GlycoMimetics Aiming At Tough Targets

By Wayne Koberstein, Executive Editor, Life Science Leader
Follow Me On Twitter @WayneKoberstein

Startups may spring from pure academics or from a healthy and heterogenous mixture of science, business experience, and inspired thinking. Rachel King, CEO of GlycoMimetics, and others brought experience to the company. Her cofounder, Dr. John Magnani, brought original science, and an expert team soon joined in response to the inspiration created by the company’s concept. The germ idea was to make a formerly “undruggable” set of disease targets druggable. Deep, careful studies of molecular structures were required, followed by rational drug design to achieve the goal of small molecule therapy mimicking natural carbohydrates critical to the “glycosylation” of cellular proteins.

GlycoMimetics is developing a drug, uproleselan, designed to mimic a glycan in blocking E-selectin, which may have several results when used with chemotherapy, potentially forcing tumor cells out of the marrow and back into the bloodstream, reducing the effective chemo dose, and lowering chemo-caused side effects such as neutropenia and digestive-tract mucositis.

Another lead compound is rivipansel, which inhibits a wide range of selectins to treat some of the worst symptoms of sickle cell disease (SCD). Uproleselan and rivipansel are both in Phase 3 clinical trials. Earlier candidates for oncology indications, some with other new mechanisms of action (MoAs), are also in the pipeline. It is a formidable lineup and a correspondingly large challenge for a small company such as GlycoMimetics.

EXPERT ENTERPRISE

Rachel King also has a deep background in the industry as a business person dedicated to a science-driven sector — in small biopharmas, Big Pharmas, and the financial side. Though she veered away from a medical education in college, she had a childhood fascination with biology that stuck with her in the business world. Beginning as a consultant at Bain, she has been an accomplished executive at her former companies such as Genetic Therapy (GT), Novartis, and the venture capital fund, New Enterprise Associates (NEA).

King spent 10 years at Genetic Therapy, from its early times through an IPO and eventual sale to Novartis, which she joined and served as a senior VP. At GT, she began a lifelong association with its founder and CEO, James Barrett. Barrett became her career mentor and helped found GlycoMimetics as its initial venture investor; he just recently stepped down from his role as the company’s board chairman. Through the years, King also has become involved in service to the industry as past chair of the board at BIO, chair of BIO’s emerging companies board, and contributor to other industry organizations.

Such a background makes it easy to see how King’s business and science leadership has likely informed the structure, strategy, and market-savvy approach of GlycoMimetics in drug development. Applying lessons from her own career and the company’s experience, she has ensured the company internalizes industrywide issues in clinical trial design, costs, and regulation as key elements in its development plans. A few years in Big Pharma were just fine for learning the big picture, but King’s true clarion began to call — the lure of enterprise inside an original startup. Her move to NEA, at the invitation of founder Charles Newhall, put her back in a working partnership with Barrett on projects including one that led to GlycoMimetics.

“At NEA, I did due diligence on some of the deals we considered and got to see how decisions were made, and I learned about how the VC world worked,” King says. “At the same time, I was looking for an opportunity to start a company that would be both a good fit for me and a good investment for NEA. John Magnani and I subsequently came up with GlycoMimetics, with NEA as our initial lead investor.”

Former CEO of PharmAthene, Eric Richman, whom King had known “from the early days” when he worked at MedImmune, introduced her to Magnani, confident they would share interests and work well together. “John had been working his whole career with the perspective of glycobiology, looking at using specialized rational- design approaches to chemistry that could make carbohydrate-related targets druggable. Specialty-drug deals were hot at that time, but I was not interested in them. I was interested in doing something more ‘high science’ even though I’m not a scientist, and John convinced me glycobiology would be a really exciting space to be in — and if we were successful, our approach might be transformative. So, based on that, we started the company together in 2003.”

At that point, GlycoMimetics had little to its name beyond some initial IP and a few early-stage compounds. “We started the company with a technology, and at first we believed we had found a drug candidate, but it turned out not to be good enough. We had to discover completely novel compounds, which John and his team eventually did. So, the early years were focused on discovery. Then we got to the interesting question of whether we could drug a particular target, in our case, the selectins,” says King, while acknowledging the process hardly fit the Big Pharma mold, which often begins with a therapeutic focus.

“If you’re a big company, you can decide strategically, ‘We want to be in lung cancer,’ and then you go figure out how to be in lung cancer. If you’re a small company, you only have certain tools at your disposal, and you ask yourself, ‘What can I do that would be meaningful with these tools, with these compounds?’”

The company subsequently chose to go after SCD, specifically the intensely painful complication, vaso- occlusive crisis (VOC), which fit the desired profile of an acute-treatment indication likely to achieve Orphan Drug status and Fast Track qualification. Also, as King says, “We wanted an indication where the biological target, to the extent we can know it, would be critical to the pathology of the disease associated with it.” The VOC indication appeared to offer a straightforward clinical path, yet it could possibly transform treatment for patients.

At the time, the orphan-drug sector had not yet heated up, and orphan programs were extremely difficult to finance, but the combined influence of Jim Barrett at NEA and the company’s foundational science won the day. While in Phase 2, GlycoMimetics secured a partnership with Pfizer, which took over further development of rivipansel, and GlycoMimetics then began to expand its own clinical development activities. Having been a public company for only five years, GlycoMimetics is already in late-stage drug development with the rivipansel sickle cell program set for a Phase 3 readout this summer. The next lead program, uproleselan in acute myeloid leukemia (AML), has just started in Phase 3 with FDA Breakthrough Therapy and Fast Track designations, as well as Orphan Drug status in the EU.

Hematology/oncology is the company’s stated focus, but the subsequent drugs in the GlycoMimetics pipeline are mainly focused in oncology. Still, says King, “Mechanistically, some of what we’ve learned about targeting selectins in sickle cell is relevant to other areas where we’re working now.”

The second product, uproleselan, also aims to relieve patients’ suffering, using a similar mechanism of selectin binding to treat blood cancer. By itself, uproleselan does not kill the cancer; it has no antitumor activity on its own. Instead, the drug affects the way cancer cells interact with the bone-marrow microenvironment. “When AML blast cells move to the bone marrow and bind to E-selectin, it makes them more resistant to chemotherapy. With chemotherapy, you can generally control the circulating cells, but you can’t kill the ones that are hiding in the bone marrow. Uproleselan makes those cells vulnerable to chemo, and we believe it is leading to better outcomes in cancer- related efficacy,” says King.

Clinical data suggest the drug’s action may also protect blood stem cells in the marrow by slowing their growth below the rate of neoplastic cells chemo drugs typically target. An additional benefit may be less chemo- caused “mucous-sloughing” and related problems in the intestines.

“One of the worst side effects of some chemotherapy for AML is that 20 to 25 percent of patients get horrible inflammation of their mucus membranes throughout the gut. Some can’t even swallow liquids,” King notes. “In our Phase 2 clinical trial with uproleselan, we had only two percent who developed such severe mucositis, a really dramatic reduction,” she says.

Meanwhile, a second-generation drug for AML, designated GMI-1687, appears to have broader action, much greater potency, and easier, subcutaneous delivery compared to uproleselan. The newer drug, now in early IND studies, may require a dose only one 500th that of an uproleselan dose, according to the company, which says GMI-1687 may “broaden the clinical usefulness of an E-selectin antagonist to conditions where outpatient treatment is preferred or required.”

THINKING TRIALS

If you are introducing an entirely new drug class for unmet needs, you would best give a thought to supporting it with more than efficacy and safety data. GlycoMimetics has noticeably built practical endpoints into its trials intended for the institutions and cost-watchers that would occupy its supply chain. Examples with rivipansel include the drug’s association (versus placebo) with patients’ reduced time in hospital and prescribed opioid use. But these are not surrogate endpoints or shortcuts to approval. Although some earlier trials used historical data rather than controls, the sickle-cell Phase 2 and 3 programs and AML Phase 3 program all use randomized control trials. The AML Phase 3 trial also carries the gold-standard primary endpoint of overall survival in cancer. King explains: “For this particular population, we felt that we might have to spend a bit more time to go for overall survival. We decided that if we demonstrated an effect on overall survival in a randomized controlled trial, it would give us the strongest possible positioning, because we’ll have data on what everybody cares about most, data that resonate with payers, physicians, and patients. It also was the best way to capture how our drug actually works.”

King says the company also has thought about how its AML approach fits into the expanding universe of nonchemo cancer therapies, especially immuno-oncology. “Cancer is not one disease. Even an organ cancer, such as breast cancer, is not one disease. There will be a need for many approaches including, we hope, the approach that we’re taking. It is encouraging to see this evolution, but chemo, certainly for now, is here to stay, and if we can improve some of the background toxicities of this particular regimen, it would be a great contribution.”

The range of GlycoMimetics’ R&D pipeline and the long-range potential of its technology suggest more than a short-term exit strategy for the company. You bet that companies are always for sale, and no company is immune from merger or takeover. But this is one company that seems to be thinking more in the direction of full integration, or at least participation, in the commercialization and marketing of its products.

“We want to strike the right balance between assets we keep under our own control and partnering to use the resources we have to build value,” says King. “Where that leads us, we’ll see. Because we have a technology platform generating these molecules with this specialized chemistry, part of building value for us is to continue to build that pipeline.”

CAREER VALUES

Companies always seem to encounter that “biggest hurdle,” when the situation may be new and unique, but at least past encounters with similar challenges can make all the difference between making it over the hurdle or losing the race. King has some useful advice to share about jumping hurdles.

“Thinking about the challenges we have faced over the years, I would say you need to have a lot of perseverance, flexibility, and the best people you could possibly recruit to your team. You should have an excellent and diverse team — diverse in its thinking and approach to problems — so that you really can have different perspectives when things don’t go according to plan. Our biggest challenge in the early days was the possibility of running out of money. That is where you have to translate something that is just exciting science into transformative care. Exciting science is valuable, even fundamental, to building an innovative company, but the science must lead to something that will make a difference for patients.”

King also emphasizes the real distinction between research and development. “Discovery research must be a bit more open to the unexpected, whereas development is a lot about excellent operations management, planning, and execution, so managing the transition from primarily R to D is also critical.”

Specific advice for dealing with the investment scene may have to wait, however, for the scene to resolve in light of current challenges. King diagnoses today’s market maladies as largely political: “What happens in the public markets will affect what happens in the private financing markets, but there’s a lot of politics right now driving the public markets. Bankers tell me they’ve spent more time talking about politics now than ever in their careers, because we’re in a wave of something that could be market-moving and unprecedented. For the industry, there is all the focus on drug pricing and, I have to say, appropriate concern raised about patient out-of-pocket costs and affordability. We do need to be concerned about patients’ affordable access to our drugs. But the political environment could be challenging, and I don’t know how that’s going to play out in the coming years. If we can come up with some constructive solutions that will continue to support the strong performance of publicly traded companies, we will continue to ensure that a good private market exists.”

As a woman in biopharma, King sees the challenges the industry faces as analogous to those women face in business — namely, the need to balance the interests of work with the human priorities of family, children, and personal health.

The same view may well reflect the GlycoMimetics approach to understanding and applying the sugary dynamics of nature. The company exemplifies a young wave of biopharma innovation as new companies take on new challenges in making formerly undruggable mechanisms druggable. Carbohydrates such as selectin ligands have been enticing drug targets for decades but have avoided any magic bullets until now. Perhaps this company has drawn a bead on the bull’s-eye, or perhaps biology will again rise up, as it has so often, to frustrate the drug developer’s aim. King and her experienced team may suggest, however, that the quality of a biopharma company’s management may be rising to the occasion in this new wave of risk taking.