Glycomimetics Inc. CEO Rachel King said "a unique constellation of benefits" brought by GMI-1271 to relapsed/refractory acute myeloid leukemia (AML) led the company to decide on a phase III endpoint of overall survival (OS) to capture the widest upside clinically. "I see the reaction in the market and I'm surprised it's been as strong as it has," she told BioWorld, adding that "when people step back and take a breath and hear what we're saying," they'll agree about the OS design. "We're doing the right thing by the drug, which ultimately is the right thing by the company," she said.

Shares of the Rockville, Md.-based company (NASDAQ:GLYC) dipped 19 percent, or $4.50, to close at $18.32 after the details were unveiled. The study will test GMI-1271 in combination with MEC (mitoxantrone, etoposide and cytosine arabinoside [Ara-C]) or with FAI (fludarabine, Ara-C and idarubicin), and the single pivotal experiment starting in the third quarter is expected to enroll 380 adult patients worldwide. In the primary efficacy analysis, censoring for transplant will not be required – another potential boon.

GMI-1271, awarded breakthrough therapy designation last year, disrupts leukemic cell resistance by blocking E-selectin, an adhesion molecule on cells in the bone marrow, from binding with blood cancer cells.

Jefferies analyst Biren Amin said that "clearly, the company had pursued event-free survival or even overall response as an acceptable endpoint, but the agency did not budge on the [OS] endpoint." In a report, he predicted that the stock price would weaken. Suntrust Robinson Humphrey's Yatin Suneja did, too, though he said the sell-off in after-hours trading Monday (when Glycomimetics disclosed the design) was "overdone."

CEO King, though, said the FDA "did not insist on OS. They agreed that remission could also be a [primary] endpoint," and "helped us get to this conclusion."

The setup could mean good things if patients on the drug move ahead to transplant, and not censoring for the procedure seems to suggest that U.S. regulators value getting more patients to that stage, "which to our knowledge has never been previously allowed by the FDA in this setting," said Suntrust's Suneja, who forecast top-line data in the fourth quarter of 2020 and said GMI-1271 could reach peak sales of more than $1 billion by 2034.

Cowen analyst Ritu Baral wasn't surprised by the market pullback either. "We think news will disappoint many investors, given the Street's consensus expectations for an accelerated path based on complete response [CR] rates, the primary endpoint of the phase II studies and one supported by key opinion leaders and even possibly the FDA," she wrote in a report.

The OS primary endpoint means a six- to nine-month delay, whereas CR could have allowed for an accelerated path, but Glycomimetics hopes the advantages will outweigh time considerations. Talks with the EMA have not been conclusive, but if European regulators also end up requiring OS as the primary endpoint, the company is covered. Also, the phase III study with an OS rather than CR endpoint could echo strong OS findings in phase I/II data, which turned up encouraging 30-day and 60-day mortality rates. The earlier experiment also yielded much lower rates of mucositis and sepsis.

No more tox vs. efficacy trade-offs?

"While a trial that generated prospective CR data first and then OS data was possible, Glycomimetics did not want to divide the alpha between the two endpoints and jeopardize the trial's chances of success," noted Cowen's Baral, adding that the company "believes that the improvements in mucositis that they have seen so far in phase I/II patients treated with GMI-1271 might prove to be a critical aspect for the drug's efficacy in phase III, since it could enable patients to tolerate more rounds of chemo, which in itself would improve the chance and depth of remission. Furthermore, achieving a deeper remission should also improve the outcomes of a potential transplant."

King called mucositis "a terrible side effect," and pointed out that the phase II trial measured grade 3 or 4 mucositis, and GMI-1271 achieved a "very dramatic reduction" for patients on parenteral nutrition. Mucositis also is believed to contribute to the risk of sepsis because of gut-lining disruptions.

During a conference call with investors, the firm's chief medical officer, Helen Thackray, outlined details of the phase III study, which will follow the same dosing regimen as the phase II trial: participants will get the drug for one day before chemo starts, twice per day through chemo, and then for two days after. "We are also pleased that FDA has agreed to a fixed-dose regimen for GMI-1271 as opposed to weight-based dosing," she said. "Moving from a weight-based dose to a fixed dose simplifies the administration of the drug, both in the clinical trial and in the commercial setting as well as ensuring more consistent exposure to GMI-1271 for each patient," she said.

Thackray cited "several key factors that helped us with this [endpoint] decision. For one, as you recall, we observed not only a high rate of durable remission but also a high transplant rate, even in the older population of patients" in earlier research.

"We believe this high rate of transplant reflects both the ability to get to remission and the durability of that remission, allowing the sometimes lengthy transplant matching and preparation process to successfully complete. In addition, patients must be in good medical condition to proceed with the transplant regimen, and we believe GMI-1271 may improve the tolerability of induction, leaving patients well enough to go to transplant," as pointed out by analyst Baral.

The phase III effort is 90 percent powered for a hazard ratio of 0.68 or better, which stacks up nicely with such historical examples as the tests of Vyxeos (daunorubicin and cytarabine, Jazz Pharmaceuticals plc) in secondary AML, which reached statistical significance with 309 patients, and of Mylotarg (gemtuzumab ozogamicin, Pfizer Inc.), tried in front-line CD33-positive AML with 237 patients. Vyxeos was approved last August and Mylotarg in September. (See BioWorld, Aug. 4, 2017, and Sept. 5, 2017.)

When a therapy is added to the chemo backbone, "typically you see an increase in side effects," King said. "The physician is trying to decide how much more benefit do I think I'll get, and how much more tox am I willing to take in order to get that benefit? It brings the physician to a point of making a clinical trade-off." In phase II, however, GMI-1271 improved the safety profile of the underlying chemo, she said.

AML is hot. Last month, Cambridge, Mass.-based Agios Pharmaceuticals Inc. said the FDA accepted the company's NDA for ivosidenib (AG-120) to treat patients with r/r disease and an isocitrate dehydrogenase 1 (IDH1) mutation. The NDA was granted priority review and has been given a PDUFA date of Aug. 21. Agios completed the NDA submission in late December 2017, and in January of this year raised $475 million in a public offering to fuel its efforts. There's been bad news, too: Also at the end of last year, Syros Pharmaceuticals Inc., of Cambridge, Mass., disclosed that just one out of 48 evaluable patients enrolled in an ongoing study of the company's lead gene control therapy, SY-1425 (tamibarotene), had achieved a complete response. The compound aimed to treat genomically defined subsets of patients with AML and myelodysplastic syndrome. (See BioWorld, Dec. 12, 2017, and Jan. 22, 2018.)