On 6 May 2024, US-based biotech GlycoMimetics announced that its E-selectin inhibitor candidate uproleselan had failed to improve the overall survival (OS) of late-line acute myeloid leukaemia (AML) patients in its Phase III, randomised, double-blinded trial (NCT03616470).

The efficacy and safety of uproleselan were evaluated in combination with a salvage chemotherapy regimen — mitoxantrone, etoposide and cytarabine (MEC), or fludarabine, idarubicin, and cytarabine (FAI) — given based on the investigators’ choice. Patients in the active arm demonstrated a median OS of 13.0 months compared to 12.3 months in the control arm, and statistical significance was therefore not met. No hazard ratio or p-value from the analysis was reported at this stage. Adverse events that occurred were consistent with the known safety profile of the MEC/FAI regimen. In the corporate update call that took place on 6 May, GlycoMimetics stated that it is in discussions with regulatory and statistical experts on further analyses of the comprehensive data set.

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This is the second discontinuation of a late-stage AML trial in 2024, after Gilead stopped magrolimab’s Phase III ENHANCE-3 trial in February, highlighting the grave difficulty in treating relapsed/refractory AML and the dire unmet medical needs of those patients.

As the company searches for the next step of development for uproleselan, the market is waiting for the upcoming interim analysis data from the agent’s Phase II/III, first-line, National Cancer Institute (NCI)-sponsored trial, where the agent is given in combination with the 7+3 cytarabine and daunorubicin chemotherapy regimen. Even if it is positive, the event-free survival data from this trial would only be powerful enough to support a filing for a much more restricted label than previously, covering only newly diagnosed patients above 60 years of age and eligible for intensive induction chemotherapy. In the meantime, further data analyses on the failed Phase III trial may bring new critical insights and eventually reignite the market’s interest in the candidate.

The chance of reviving uproleselan is slim

The expression level of E-selectin ligand may serve as an important prognostic factor that could redeem uproleselan in this trial, as its Phase I/II result revealed a higher E-selectin ligand expression observed in previously treated patients, achieving a complete response and prolonged median OS. It is key for the company to determine what level of E-selectin expression would be appropriate for uproleselan to exert adequate efficacy and durability, similar to the tumour proportion score (TPS) ≥1% restriction imposed on the labels of PD-1 inhibitors. Other stratification factors, such as patient age, disease status and prior treatment exposure, may reveal a different positioning for the E-selectin inhibitor to deliver its therapeutic value.

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There may also be new opportunities for uproleselan in another use case and patient segment. Uproleselan demonstrated encouraging preliminary efficacy and safety as a frontline combination with the standard-of-care AbbVie’s/Roche’s Venclexta (venetoclax) and azacitidine in a Phase I, investigator-initiated trial (IIT) (NCT04964505) treating patients who are ineligible for intensive induction. In secondary AML, uproleselan in combination with cladribine and low-dose cytarabine produced a 39% overall response rate in a Phase Ib/II IIT (NCT04848974). In a different scenario, these trials may work as a new space in which GlycoMimetics can explore uproleselan’s value. However, the chance of reviving uproleselan remains slim as the biotech is running short of time and cash to launch another large-scale, late-stage trial.

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As GlycoMimetics’s commercialisation partner in the Greater China region, Apollomics is conducting a Phase I pharmacokinetic and safety study (NCT04839341) in Chinese patients with relapsed/refractory AML. GlycoMimetics did not comment in the latest update call about uproleselan’s future clinical development in the Chinese market. The Chinese biotech has yet to release a statement regarding the future of the E-selectin inhibitor. With uncertainties surrounding both the China-based trial and the agent, in the immediate future previously treated AML patients will continue to face an under-addressed medical need and will lack therapeutic options.