GlycoMimetics is conducting a pivotal Phase 3 trial in the US, Europe and Australia to determine if its drug candidate, uproleselan, can successfully treat patients with relapsed and refractory acute myeloid leukemia (AML), a blood cancer.

The unique aspect of uproleselan is that it does not kill cancer cells. It is used in combination with chemotherapy regimens, in this trial, either MEC (mitoxantrone, etoposide and cytarabine) or FAI (fludarabine, cytarabine and idarubicin).

Uproleslan, a small molecule E-selectin inhibitor, chases cancer cells hiding in vascular niches of the bone marrow back out into the patient’s blood system where they can be destroyed by the chemotherapy. These cancer cells concealed in the bone marrow are believed to be the source of relapses in patients with AML and other blood cancers.

GlycoMimetics co-founder and CEO Rachel King said uproleslan also has another potential unique quality. It has demonstrated the potential to reduce toxic side effects of intensive chemotherapy, particularly mucositis, which is inflammation of the digestive system. Mucositis can be so severe and painful for some patients they cannot drink water. Instead they receive nutrition and fluids intravenously.

Uproleslan’s potential to enhance the cancer killing ability of chemotherapy while simultaneously reducing its toxic side effects earned it a Breakthrough Therapy designation from the US Food and Drug Administration (FDA) in 2017. 

GlycoMimetics’ other drug development programs include its lead drug candidate, a pan-selectin inhibitor, rivipansel, in clinical trials with its partner, Pfizer Inc., for sickle cell disease. The company also has another small molecule inhibitor of E-selectin and CXCR4, a chemokine receptor, for use with chemotherapy in treatment of blood cancers and solid tumors, such as breast and prostate cancers.

WuXi AppTec Communications spoke with King about the FDA Breakthrough Therapy designation for uproleslan and what it has meant for her company as part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines.

King and co-founder John Magnani, the company’s chief scientific officer, launched GylcoMimetics in 2003, when King was serving as an executive in residence at New Enterprise Associates, a venture capital firm. She also worked with Genetic Therapy Inc., becoming its CEO following its sale to Novartis, and was a senior vice president at Novartis. King has a B.A. from Dartmouth College and an MBA from Harvard Business School.

WuXi: What qualifies uproleslan for the FDA Breakthrough Therapy designation (BTD)?

Rachel King: We submitted data from our Phase 2 AML (acute myeloid leukemia) trial in which we were treating patients with relapsed refractory disease. That’s when we submitted for BTD.

I can’t speak to why the FDA granted it, but I can speculate that it was because the drug had a unique profile both in terms of the potential efficacy and the potential safety. We were looking at impact on response rates and also of safety of patients coming through chemotherapy. We’ve since continued to add data, in particular looking at other endpoints, including overall survival.

But at the time we applied for BTD the information we had was on the response rates and the safety profile of the drug, in particular in patients who had relapsed-refractory AML. The clinical data were compared to historical demographically matched controls, so we did not have a concurrent control group in the trial that we were running. It was that data set submitted to the FDA and it was compared to what would have been expected from demographically matched controls.

WuXi: How does your drug candidate differ from existing therapy?

Rachel King: It differs in terms of its mechanism, and I’ll say a bit about that; and we believe it’s going to show it differs based on its safety and efficacy profile.

In terms of the mechanism, the drug targets E-selectin, and as far as we know it’s the only E-selectin specific antagonist in clinical trials; and also as far as we know, it’s the first time an E-selectin antagonist has been tested in this clinical setting.

It’s unique in that it’s actually not cytotoxic. The drug, on its own, does not kill AML cells. But what it does, is it affects how the AML cells interact with the host, the cancer patient. That is, how it interacts with the patient’s own bone marrow.

The way we believe it works is that E-selectin is a protein that is expressed all the time, constitutively, on the lining of the blood vessels in the bone marrow, the vascular endothelium. The ligand for E-selectin is on the surface of the AML blast. That makes it possible for the AML blast to traffic to the bone marrow and to become secure in the bone marrow, effectively sequestered there.

And when you give a patient chemotherapy what we believe is happening is that you’re treating the blasts that are circulating, but not treating the blasts that have become protected in that bone marrow space. Those blasts in the bone marrow become the source of subsequent relapse.

What we believe we are able to do is disassociate the blasts from those protected spaces in the bone marrow and make them easier for the chemotherapy to kill. It’s really a unique mechanism.

One of the things that’s particularly interesting about that, is the mechanism is also relevant for how normal white blood cells would traffic in the body when there is an inflammatory response.

One of the major side effects of the type of chemotherapy these patients are often given, is an inflammatory response that occurs in reaction to the chemotherapy. It’s a side effect called mucositis, which is the inflammation of the lining of the entire digestive system. It can become so severe that many patients can’t even drink water by mouth. It’s a really horrible and irritating inflammation of the entire digestive system.

One of the things we observed in our clinical trials and also early in preclinical trials in animal models is that our drug also reduced the mucositis associated with chemotherapy.

So in the aggregate, we believe we have a drug that has a unique mechanism of action, which can be used to enhance the activity of the chemotherapy agents that will kill the cancer cells, and potentially, also to improve the safety profile by reducing mucositis. It’s really quite a unique set of potential benefits.

WuXi: What impact does the FDA breakthrough designation have for your company?

Rachel King: It’s actually had a quite profound impact on our company. The reason is that when we got the BTD, not only were we able to engage more closely with the FDA, which is important, but it also increased the profile of the company in such a way as to make it possible for us to finance the subsequent development of this agent.

I think that’s a critical benefit, and really an example of how, in this case, a government policy made a huge difference to a small company. Because we were able to get that BTD, we got the visibility to potential investors that made it possible to raise a substantial amount of money so now we can determine if this product actually will turn out to be a breakthrough. Now we have the financing in place to conduct the Phase 3 trial.

I think the access to financing that was generated by the increased visibility after we got the breakthrough designation was critical. Now, of course, most people associate the BTD with improved access to interactions with the FDA and that also is critical and we have also had that benefit. We’ve been able to engage multiple times with the agency around issues related to the product and that has been quite helpful.

WuXi: Did the designation affect your stock price?

Rachel King: Yes, it also affected our stock price.

One of the challenges that we have as a public company, while we were in the earlier stages of developing this drug, was that we didn’t have a lot of trading volume in our stock. That meant that it was very difficult for new investors to come in because if there are not a lot of shares that change hands it’s difficult for them to buy in.

After we announced the BTD we had a huge spike in our volume and, in addition, a spike in our price. It was the combination of the volume and the price that put us in a good position to raise additional funds.

WuXi: What role, if any, have patients played in your drug development and clinical trials?

Rachel King: Patients have played a critical role, of course, by participating in the clinical trials.

In our sickle cell program we did engage early with the Sickle Cell Disease Association, and I know Pfizer has continued to do so. We didn’t work specifically with patient advocacy groups around the BTD in AML, but I expect that as uproleselan approaches commercialization our involvement more formally with patient advocacy groups will increase.

Until now the main role that patients have played in the development of this drug is in their willingness to participate in clinical trials, which we are deeply grateful for, and we hope they benefit.

We have not had many formal interactions with patient advocacy groups in AML yet, but we do recognize that some of these groups have started to publicize that this (drug) does have a BTD and we believe that’s giving increased visibility of the trials to patients who are involved with those groups.

WuXi: What is the significance of your breakthrough designation to patients beyond the potential clinical benefit? Will it reduce the overall cost of treating their disease?

Rachel King: Primarily, we hope it’s going to have an impact on survival, which is what everybody hopes, of course.

But I think that the effect we’ve seen, at least initially – and we have to prove this in Phase 3 trials – on the reduction of side effects in chemotherapy really is profound. For patients who get this particular type of chemotherapy that we used in our Phase 2 trials – it’s called MEC (mitoxantrone, etoposide and cytarabine), a three drug regimen – something like 20% to 25% of them suffer very severe mucositis, which again means they are not even able to drink.

They have to be on IV nutrition and IV fluids, and not only is that a huge physical burden on the patient, but it also makes them more susceptible to serious complications that could even lead to death from the chemotherapy itself.

To make the chemotherapy regimen more tolerable for the patient is a huge potential benefit and we certainly hope that continues to be demonstrated in the context of our Phase 3 trial. I hope that in addition to proving the outcomes related to survival, we’re able to reduce the side effects from the underlying chemotherapy such that the patients are able to more successfully come through treatment and do so without the debilitating side effects that many currently now have to endure.

WuXi: Do you have other drug candidates in your pipeline that qualify for breakthrough designations?

Rachel King: So far this is the only one we have that has been granted BTD, but based on the experience we’ve had getting the uproleslan designation, we certainly will consider applying for other products as they come through the pipeline. We are certainly very excited about some of the other things that we have at an earlier stage; that we think may have a shot at getting breakthrough designation.

WuXi: What lessons can other companies learn from your drug development experience?

Rachel King: One is that sometimes it’s worth applying for the breakthrough designation early.

A number of companies apply for breakthrough designation after they get their Phase 3 data. At that point you’ve already done your definitive trial, and as I understand it, it’s helpful at that time also.

But in our case we filed much earlier than that. So one lesson is that it’s worth a try to file early, in particular because as I said the visibility that we got around it was really meaningful in our ability to finance.

I would say another thing would be we very carefully thought through gathering a broad set of endpoints in our trial, including going beyond the traditional endpoints. That included, for example, gathering very specifically, data around mucositis; and I’ve described that benefit.

But also, it included gathering data around some biomarkers that relate specifically to how we believe our drug works. And so, we’ve had an active program as part of our development plan to gather biomarkers around the particular targets that this drug hits; and that has helped us to understand and make the case for how this drug might be working.

I would add that the importance of looking at biomarkers – and I can’t speak for the FDA when they were making their evaluation – and the inclusion of some of the biomarkers helped to demonstrate that the drug was hitting the target as intended and that mechanistically it was working the way we had hoped.

So in addition to applying early, I would add that looking at other endpoints was really important, including the evaluation of new biomarkers.

WuXi: Have FDA initiatives such as breakthrough therapy and fast track designations, changed the paradigm of clinical drug development? If so, how?

Rachel King: I think they have, and our experience is a great example of why they are so important. Because clinical development is so expensive and takes so much time, if there’s a way to somehow improve the economics around drug development – by making it more straightforward, by reducing risk, and that gets at the whole idea of improved communication with the FDA – I think that really helps.

I don’t know how many companies might have been out there in years past with potential breakthroughs and couldn’t raise the money to take the products forward. So the ability to access financing is really critical for companies like ours. And often for investors, they’re keenly interested in what the FDA thinks about a potential therapy.

Here’s a chance early in development to get a window, a preliminary sense, on how the FDA views a therapy. That makes a huge difference to small companies like ours, where we’re trying to rise above the din of all of these companies that are developing drugs.

It’s tremendously useful for visibility and practically useful because the meetings with the FDA are extremely helpful in terms of reducing the risk, when you think about what endpoints might be helpful in our particular study design.

WuXi: Looking at the entire drug development process, from discovery all the way to drug approval, what would be the 4 or 5 key areas or processes you would change or improve in order for companies to bring more and better drugs to patients each year?

Rachel King: One thing I would highlight, which grows out of comments I’ve made on the BTD, is that opportunities for better communication with the FDA or for clarifying expectations – clarifying the path forward; things that are able to reduce the regulatory risk – are hugely important because this is all about managing risk and reward in the context of an incredibly expensive and time consuming undertaking. So I would highlight improved opportunities for communication.

Another thing I would highlight is the potential for the use of biomarkers as surrogates, and particularly in disease indications where, for some reason, it’s difficult to evaluate the impact of the drug. For example in something like Alzheimer’s disease, where it takes a long time for the disease to develop, the clinical trials one would expect to be hugely long and expensive, and even to the point where a major pharmaceutical company couldn’t finance them.

The ability to determine what biomarkers could potentially be surrogates for evaluating diseases over the long term is really critical. And that’s relevant also for diseases – like in our experience – where the use of the biomarker helps along the way to increase confidence that a novel target is relevant to a particular disease.

So again that’s an aspect of reduction of risk. Use of biomarkers to help reduce risk during the clinical development phase either by clarifying that a particular mechanism appears to be involved in a disease or the use of biomarkers as surrogates for approval of products where the clinical trials are very long or difficult to conduct.

Then I would also add that – this seems like I’m getting more into the weeds – clinical trials are hard to manage. They’re difficult to get started. It takes a long time just to get a single clinical site up and running. So the degree that clinical sites are able to band together with centralized IRBs (Institutional Review Boards) is hugely helpful.

If you can go to only one IRB and cover multiple clinical sites that’s tremendous. We have seen the benefit of that when we’ve gone to centralized IRBs. We’ve also seen that benefit, in the context of one of our trials that’s taking place together with the National Cancer Institute. They have some centralized processes that expedite getting sites up and running. So things that expedite the recruitment and initiation process for clinical sites are very helpful.

And I would add finally that, in a broad category, things we can do for the whole ecosystem that protect access to capital that companies, like ours, require are helpful. Investors can put their money in lots of places. They can put it in IT. They can put it in real estate, and a lot of different areas. We need to continue to have the incentives that enable companies like ours to raise funds and there are a lot of things that go into maintaining a healthy ecosystem overall for investment. We need to keep an eye on the overall climate to encourage these kinds of risky, long-term investments so we can continue to attract capital.

WuXi: What will be the one or two most significant technological advances in drug development over the next year or two?

Rachel King: One is the really interesting approach of the National Institutes of Health’s All of Us Research Program. It has a process of gathering health records, health data on a large population of people, who can volunteer to give their health history on an ongoing basis as well as blood samples, agree to be followed, and to have tissue samples and blood samples analyzed so people can study the population dynamics of disease.

That’s tremendously exciting. We’re going to learn a lot from that program that we can’t foresee and that may really help to guide drug development and understanding of health and disease.

I also think biomarkers – I’m going to come back to this again – are not as flashy as CRISPR, but that speaks to the All of Us Research Program patient database. What the use of biomarkers speaks to is a better understanding of disease and the ability to more precisely target treatments to the patients who more likely will benefit from them.

That’s where I think we’re going to see exciting advances and it may not be so much that it’s a flashy new technology, as much as it is we are able to apply the technologies we have, along with some new ones, in order to precisely understand the basis of a particular patient’s disease and how specifically to target treatment for that person.