Karyopharm Therapeutics Inc.'s phase II failure with lowered-dose selinexor in acute myeloid leukemia (AML) "put[s] to rest the sepsis question," which was "a big overhang on the stock, frankly, and on the drug," CEO Michael Kauffman told BioWorld Today, as trials continue with the compound in other, somewhat less intractable indications.

Newton, Mass.-based Karyopharm said late afternoon Thursday that the results of a planned interim analysis of the phase II SOPRA study evaluating single-agent selinexor in relapsed/refractory AML showed the test will not reach statistical significance for overall survival (OS), the study's primary endpoint.

But selinexor-treated patients who achieved a complete response (CR) did exhibit a substantial OS benefit as compared with the physician's choice (PC) arm, the company said, and the data safety monitoring board (DSMB) agreed that patients would be permitted to continue on the selinexor arm or the PC arm, as applicable, following discussion between the patient and his or her treating physician. Meanwhile, Karyopharm is hardly giving up on the drug, and forges ahead with development in a number of other indications.

Shares of Karyopharm (NASDAQ:KPTI), which had ended the day at $13.84, up $2.81, or 25.5 percent, fell more than 16 percent in after-hours trading Thursday.

Selinexor emerged from Karyopharm's Selective Inhibitor of Nuclear Export, or SINE, platform. AML is "by far the toughest nut to crack, but we and our investigators were encouraged by the 10 percent response rate in phase I," Kauffman said. "Many companies go and do a big phase II that's not controlled and they come out with a much more solid response rate, and because they didn't do a controlled study in phase II, they have to go to phase III. Then they find out that in AML – which is different from many other diseases – responses don't always translate into a survival benefit." Karyopharm, he said, wanted to answer the main question as early as possible.

SOPRA enrolled patients, 60 and older, with relapsed or refractory AML who were ineligible for intensive chemotherapy and/or transplantation. Patients were randomized to receive either single-agent oral selinexor 60 mg twice weekly or PC, which included best supportive care (BSC) alone, or BSC plus either Vidaza (azacitidine, Celgene Corp.), Dacogen (decitabine, Otsuka America Pharmaceuticals Corp.) or low-dose cytosine arabinoside. Based on unaudited site data, SOPRA enrolled 176 patients with a median of two prior regimens in the U.S., Canada, Europe and Israel. Among those on the selinexor arm, 13 percent demonstrated a CR with or without full hematologic recovery compared to 3 percent of patients on the PC control arm. Some patients remained on selinexor for more than one year, but that did not result in a statistically superior OS compared to the PC arm. The DSMB found no new clinically significant adverse events in the patients receiving selinexor.

Kauffman pointed out that not only were rates of sepsis lower on the selinexor arm compared to PC patients in SOPRA, but so were the levels of febrile neutropenia (FN): sepsis 4.9 percent, FN 14.7 percent on the drug arm; sepsis 6.1 percent, FN 36.4 percent on the PC arm. As expected, the most common selinexor-related adverse events were nausea, anorexia, fatigue, vomiting and thrombocytopenia. Patients who have benefited from selinexor treatment on the SOPRA study were given the option to continue therapy.

"Of course we wanted to win," he said, and in a sense, the drug did, with clear responses about four times higher than the control arm – not bad for an oral therapy with a side-effect profile similar to or better than the control arm.

"It was very clear that pretty much uniformly across our indications, 60 mg is the most efficacious dose," Kauffman said. "When you look at the data with a longer-term view as opposed to the usual one-month, dose-limiting-toxicity view, which is historically the way companies have done it, you generally end up with a higher dose. If you look over three or four months, especially with targeted therapies, then you often end up with a dose that's lower than the maximum tolerated dose. That happened to us."

He said the company is "very comfortable" with the efficacy "in a population that pretty much doesn't get responses," adding that it represents a "pretty darn good number in this second-, third- and fourth-line population. I'm certain that lowering the dose here was absolutely the right thing to do [in terms of efficacy as well as safety]."

In the summer of 2015, a higher-than-expected rate of sepsis prompted Karyopharm to drop the dose from 100 mg, and the company pointed out at the time that the move affected only SOPRA. (See BioWorld Today, Aug. 11, 2015.)

ANALYST: DLBCL GREATER HURDLE THAN MM

Karyopharm is exploring other indications, and it expects to report top-line data from a randomized phase IIb SADAL study evaluating single-agent selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) shortly and top-line data from the phase II portion of the randomized phase II/III SEAL study evaluating single-agent selinexor in patients with advanced liposarcoma in mid-2017.

Jefferies analyst Brian Abrahams expects SADAL data to be unveiled at the American Association for Cancer Research meeting in April. "Though an abstract has not yet posted, the title suggests Karyopharm will present phase IIb SADAL DLBCL data (timing in-line) showing durable responses," he wrote in a report Thursday. "Success in DLBCL could provide additional upside to our valuation. Our understanding is that the data will include evidence of durable responses in both GCB and non-GCB subtypes of relapsed/refractory DLBCL [patients]. It is important to note that the trial is comparing two selinexor doses, a high 100 mg (high) vs. 60 mg (low) oral dose BIW (n=200 pts). Our sense has been that the company is encouraged by response/durability but that the lower dose is preferable – if regulators are amenable to streamlining the study – given toxicities with the higher doses that we would expect based on the totality of prior data for selinexor."

In May 2015, the company started a phase IIb trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). "Though we have seen some promising prior signs in DLBCL, we view the hurdle to entry as greater than MM, and conservatively estimate their probability of success in this indication at 25 percent. Nonetheless, the large market indication is a major opportunity, and we believe peak worldwide sales could reach $884 million by 2027," Abrahams wrote.

Last December at the American Society of Hematology meeting in San Diego, Karyopharm offered updated results from the phase Ib dose-escalation portion of its ongoing STOMP study showing high response rates when selinexor is combined with the proteasome inhibitor Velcade (bortezomib, Takeda Oncology Co.), including in patients with MM otherwise refractory to proteasome inhibitors.

Other presentations at the meeting described clinical data demonstrating the activity of selinexor in combination with Kyprolis (carfilzomib, Amgen Inc.) and Pomalyst (pomalidomide, Celgene Corp.) in MM, as well as selinexor with dexamethasone in quad- and penta-refractory MM in the company's STORM trial.

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