Karyopharm’s Xpovio In Multiple Myeloma Priced At $22,000 Per Four-Week Cycle
Executive Summary
Immediate interaction with US FDA after stressful advisory committee facilitated accelerated approval in fourth-line myeloma, company says. Four different dosing regimens will be priced at $22,000 for four weeks.
Karyopharm Therapeutics Inc. obtained approval for Xpovio (selinexor) to treat penta-refractory multiple myeloma patients on 3 July, with a full approval hinged on the ongoing Phase III BOSTON trial, despite safety concerns and other issues overhanging the drug.
Pessimism reigned regarding the chances for the first-in-class nuclear export inhibitor to gain accelerated approval following a US FDA advisory committee review in February, but investors turned optimistic as the agency's decision was announced.
In fact, Karyopharm's stock surged 36% to $11.09 per share even before trading of the company's stock was halted just after 11 a.m. Eastern – a few hours before Xpovio's approval was announced. The stock resumed trading and was up another 6% in the after-hours market.
Karyopharm's 3 July news also included an announcement that chief commercial officer Anand Varadan will depart the company effective 5 July. Vice president of sales Perry Monaco was promoted to a senior VP position to oversee the Xpovio's launch.
Executives said during a same-day investor call that the drug should be available to patients by 10 July, noting that a considerable amount of Xpovio already has been manufactured. Karyopharm set the drug's wholesale acquisition cost at $22,000 per four-week dosing cycle, which will be the same for all four approved dosing regimens.
“We wanted to make sure that cost was not going to be a factor in determining the optimal dose for a patient,” CEO Michael Kauffman told Scrip. “It would be absolutely the wrong thing to do medically. The price itself was basically placed at the higher end of what’s currently done in myeloma now with Pomalyst (pomalidomide) and with Darzalex (daratumumab), particularly in the late stage, and it’s a bit lower than some of the other drugs in hematologic malignancies for these patients who unfortunately have exhausted all available options. But what we didn’t want to do was provide an incentive to get the wrong dose.”
Celgene Corp.’s Revlimid (lenalidomide) is the top-selling multiple myeloma drug globally, but it is expected to face generic competition in 2022. (Also see "Multiple Myeloma: A Growth Market Set To Shrink As Revlimid Generics Hit" - Scrip, 11 Sep, 2018.) That means the Xpovio launch will occur in an indication with significant branded drug competition and expectations of increased genericization, adding to the potential challenges posed by the departure of Karyopharm’s CCO.
The company did not comment on why Varadan is leaving the company, but Kaufmann wished the outgoing executive well during the investor call and noted that Varadan "played an integral role in our commercial preparedness."
Outlook Was Bleak After Advisory Committee
Commercialization of Xpovio appeared uncertain after a 26 February meeting of the FDA’s Oncologic Drugs Advisory Committee (ODAC), during which the panel voted 8-5 that approval of selinexor should wait until the Phase III BOSTON data were available. At that point, chances for accelerated approval did not look good, Kauffman admitted. (Also see "Karyopharm Selinexor Approval Likely Awaits BOSTON Trial, But US FDA Promises To Move Quickly" - Pink Sheet, 26 Feb, 2019.) But near-immediate dialogue between the company and the agency addressed issues of concern, he noted, enabling the accelerated approval to go forward. (Also see "Keeping Track: Poteligeo, Onpattro, Galafold And Annovera Approved; Selinexor Submitted" - Pink Sheet, 12 Aug, 2018.)
FDA officials told Karyopharm that despite the vote recommending against accelerated approval, they also took note of other commentary in favor of the approval, including those by the one multiple myeloma expert on ODAC. “They also listened very carefully to the patients and the doctors who spoke during the public session,” Kauffman said. “There was a definite sense at FDA that the ODAC vote, which was reasonably close, maybe didn’t quite reflect the reality” of the drug’s risk-benefit profile in a patient population with very limited options.
The discussions also identified additional data that the agency wanted to see, which Karyopharm provided, the exec said, and clarified that the company, which had no commercial products, was not able to offer patients an expanded access program while approval was pending. The FDA had indicated that Karyopharm was capable of doing such a program, which may have swayed the votes of some ODAC panel members, Kauffman said.
Going into the advisory committee, briefing documents mentioned concerns about drug toxicity and also questioned how clear the benefit of selinexor was in a combination regimen with dexamethasone. (Also see "Karyopharm’s Selinexor: US FDA Unconvinced By Efficacy In Single-Arm Trial" - Pink Sheet, 22 Feb, 2019.) The new drug application (NDA) was backed by the Phase IIb STORM study, which showed a 25.3% overall response rate in a subgroup of 83 patients. However, those responses included one stringent complete response, no other complete responses, four very good partial responses and 16 partial responses.
Warnings And Precautions, But No Black Box
The accelerated approval – for combination therapy with dexamethasone in multiple myeloma patients who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, two immunomodulators and anti-CD38 antibody therapy – includes a label with no black box warning.
However, there is language regarding monitoring instructions, recommended concomitant therapy, and warnings and precautions about thrombocytopenia, neutropenia, gastrointestinal toxicity, hyponatremia, infections, neurological toxicity and embryo-fetal toxicity. Prescriptions will be accompanied by a medication guide, Karyopharm noted.
Addressing the safety and tolerability language in the label, Kauffman pointed out that penta-refractory myeloma patients are very sick, with an average life expectancy of three-to-five months, [so adverse events when introducing a new medicine isn't unexpected]. [He noted that while] Xpovio has side effects, including numerically more incidents of nausea and anorexia than seen with other myeloma therapies like Pomalyst and Kyprolis (carfilzomib), [they aren't of a magnitude of concern to doctors Karyopharm has spoken with].
“What we didn’t have was major organ toxicities or major adverse reactions,” Kauffman said. “We did have a number of serious adverse events, but the percentage was similar to Pomalyst and Kyprolis and the nature of those serious adverse events were really what happens to people who have three-to-five months to live. I think FDA’s safety group understood early on that there was nothing that was going to be of sufficient magnitude or concern to a physician that they would need a black box.”
A 70-Person Team To Call On Myeloma Doctors
On Karyopharm's call, Monaco outlined a launch strategy in which 70 sales reps and nurse liaisons will call on 1,300 key physicians, including about 400 who treat more than 50% of the projected patient base. Karyopharm said an estimated 69,000 myeloma patients currently are on drug therapy and about 6,000 of those individuals fall into the penta-refractory group. Xpovio represents the first approval against a new myeloma target since 2015, the company pointed out, since Bristol-Myers Squibb Co.’s anti-SLAMF7 therapy Empliciti (elotuzumab). (Also see "BMS/AbbVie Empliciti Leaps Ahead, Wins Fast FDA Nod" - Scrip, 30 Nov, 2015.)
While it awaits data from the BOSTON trial, an event-driven study that could read out later this year or early in 2020, Kauffman said the study offers the potential to quickly advance Xpovio to second-line myeloma therapy. The drug is a good candidate for earlier lines of therapy, he asserted, because it offers a new mechanism of action, is oral and combines well with other agents. Karyopharm also has studies underway investigating first-line myeloma therapy with Xpovio, he said.
Datamonitor Healthcare analyst David Dahan suggested that early uptake of Xpovio will be limited.
“Since doublet regimens are typically reserved for heavily pre-treated patients who are not fit enough for more rigorous triplet therapies, it is likely that selinexor’s initial target patient population will be limited,” Dahan told Scrip. “However, Xpovio is also being evaluated in the Phase III BOSTON trial as part of a triple combination with Velcade (bortezomib; Takeda Pharmaceutical Co. Ltd./Johnson & Johnson) and dexamethasone in the second- to fourth-line settings, which will help the drug increase its commercial potential.”