Karyopharm's Xpovio nabs myeloma nod despite checkered past. But 5th line?

FDA Building 2
The FDA approval for Karypharm Therapeutics' first-in-class Xpovio in multiple myeloma is dependent upon results from a confirmatory trial. (FDA)

Karyopharm finally got its much-needed first commercial approval for a drug that has stirred up safety concerns—and suffered plenty of speed bumps—along the way. Now the company must cope with a limited FDA nod, and with a brand-new marketing chief to boot.

The FDA waved through Karyopharm’s oral drug Xpovio (selinexor), used in tandem with dexamethasone, for multiple myeloma patients who’ve received at least four prior therapies and whose disease is resistant to several other forms of treatment.

Karyopharm is launching the drug by Wednesday at a list price of $22,000 per month. But leading its fully installed sales team of more than 70 staffers will not be Anand Varadan, who just resigned as chief commercial officer.

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Instead, Perry Monaco has been promoted to head up commercial operations as senior VP, the company disclosed in a securities filing.

Xpovio's accelerated approval marks a temporary win for Karyopharm: The drug’s final approval will depend on results from a confirmatory trial. And the company has a lot of persuading to do. The FDA went against its advisory committee's advice in granting the green light ahead of that trial, despite safety concerns.

The drug is first in a new class of selective inhibitor of nuclear export (SINE) drugs. Xpovio works by inhibiting the XPO1 protein, which causes tumor suppressor proteins to accumulate in the cell nucleus and eventually kill off the cell.

In a phase 2b trial dubbed Storm, the Xpovio-dexamethasone combo elicited an overall response rate of 25.3% that lasted a median of 3.8 months in a prespecified subgroup of 83 patients. These patients had failed on existing multiple myeloma drugs, including Takeda’s Velcade, Amgen’s Kyprolis, Celgene’s Revlimid and Pomalyst, and Johnson & Johnson’s Darzalex.

RELATED: FDA delays Karyopharm PDUFA to review extra information

Jefferies analysts at that time called the data “an inflection point” for Xpovio, noting that the response rate was “superior to historical Darzalex" in patients who'd failed on four prior rounds of therapy. But cancer experts on an FDA advisory committee weren’t impressed. Raising safety red flags, the experts voted 8-5 against the drug’s approval.

More than one-quarter of patients—27%—dropped out of the Storm trial because of adverse reactions, and 65.3% of patients had their Xpovio dosage interrupted.

Surprisingly, the drug’s label didn’t include any black-box warning on safety. Instead, the FDA codified a long list of adverse events associated with the drug, and the label requires physicians to keep a close eye on each patient's blood count, basic serum chemistry and body weight, and adjust dosage accordingly.

During a briefing with investors on the approval, CEO Christopher Primiano was quick to point out that the drug’s targeted patients are already heavily treated, with multiple existing conditions that render them vulnerable.

“It will be key for Karyopharm to provide active support to work through the many potential toxicities associated with Xpovio,” RBC Capital analyst Brian Abrahams said in a Friday note to clients. “This will not only be to enable patients to stay on the drug, but also to ensure docs maintain positive perceptions ahead of the potential expansion into earlier-line combos, where toxicities are lower and the patient population less fragile.”

To that end, Karyopharm will be teaching doctors what to expect when using Xpovio and how to manage adverse reactions—given the many possibilities—and on guidelines for reducing doses as needed, Monaco said on Wednesday’s call.

RELATED: J&J's Darzalex pads blockbuster sales with another myeloma nod in new patients

About 6,000 U.S. multiple myeloma patients are treated in the fourth or later lines of therapy each year, Monaco said. “As we believe the value of Xpovio to the patient is independent of what dosing regimen is most appropriate,” the company is pricing all four different four-week dosing package options at the same $22,000, he said.

The price is higher than what Abrahams’ team had previously expected, though the RBC analyst noted the approval is in a more restricted population and each eligible patient’s treatment duration will likely be shorter, at about three months.

Assuming a 40% penetration, Abrahams estimates the approval will bring in about $130 million in peak sales. While the initial indication is small, Abrahams said Xpovio could find more opportunity in earlier-line multiple myeloma and in diffuse large B-cell lymphoma, “with the accelerated approval substantially increasing the likelihood this will be achievable.”

Xpovio’s fate will be decided soon. Top-line data from the confirmatory phase 3 study called Boston, which combines Xpovio with Velcade and low-dose dexamethasone, will come out later this year or early next. In DLBCL, Karyopharm plans an FDA filing in the same time frame.

If everything goes Xpovio’s way in its indication expansion, Abrahams predicts the drug could surpass $900 million in overall peak sales.

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