GlycoMimetics In Vaso-Occlusive Crisis Of Sickle Cell Disease Has Decent Potential

About: GlycoMimetics, Inc. (GLYC)
by: Avisol Capital Partners

GlycoMimetics has an outlicensed lead candidate targeting VOC in SCD patients.

Despite failing a phase 2 trial, the drug shows clinical and therapeutic effect in this disease with high unmet medical need.

With a good amount of cash, another late-stage candidate and an upcoming catalyst, the company seems investible.

GlycoMimetics (GLYC) has a platform whose lead candidate, rivipansel, is licensed to Pfizer (PFE) and is in an SPA-moduled late phase 3 stage targeting vaso-occlusive crisis (VOC) in sickle cell disease (SCD). Although GLYC will receive only milestone payments and low teen royalties, an approval will prove that the platform works, which will make its next candidate, fully owned uproleselan targeting r/r AML, very valuable. The company is not lacking in cash, and we expect the milestone payments from Pfizer to add to its cash balance once the lead drug candidate gets approval. If all this happens, it would turn out to be a very interesting investment.

The platform

GLYC specializes in producing a class of drugs called glycomimetic drugs. These are small molecules that mimic the structure and activities of naturally occurring carbohydrates. These carbohydrates occur on cell surfaces, “where they act as recognition molecules for other cells, functional molecules, and pathogens.” These carbohydrates become involved in a large variety of diseases, from inflammation to cancer and infectious diseases. However, naturally occurring carbohydrates have historically not been good therapeutic candidates because they lack properties like increased affinity, serum half-life, stability and bioavailability. GLYC designs mimetics, or artificial small molecules that mimic the properties of these carbohydrates, to address a variety of diseases.


GLYC’s lead drug candidate, rivipansel, is a pan-selectin antagonist targeting VOC in SCD patients. Uproleselan is an E-selectin antagonist currently in phase 1/2 clinical trial targeting acute myeloid leukemia (AML), as well as phase 3 trial to treat relapsed/refractory AML.

Selection is a soluble lectin that binds to carbohydrates, not only at the cell surface but also causing inflammatory cascades when present in the bloodstream. These are adhesion molecules expressed by leukocytes, “and are involved in the primary interaction of lymphocytes with the endothelium of blood vessels. The binding of selectins serves as a biologic brake, making the leukocyte quickly decelerate by rolling on endothelial cells, as the first step of extravasation.” Leukocyte extravasation is the leakage of leukocytes from the blood and towards damaged tissue sites, and is an innate immune response. When a foreign body releases pathogens, cytokine molecules trigger the blood vessel endothelium to release these adhesion molecules, which act somewhat like velcro and force the leukocytes to gather near the site of the pathogen expression. This causes an immune response, and GLYC’s pan-selectin antagonist acts as a control of this immune reaction which can sometimes be dangerous for the body.

The selectins comprise a family of 3 members: P-selectin, E-selectin and L-selectin. They all mediate adhesion between blood cells (leukocytes) and the endothelium. More details are available in the medical text below, although this is not absolutely necessary to understand what the company does.

(Source: Author screenshot from material linked above)

Selectins promote extravasation of of cells out of the bloodstream, and are therefore strong therapeutic targets, especially in inflammatory diseases and metastatic cancer.

Engagement of selectins by their ligands leads to cellular activation and adhesion and plays a role in thrombus formation. In sickle cell disease, the selectins underlie vaso-occlusion, which results in vaso-occlusive crisis. In SCD patients high levels of soluble E-selectin (sEsel) are associated with increased mortality (Kato, BJH 2005). In addition, SCD patients exhibit chronic activation of the coagulation cascade and of leukocytes.”


A near-term catalyst for GLYC is the data expected mid-2019 from the phase 3 trial for rivipansel for the indication of vaso-occlusive crisis of sickle cell disease.

Data from another ongoing phase 3 trial of uproleselan for the indication of Relapsed/Refractory AML is due in 4Q 2020.


Previous trial data

After showing positive murine data in 2008, published in the Blood Journal, GLYC announced phase 2 results just a little over 4 years ago. This was a 76-patient, randomized, double-blind, placebo-controlled trial of efficacy, safety and pharmacokinetics in VOC-SCD patients aged 12-60.

The core text from the results published in the Blood Journal is as follows:

All subjects reached the composite primary end point of resolution of VOC. Although time to reach the composite primary end point was not statistically different between the groups, clinically meaningful reductions in mean and median times to VOC resolution of 41 and 63 hours (28% and 48%, P = .19 for both) were observed in the active treatment group vs the placebo group. As a secondary end point, GMI-1070 appeared safe in acute vaso-occlusion, and adverse events were not different in the two arms. Also in secondary analyses, mean cumulative IV opioid analgesic use was reduced by 83% with GMI-1070 vs placebo (P = .010).

The company press release says the following about the efficacy data:

The primary efficacy endpoint was reduction in time to resolution of VOC, defined as 1.5 cm sustained decrease in visual analog scale (VAS) pain score from baseline and transition to oral pain medications; or feeling ready to leave the hospital; or actual time of discharge from the hospital. In the primary efficacy analysis, the median time to resolution of VOC was reduced by greater than 2.5 days following treatment with rivipansel (time to resolution was 69.6 hours for the rivipansel group compared to 132.9 hours for the placebo group; p=0.187.)

Other salient points of note (sourced from references scattered throughout the article):

“The time to transition to oral analgesics was also decreased in the GMI-1070 group compared with placebo; this reduction was 76 hours in the pooled GMI-1070 group (log rank P 5 .089) and reached statistical significance in the pediatric GMI-1070 population (87.8 hours, log rank P 5 .037).”

“...improvements, some quite large, were seen in every efficacy end point explored, whereas previous trials in VOC have shown only modest, if any, improvements in some but not all end points measured.”

“In addition, the improvements observed here appeared independent of age and HU use and were achieved without worsening of other parameters, such as requirement for blood transfusion or frequency of AEs.”

So, on the positive side, we see that the drug does work, with all patients reaching the composite endpoint of resolution of VOC. We also see that it is safe and can reduce the use of IV opioid analgesic, the current mainstay of VOC-SCD, by a large difference with strong statistical significance compared to placebo. However, the time to resolution creates a problem; although it is clinically meaningful - a somewhat vague term that is used to describe un-analysed drug effect, here 41 hours vs. 63 hours for placebo - the difference between drug and placebo is not statistically significant. This could be for a number of reasons non-detrimental to rivipansel’s case, and only a phase 3 trial in a larger population can bring this out. However, it could be also for one single reason that is detrimental to the drug - that the drug works, but only marginally. The phase 3 trial can also bring this out. So, it would have been a happier situation if the difference were statistically significant.

The study authors noted, as possible cause of lack of stat sig despite clinical significance: “Although this randomized phase 2 study was powered to detect an efficacy signal and effect size estimation for planning a phase 3 study, patient variability, characteristic of SCD, may have been accentuated by the adaptive study design and precluded achieving significance for the primary end point in this sample size.”


GLYC is well-funded, with a market cap of $531.56 million, a cash balance of $212.27 million as of the December quarter and cash burn is -43.33 million.

The company has significant milestone payments potential - see below:

(Source: Corporate Presentation)

Here’s a chart showing recent insider buy/sells. Insiders are apparently not buying the stock:


And here’s a quick snapshot of fund ownership:



Vaso-occlusive pain is a serious complication of SCD. Hydroxyurea is the only drug currently approved by the FDA for SCD, but it comes with some serious adverse effects and also does not work in some patients. Current standard of care for VOC-SCD patients is pain management using IV opioids. This usually requires extended hospitalisation, often upto a week. There are more than 100,000 hospitalisations due to VOC each year in the USA. The aim of rivipansel is to reduce IV opioid use days, reduce hospital stay and reduce the number of days needed to resolve the VOC. A number of other drugs - including heparin, eptifibatide, prasugrel and propranolol - have been studied for their capacity to inhibit cellular adhesion of leukocytes.

The Blood Journal article discussed some competing studies:

“Three relatively large trials of novel therapies for VOC have been completed in the last 15 years. The trials of purified poloxamer 188 and inhaled nitric oxide, respectively, showed only minimal and no improvement in time to resolution of VOC between treatment groups. More recently, a study of tinzaparin vs placebo during VOC was reported to improve time to resolution of VOC,24 although both treatment of pain and definition of resolution of VOC were distinctly different from those typically used in the United States.”

The inconclusive nature of these studies, coupled with lack of treatment options except painkillers, and the large, billion-dollar potential market, shows that rivipansel has considerable potential if even moderately successful in its phase 3 trial.

There is a potential competitor here in Novartis AG (NVS), whose phase 2 SUSTAIN trial of anti-P-selectin antibody crizanlizumab showed treatment effect in pain management in SCD patients.


On the risk side, the company just filed a $250 million shelf offering, so expect some dilution up ahead. It has enough cash, and the lead drug is being developed by Pfizer anyway, so the offering may actually indicate management sentiment regarding potential for the rest of the pipeline.

We would also have been happier with a clean primary endpoint data with clear stat sig, which did not happen in phase 2.

Lastly, rivipansel is licensed out, so even if it succeeds, don’t expect any major windfall for GLYC. That will simply be a precursor for the company's other late-stage drug, uproleselan, to achieve its own potential.


I think, on balance, that this company has a decent chance of success despite not achieving primary endpoint in the phase 2 trial. Many phase 2 trials achieve primary endpoint but then the drug fails in phase 3; so it isn’t too much to expect, given the strong therapeutic signals, that the opposite may happen here. The company has cash, and the fallback option in r/r AML - which we haven’t covered here - is also an added benefit. Overall, I would buy at these low prices and wait for phase 3 data readout. As always, our core biopharma investing principle should be followed - don’t feel guilty about taking profits on a 10-20% rise of a stock’s price.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.