (Emergency Room) on the west side of Chicago for many years. I got bored with that and decided I wanted to do something different. So, I went back to school in San Diego to get an MBA, and was plugged into the local biotechnology community about 18 years ago.

I have been primarily doing early-stage drug development ever since, because that is what San Diego does best. I started my current company, Curtana, 10 years ago, and the focus has always been to develop a drug against a novel target called Olig2. The research suggested that if you could block Olig2, there should be a dramatic effect on brain cancer, specifically gliomas, glioblastomas, and medulloblastomas.

We put together a team and are now at the point where we have been working on the drug for 10 years. We have a very good-looking drug that is administered as a once-daily tablet, and are getting ready to start our clinical trials. We have done all our animal research, and the drug looks promising. However, we are not going to cure the disease. You would like your drug to have a dramatic effect, and we hope that is the outcome. But the challenge here is quite large, in that a five-year survival rate is less than 10%, and as you get older, those numbers drop even more. If we can move that bar, even if we can only make that 5-year survival rate 25%, which is still a horrible prospect for a patient, it will add meaningful years to peoples' lives and that makes a difference for them.

I look at it like this is the beginning of a journey like what breast cancer went through for the last 40-50 years; 40 years ago, the five-year survival rate for breast cancer was about 40%. Now, it is almost 90%. No single drug created that leap – it was using multiple drugs and dividing the population into different subtypes to better treat them.

I think we will see improvement in long-term survival over the next 10-20 years, because there is a lot of exciting stuff going on. Biologically, brain cancer is a very complex tumor. There are several different cell populations within the tumor that all need to be addressed. There is not going to be one magic target or drug that will make a huge difference, because the tumor will just mutate around it and adapt. To address the cancer efficiently, you are going to need combination therapy. That is what it is going to take to make a difference.

I do not interact often with patients. I do get to speak with some patients who are going through this, and families who have lost family members or children to brain cancer, because they want to make a difference in the field. I am on the research side, even though I am a physician and spent years with patients. I have a team, and we work with some of the top researchers worldwide. But I understand what some of the challenges are, particularly for patients who may not have the resources to access the best care.

After spending years in Emergency Medicine, what made you decide to enter the neuro-oncology research field?

I have worked in many different companies during my biotech career and honestly, it was total serendipity. I had another company that was working in the sleep-disordered breathing and pain space, and came across some literature that the target we were going after might have utility in brain cancer. Not being a brain cancer expert, I went up to the university and talked to the head of neuro-oncology about what my company was doing, and over the course of the conversation, he mentioned that he had been working on something for the past 10 years and thought that he could change how brain cancer is treated. He wanted some advice on how companies function and his next steps. That is how I found out about Curtana. Needless to say, I love the idea. I love the passion of the researcher. That is how he and I started the company.

How does the target receptor your drug targets change how brain cancer acts? How will it impact brain cancer treatment?

The prevailing theory around our drug is that brain cancer arises from neural stem cells that become cancer stem cells. All cells have occasional mutations, and there are repair mechanisms for fixing that or killing the cell if it can’t be fixed. Sometimes those mutations start piling up, and the cells go through an epigenetic shift, becoming brain cancer stem cells. Olig2 is a transcription factor that is involved in brain development, so it is active during the first 2-3 years of life. It drives the growth of the brain and tells the brain cells to go into different cell lineages. As those cells mature, they lose expression of Olig2. Most of the cells in your brain do not express Olig2, it is in only the neural stem cells that are in your brain. A lot of Olig2 expression is not part of normal biology in the healthy brain.

What brain cancer has done is that it has hijacked Olig2 and some other transcription factors and is using its growth-driving program for its own survival. Olig2 makes the brain cancer cells resistant to chemotherapy and radiation. When we treat with current therapies, you are knocking out the more differentiated cells that are not expressing Olig2, but the cells that are expressing Olig2 remain. Then, the cancer comes back in all of those patients. This is why we thought that Olig2 was a really attractive target, because it is at the core of the chemo-radiation resistance in the tumor.

Now, it turns out, there are four different molecular states of brain cancer cells. One of those states are the cells overexpressing Olig2. There are also states where the cells overexpress other transcription factors and cell surface markers. While we are hitting a significant portion of the cancer stem cells, there are other factors there that need to be targeted. When we combine our drug with radiation, chemotherapy, or some other drug, it does better than either one alone. The hope is that, ultimately, we can knock out all of the cancer stem cell populations, and that will stop the tumor in its tracks.

And you said that Curtana is starting the process of clinical trials. What is your opinion on clinical trials? How do they benefit patients?

The first thing that the FDA requires is that you show the drug is safe. Our mandate as physicians is to do no harm, so the last thing you want to do is give somebody a drug that could kill them or make them super sick in your attempt to make them better. The phase l trial is all about safety. How much of the drug can you give? What are the side effects of this drug? Because this is a novel drug, we have a sense of what the side effect profile looks like based on the animal work, but we are not rats or monkeys, so until you get into humans, you don't know for sure.

Since the focus is on safety, you have to do dose escalation, starting with low doses in a few patients and working your way up. You can't go right to what you think will be the correct dose, because what might be tolerated in a monkey or rat can kill a human. For patients, phase l of a clinical trial is a tough decision. You know you are not getting the optimal dose, you are probably getting a sub-therapeutic dose. Some people, particularly after they have gone through several cycles of chemotherapy, are willing to participate in a phase l trial that has a low probability of some benefit. They have the understanding that they are going to be helping other patients down the road. As you get into the higher doses, if it works the way we think it will work, it may benefit phase l patients.

As we get into a phase ll trial, we are now combining our drug with other therapies and giving patients what we think is the optimal dose. Hopefully, patients will benefit from this therapy. However, a lot of stuff doesn’t work. Our preclinical models have limits, and our understanding of the biology, while it is orders of magnitude from what it was hundreds or even 50 years ago, is still woefully ignorant.

We don't have computer models of living cells. We can model stuff, but it is all still pretty crude. I don’t think there is any way around it. People complain about the regulations and the FDA, but I don't think the FDA is the problem. They are cooperative. They are easy to work with, but it just takes time. It is frustrating for people to see that it can take up to 10 years to get a drug to be approved. If we knew that every drug going into the clinic was going to work, we could blast it right through the FDA. But we don't know if the drug is going to be safe, or going to work. Most drugs don’t work. Even though we think they will, based on the animal work. And so, ethically, you can't give patients drugs or charge for therapies that aren't going to work.

I know there are lots of opinions on it and there have been a lot of modifications made to the FDA regulations, such as fast-track designation, accelerated approval, and breakthrough designation. There are mechanisms to speed things through if a drug is working, but at the end of the day, it is all about the data. If the data looks good, then the FDA is wind at your back. If the drug doesn't work, it doesn’t work. You can’t blame the FDA for that.

I know you didn’t ask specifically about that, but that is, I think, the general public’s perception; that evil forces are conspiring to slow down drug development, keeping treatments away from patients — and that the FDA is this roadblock.

Do you think that innovative therapies should be available to anyone with brain cancer?

The vast majority of people are going to get access to the drug. There are certainly going to be cases where getting novel therapies is an issue, and this is a problem that needs to be addressed in this country. But companies may supply drugs under compassionate use, patients can get Medicaid, and social workers can often find ways to get patients plugged into a program.

One of the biggest challenges I have noticed in the neuro-oncology space is that the majority of brain cancer patients never see a neuro-oncologist. They can get surgery and chemotherapy, but they never get referred to a neuro-oncologist, or go to a tertiary care center. Oncologists won’t refer them to more specialized care, because if they move a patient away from their practice into somebody else’s practice, the oncologist isn't going to get paid. Therefore, these patients won’t be able to access clinical trials. People are trying to solve that problem, building larger databases and trying to find ways to work with the community-based oncologist. That, however, is a solvable problem that has nothing to do with the science of the drug. It shouldn’t be that only 1 in 10 brain cancer patients get into a clinical trial. We shouldn’t have to be struggling to get patients into trials.

How is Curtana doing patient recruitment for clinical trials?

We are working with some of the top brain cancer centers. The doctors in the trial are excited about the work we are doing, so they are referring patients to our clinical trials. Because of this, we are not going to have an issue getting patients into our trial, specifically, the phase l trial, which is a trial with fewer patients. At the end of the day, it is the physician who can offer their patients multiple opportunities to get into trials, based on whatever inclusion criteria there are. So doctors believe the science makes sense, and that there can be some benefit for their patients.

What do you hope Curtana can do in the future to make their therapies more accessible?

Our job will be to initially show that the drug is safe and that it has some evidence of efficacy. Most small companies will then partner with a big pharma company, because to do the larger, phase lll trials, you may need their help for the commercialization process of manufacturing, marketing, and distribution.

What most companies do to get their treatments to patients is get a sales force that works with the neuro-oncologist, because once the drug is approved, you have to educate the doctors. Doctors are not watching the FDA and looking for drugs to be approved, they are busy taking care of patients. Even though a drug might work great and a doctor might have read about it, they need to be educated. They need to understand how the drug works to explain it to patients, and know how to prescribe the drug. You need a highly educated sales force that has access to doctors to get them to start using the drug.

For patients who can’t afford the drug, a lot of companies will set up a compassionate use program. In situations like brain cancer where the patients have a high mortality rate, companies will find a way to get them the treatment they need. Sometimes patients are reluctant to go, don't have access, may not have the transportation means, or do not have the family support to access a doctor, so they are diagnosed late. There are a lot of social issues that impact the quality of care that go beyond being in a city where there is the right kind of physician. It is a social issue beyond what is built into the medical delivery process.

Thank you very much for speaking with me!


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