Dr. Craig Crews, PhD, Crews Laboratory at Yale University

Interview date: September 13, 2013

On this week's show, Dr. Craig Crews of the Crews Laboratory describes his discovery and development of carfilzomib. He discusses the challenge labs have with only 10 out of 100 submitted research projects getting NIH funding and the need for patients to push for greater federal funding if we are to have more successes in the future.  He describes a drug's "Valley of Death" - or the jump from the academic institution into the next stage of development, and how he overcame that for carfilzomib by creating his own biotech company. He describes the drug funding continuum and the important role of new biotechs to fill an existing gap and get a drug across the finish line. He shares the fast-track success of carfilzomib because the Phase II results were so promising and his lab's quest to teach the ability to pick future winners by looking at promising outliers.

Jenny: Welcome to another episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. There are two ways you can subscribe to mPatient News. To hear about our previous episodes and learn more about our upcoming shows please subscribe to our mPatient Minute, a weekly newsletter that contains all show information in one e-mail. You can also subscribe to all posts as they come out.

With the recent acquisition of Onyx by Amgen, I was curious to know how myeloma drug goes from an idea to real therapy being used successfully in the clinic. We're very fortunate to hear from a top researcher, Dr. Craig Crews of the Crews Laboratory at Yale University, who achieved this very thing with his discovery and development of the drug carfilzomib for multiple myeloma.

So thank you, Dr. Crews, for joining me today.

Dr. Crews: My pleasure.

Jenny: Before we start I'd like to give a short introduction of you for our listeners, if that's okay.

Dr. Crews: Please.

Jenny: Dr. Crews is a Lewis B. Cullman Professor of Molecular, Cellular and Developmental Biology and Professor in the Departments of Chemistry and Pharmacology at Yale University. He performed his undergraduate work at the University of Virginia in Chemistry and earned his PhD in Biochemistry at Harvard University. He is the recipient of the Senior Scholar Award at the Ellison Medical Foundation, continues as a visiting professor at a university in Germany, received the Bessel Research Award from the Alexander von Humboldt Foundation in Germany, and is a fellow of the Royal Society of Chemistry.

Earlier in his career he was also awarded the Donaghue Foundation Young Investigator Award and the Burroughs-Wellcome Foundation New Investigator Award. He also serves on the editorial board of ChemBioChem and Chemistry & Biology. Dr. Crews has created multiple patents focusing on enzyme and proteasome inhibition. His drug carfilzomib, now called Kyprolis, was approved by the FDA for relapsed multiple myeloma in July of 2012.

Dr. Crews, we all thank you for your deep research and for developing an improved therapy for multiple myeloma.

Dr. Crews: My pleasure.

Jenny: So I guess the first question would be, how did you come to the idea for a new proteasome inhibitor for multiple myeloma?

Dr. Crews: Well, it was quite by accident. I was studying a compound from nature. It was a small molecule that was found in a microbial broth that had been discovered actually by a pharmaceutical company, Bristol-Myers Squibb, in Tokyo. They were interested in looking for novel anti-tumor agents and they had found one that was quite promising but they ultimately made a business decision not to explore it any further because they didn't know how it worked. They anticipated that the FDA would want to know that information before they would approve any drug based on that natural product, and so they published it once they decided they weren't going to develop it any further.

So I became aware of this molecule called epoxomicin as a recently appointed assistant faculty member at Yale in the late 1990s when I was reading a journal article about this, and I became intrigued. It was a very potent compound without any idea of how it was working, and so I wanted to see if we might be able to help answer that question. What was the mechanism by which this compound from this bacterium could really kill tumor cells?

I applied for a grant from the National Institute of Health, NIH, and I was fortunate enough to get funding for this very basic question of how this compound affects tumor cells. I set out to do this but the first stumbling block was we didn't have access to any of the compound because Bristol-Myers Squibb had subsequently closed their research center in Tokyo and I couldn't get my hands on any of the material. So my lab, which is half chemists and half biologists, we set out to actually make our own version of epoxomicin. When we did that, which happened to be the very first reported synthesis of this compound, this allowed us not only to study its effect and confirm its effect on tumor cells but it also allowed us to start tweaking the structure of the natural product.

The first tweak we did was to basically put a handle, if you will, a molecular handle, on the compound and we went fishing. By that I mean we would add it to cells, it would get inside cells, and we wanted of course to know how it worked and that meant we had to find what protein was binding to this compound. So when we fished out of the cell the protein bound to this compound, we found that it was the proteasome.

For your listeners, the proteasome is a large cylinder, a very complex machinery inside the cell, whose job it is just to degrade proteins. This was the first clue that our molecule could be working through blocking the function of the proteasome. It could be inhibiting the function of the proteasome because it was binding.

At that point we published our results and were quite excited about this because we knew from the work by Millennium of a small molecule that was working its way through the FDA approval process for multiple myeloma, and we know that compound today as Velcade or bortezomib. So what we subsequently did we asked ourselves -- even though this was a potent molecule, now that we know what the target is of this molecule inside the cell -- we asked ourselves if we could improve upon Mother Nature.

I threw it back to the chemists in the lab and challenged them to tweak the compound structure a little bit here, a little bit there, and come up with something that was an improved version. When they did that, after a fair bit of work as you can imagine, we came up with a molecule that we call YU101 -- for Yale University 101. It was that molecule that we are able to demonstrate was many times better than the natural product from nature, epoxomicin, and was many times better than Velcade, the compound that was soon to be approved for multiple myeloma.

So it was at that point that we confirmed that it was, yes, still a potent anti-tumor agent and we were able to do that here at Yale, but that is as far as my lab felt comfortable in taking this project. Because we really were able to take it from a very basic research question through to answering that question and then flipping it over to a more translational medicine effort to improve upon this, to make a lead compound if you will, for further development as a potential therapeutic. But it was at that point that Yale University and myself and several other researchers started a company, and that company being called Proteolix.

Proteolix took YU101, added one last tweak to it to allow it to be more easily dissolvable in water, and took that into the clinic. That molecule is today carfilzomib or known as Kyprolis as you mentioned.

Jenny: You started this at what point? When were you getting the NIH grant and how long did this process take?

Dr. Crews: I got the NIH grant in the very beginning and so the grant application is relatively straightforward in terms of the application. We pose a question, we explain how we're going to address that question and then a team of our peers, scientists, serve on a review panel at the NIH to then pass judgment if you will, on whether it should be funded. I should pause right here and just emphasize what I think is well known but maybe it's not, and that is the funding for biomedical research in the US had decreased in the last 10 to 15 years to the point where for every 100 applications that are put in to the NIH, 90 of them are being rejected. It's clear that there are some that should be rejected but as you can imagine year after year after year, the bad ones -- the mediocre scientists -- they leave the field and we're really cutting into bone now in terms of rejecting really good science.

That's not even addressing the question of making sure there's an environment, funding environment, that is supportive of young investigators like myself years ago when I was starting out and was given a chance. So I encourage all of your listeners to be active supports of not only the applied side but also the basic research side of the US biomedical community because you never know where the next breakthrough drug is going to be coming from.

Jenny: Right, and how as patients can we best do that?

Dr. Crews: It's engaging your congressmen or congresswomen, making sure that they know that this is a priority to you, making sure that they're aware that it's not always possible to predict what the best drug is going to be and the importance for studying very, very basic things. Why on earth would, if you think about it, studying something that comes from some bacterium, some compound and how it works, is so far removed from ultimately the drug that was approved. But it's that type of very broad scientific inquiry that has set us apart as a country for decades from all the other countries and has fueled the biotech industry as well as the successes that we have seen in pharmaceutical development. Some might argue that the decreased number of new drugs in the pipeline today may be a reflection of the decreased investment that began unfortunately about 15 years ago.

Jenny: Well it is a challenge and we've heard that from other myeloma researchers as well and I think we'd like to know what we as patients can do. So those suggestions are great.

So you've kind of taken us through the actual compound and then when you passed it off at Proteolix. Can you give us an overview of what happened then or what the other steps were to turn it into a drug?

Dr. Crews: Sure. So as many of your listeners may know, the drug approval process has three phases. The first is Phase 1 trials are safety trials and are designed to determine what concentrations, how much of the drug can be safely administered to patients. It's a very important clinical trial because we obviously want to be dosing at the safest concentrations possible. But it's oftentimes not always possible to be able to see an effect in Phase 1 clinical trials, so it requires a bit of altruism on patients' part to volunteer for Phase 1.

Once the amount of drug that can be safely administered to a patient is determined, then the next step being Phase 2 of the clinical trials begin and in the Phase 2 clinical trials the FDA is asking the company to prove that their drug candidate is better than anything else that's out there. The point of view from the agency is, "Why should we allow another 'me too' drug? It has to be better." So these patients that are enrolled in Phase 2 clinical trials will have already exhausted a series of other options, clinically speaking or therapeutically speaking, and therefore they're very challenging patients. That's the point, is the set a higher hurdle for any drug candidate coming out of Phase 2.

But if successful, if there is some hint that the drug is working in these patients that have seen a lot of other therapeutics and it failed them, so that's when Phase 3, and the final registrational trials as they're called, begin. They're called registrational because if successful, then one can register for an FDA approval based on those clinical results.

So in the Phase 3, which are a much, much larger trial series in terms of larger numbers of patients enrolled, this is where patients who have not had any prior or have a limited prior exposure to other drugs. The idea is the FDA wants to see how this drug candidate behaves as if a patient had walked off the street into his or her doctor's office and been presented for the first time with a therapeutic option. So oftentimes these trials are run in a comparison with the standard of care, the best in class of another of whatever is currently the best out there but the point being that these patients would not be as --

Jenny: Maybe not at an advanced disease stage, maybe?

Dr. Crews: Not so much advanced. It's that they haven't seen other compounds.

Jenny: Or other prior therapies?

Dr. Crews: Prior therapies, exactly. So as I'm sure you know prior therapies can change the course of the disease. The disease changes once it's been exposed to something else. In changes in response to these therapies and so the FDA wants to have a head to head comparison with what's currently best in class and see how the candidate behaves. So that's how things -- so that's the Phase 3.

In the case of Proteolix and carfilzomib, Kyprolis, because our Phase 2 data were so convincing and so compelling, we actually got the -- or I should say the company that acquired Proteolix, that company being Onyx Pharmaceuticals -- made the business decision to actually apply for FDA approval based on the Phase 2 data. They were successful. So the FDA said, "Listen. Given the limited number of options out there today, even though we haven't yet done all of the clinical trials, we will approve Kyprolis for those patients that are relapsed, refractory patients." These are the patients who have failed other therapies. As I said, those are the patients that are recruited for Phase 2.

There are ongoing Phase 3 clinical trials and so if successful in those, then the company can apply for approval for what's known as frontline treatment, meaning that as I said naïve patients that have just newly been diagnosed would be offered Kyprolis as their first option. But those data aren't yet available because the clinical trial is ongoing.

Jenny: Right now you need to get a prior therapy, correct?

Dr. Crews: You have to failed prior therapy, yes, for Kyprolis.

Jenny: So in total, how many trials really need to be run on the new drug like carfilzomib before it's FDA approved?

Dr. Crews: In theory three, Phase 1, Phase 2 and Phase 3. But in reality, there are -- after Phase 1, which simply as I said sets the safety parameters, there are often multiple Phase 2 and multiple Phase 3, the idea being that you might want to try your candidate in combination with something else. Each change in the design of the trial necessitates a new trial, and so if you want to couple Kyprolis with an IMID class from Celgene, one of their molecules, to see if in combination it works better than the Celgene's compound by itself, then you need to do those types of studies.

So that's why it can be a bit confusing when a patient goes on clinicaltrials.gov, the website that lists all of the clinical trials ongoing today, searches for multiple myeloma or searches for Kyprolis. They would see a number of trials that are either wrapping up or are starting.

There are new indications too. We've seen success obviously with multiple myeloma but this particular drug, this proteasome inhibitor Kyprolis, might have some efficacy, might be effective against, say, solid tumors. So that necessitates another series of clinical trials.

Jenny: And in terms of funding, so the NIH grant did the initial funding and then when it was developed by Proteolix, how did they receive their funding? Then it kind of went to Onyx, whom I'm assuming funds that research themselves, or are there other funding steps along the way?

Dr. Crews: The founding of a biotech traditionally involves recruiting of money, capital, from venture capitalists. So these are investors who are willing to take the risk that they might strike it big or they might lose everything. The model has traditionally been, given the high failure rate in these companies, is that they're hoping that one out of every eight or one out of every ten companies that they start will hit it big but that the return -- the amount of money they make on that one that is successful -- is more than eight or ten times the initial investment. So that's how they ultimately will make money even though nine out of ten companies will fail.

Just to give you some numbers here, the company Proteolix was started with an initial investment of $18 million and that allowed the tweaking of the structure of YU101 into the final candidate Kyprolis as I mentioned, and also started funding safety trials, Phase 1 trials. But subsequent trials required additional investments and so those initial investors went out and talked to their friends and sometimes went back to their own firms asking for additional money. The bottom line if you will is that by the time Onyx seven years later bought Proteolix, the investment of all of the investors in Proteolix was over $140 million.

Jenny: Wow.

Dr. Crews: Onyx, however, purchased that for what will be upwards of $850 million if the drug makes all of its clinical milestones. So the investors made money and they're now able to take those profits and go off and do those again with another ten companies, hoping that one of them will be successful.

Jenny: And similar. We would love for them to be similar.

Dr. Crews: Yes, and just to wrap up the story here on terms of the investment side, last week Onyx -- having made that $850 million investment in Proteolix -- now sold itself for $10.4 billion and it was purchased by the largest biotech in the world called Amgen. So Amgen sees this successful multiple myeloma drug which is projected to be upwards of $2 billion a year in sales in a couple of years and they wanted to have that in their portfolio.

Jenny: It's a huge success story, beginning with you, so we thank you, and one for patients as well. Now I've heard researchers talk about what they call the Valley of Death for a drug. Can you tell us what that might be and how you overcame that with carfilzomib?

Dr. Crews: Right. So the Valley of Death refers to how far an academic researcher can take a project within a university setting, which is limited. We don't have the resources of a large pharmaceutical company. We don't have the animal testing oftentimes. We don't have the large team of medicinal chemists and whatnot, or pharmacologists. So there are a lot of discoveries that have great potential but no one's picking them up as projects.

Previously the pharmaceutical companies internally had the bandwidth to be able to look at what is being done in academia, in the universities, and to say, "That looks interesting. Why don't we work on that for a little bit and see if we can make something of it?" and so it was much more exploratory research. They were willing to take a project that was high risk and to de-risk it if you will, to kind of figure out and answer some of the obvious questions. For the most part they didn't pan out but some did, and that served as the very beginning of the drug pipeline for these drug companies.

What unfortunately has happened is with the mergers and acquisitions and all of the restructuring within the large pharmaceutical industry, the internal research and development has taken a hit and a lot of the capacity to be able to evaluate very early discovery projects reported by academics like myself no longer is in place. So they have turned their attention, the large pharmaceutical companies, instead of building it from within they'll rather go out and purchase companies like Proteolix. What that means is that works for a while, while there still are companies like Proteolix. But if there's no one out starting companies and there's no internal transfer from the university labs into large pharmaceutical labs at the very earliest stages, then the pipeline dries up.

So this Valley of Death, how do you take a project that's very promising but has a lot of obvious questions of whether it can be useful as a drug, how do you take that project from, say, my laboratory and get a large pharmaceutical company interested in it where they are saying, "Well, that might be interesting but we have all these concerns that need to be first addressed," and we're looking ourselves at this side of the Valley and say, "Well, we don't have the capacity to do this." So this is where biotech is stepping in, where the venture capitalists are saying, "We're willing to assume the risk." There are questions, yes, but we see that. If we answer those questions successfully then we might be able to turn around and sell this project or sell this company to a pharmaceutical company.

In a part you might think – one way of saying it is the large pharmaceutical companies are outsourcing, if you will, a lot of the innovation that they originally had internally but now they are outsourcing it. The challenge of course is how do we educate from my side, my fellow academics, the university professors, how do I educate them saying, "Listen. We need to take it to the next level. It's not sufficient. It's not enough just to discover something and publish it and hope that someone's going to pick it up. You have to champion this. You have to be an advocate for this. You have to fight for what you think has great potential."

What I'm trying to do here at Yale and others in other universities are trying to make this transfer technology from an academic lab to, say, a start up biotech easier. That requires educating my fellow professors and saying, "It's not that hard. It is possible to be able to attract people that are willing to invest in your story," and so I am very, very concerned about the Valley of Death but I feel that I'm optimistic that we might be able to overcome this.

The other thing that I do feel that I'm optimistic about is foundation-based venture philanthropy. So I know -- for example, Polycystic Kidney Disease Foundation, PKD Foundation, the Cystic Fibrosis, and definitely the Leukemia and Lymphoma Society -- they are these large foundations that as you may be aware are taking a more aggressive stance to helping biotechs, not just the academic research but allowing some of their funds to go to for-profit entities for the purposes of advancing drugs of their interest. My point is that this might be another entry, another way to address the Valley of Death, is my point.

Jenny: Yes, the LLS is very involved in helping support actual drug development, like Gleevec is one of the examples there that was funded both by the NIH and the Leukemia and Lymphoma Society. The myeloma space also has its foundations, the IMF, MMRF and the mMore Foundation, to fund myeloma research and in some cases start development.

Now, I have another question on a different topic. Now that you've run through the process successfully, what are the key lessons you've learned and would you do anything differently in the next go-around?

Dr. Crews: Yes. So key lessons: the most important one is that it is possible. Oftentimes people don't start something because no one has gone before and they think things aren't possible. So I hope that one takeaway at least for my colleagues is that if there is something that is a potential therapeutic that came from your laboratory, I would encourage people to find the necessary capital and team to start a biotech if they can't directly engage a large pharmaceutical company. So yes, I think that that's the most important thing. I've been fortunate in that this particular story was a fantastic one and of the team at Proteolix were able to develop this drug in such record time. Now obviously it's approved and it's helping patients.

The fortunate thing for me personally is that with this prior success, it's allowing me to more easily attract the investment in my next company, which I just recently have started this summer. We're still looking for what indications, but certainly multiple myeloma is what I know well. It is going to be an oncology-focused company.

Jenny: Well this is a good next question then for you. My husband, and when he talks sometimes he quotes Bob Metcalfe of 3Com and he was the inventor of the Ethernet, he said, "Most successful entrepreneurs I've met have no idea about the reasons for their success. My success was a mystery to me then and only a little less so now," which I think is a funny quote but I think sometimes it's true in entrepreneurship anyway. So in science is it similar, or how can we replicate your success and the success of others when it comes to myeloma discoveries?

Dr. Crews: That's a good point. I teach graduate students. These are the people who are actually doing the work in the laboratory and I'm training them to be future researchers, future professors. One of the things that I try to teach, and I'm still grappling with this after 18 years, is how do you teach creativity? How do you teach innovation?

It's basically, I believe, it comes down to the ability to recognize opportunities. We are flooded as you can imagine everyday with new pieces of information and the vast majority of the information sit nicely into the preconceived models that we had constructed in our head as to how things should be working. Obviously we have assumptions, models, and we test them and that's the whole concept of experiments. But there are occasions when things don't work exactly as you anticipate they are working and it's those outliers, and you can imagine you can spend an extremely unproductive lifetime tracking down all of these outliers that might not be important.

But I am trying to teach my laboratory how to recognize when an outlier is worth pursuing, and so that's something that I think is a lifelong lesson that if learned could really have a major impact on the success of someone's career, whether that career is solely in academic research or if they have an interest in actually therapeutic development as a drug developer.

Jenny: I think that's an acquired skill, picking winners.

Dr. Crews: Yes.

Jenny: I think it's definitely a difficult skill. If it weren't we would have a lot more successes.

Dr. Crews: Right, and so that's what I'm trying to do, is see if I can distill some of the skill set that I have developed over the years that to me feels natural, trying to distill it into something that I can describe to someone else.

Jenny: Well , excellent. Along those lines as well, as a new set of targets potentially for you, I see that you are also awarded the Ellison Medical Foundation Senior Scholar's Award in Aging and I know there was a recent paper from Dr. Gareth Morgan (and the Institute of Cancer Research) in the UK about aging and myeloma. So I'm wondering if your work in this area, it can also be applied to myeloma or if you've looked at that at all.

Dr. Crews: I haven't looked at that. That's a very interesting connection that I haven't explored and I'm not familiar with that work you cited. I should definitely look that up.

Jenny: It's pretty recent, just in the last couple of weeks.

Dr. Crews: I'll want to look that up.

Jenny: So I guess a final question. How can patients help you do your work in the best way you can?

Dr. Crews: Oh, that's easy. It's the message I gave before, and that is we need grassroots support for more biomedical funding. I can't overemphasize this in that this sequester has hurt us so much. I'm laying off researchers. I can't hire or buy the pieces of equipment that I need, and this was on top of already many, many years of anemic funding. This doesn't happen magically, the funding. Research attracts the funding. If there's more funding, there's more research and so I would just encourage your listeners to let their voices be heard and to continue to make sure our legislators know the importance of basic research.

Jenny: You've given us some marching orders. Now we have two ways patients can make a difference in setting the pace of cancer research. So one would be join the clinical trials, which is the reason we're doing this series, and what you're saying is that we can make a difference in helping support the idea of more federal funding for cancer research.

I just want to mention that this is possible and I learned about this from the book Emperor of All Maladies. In the 1940s no one was talking about cancer research and a woman named Mary Lasker whose husband died of colon cancer, she sort of took it upon herself to decide that federally funded research needed to be in place. So she was very instrumental. She and her husband at the time were very instrumental in helping kind of reinvent the American Cancer Society and turn it into an organization whose mission it was to promote cancer research. She liked to say, "If you think research is expensive, try disease," which I think we've all found to be true and because of her efforts over many, many years she helped expand the NIH budget from $2.4 million in 1945 to $5.5 billion in 1985. It's a clear example that patients and caregivers can make a big difference in having federally funded cancer research. So thank you for pointing that out.

Dr. Crews, we are so grateful that you took the time to join us today. We are very fortunate to have your energy applied to the target of myeloma and hope that we can do multiple things to help support you in your valued work.

Dr. Crews: Thank you very much and I wish you the best.

Jenny: Dr. Crews performs his research as part of the Crews Laboratory but he is not actively treating multiple myeloma patients, and so he is not available for advice or questions.

Thanks for joining us for another episode of Innovation in Myeloma on the mPatient Myeloma Radio Show. Join us next Friday for another episode to learn more about how your participation can help push faster towards a cure.