With rejection for slow-release Jakafi, FDA sends shock waves across Incyte's pipeline: analyst

After two years of making inflammatory disease a key focus, Incyte has started drawing attention to its oncology portfolio lately. But not all attention is positive.

The FDA has rejected an extended-release formulation of Incyte’s Jakafi, the company said Thursday. Jakafi, or ruxolitinib tablet, is currently given twice-daily to treat the blood cancers myelofibrosis and polycythemia vera, plus graft-versus-host disease. Incyte is trying to introduce a once-daily version.

Information around the FDA’s complete response letter was scant. In a statement, Incyte said the FDA acknowledged that the studies supporting the application showed bioequivalence between the two formulations based on area under the curve (AUC)—a measure of a person’s systemic exposure to a drug. Still, the agency “identified additional requirements for approval,” the company said.

In a Thursday note to clients, analysts at William Blair noted that the once-daily formulation didn’t meet bioequivalence for Cmax, another pharmacological measurement of the peak concentration of a drug in the blood or in a specific area of the body. The analysts said they questioned the results back in 2021, but Incyte at the time maintained that the FDA viewed AUC as the important measure for a filing.

Incyte plans to meet with the FDA to determine next steps, the company said. Mizuho analysts, in a Thursday note, estimated that the rejection could cause a yearlong delay for the drug.

For now, the FDA rejection marks a setback for Incyte’s broader pipeline ambitions beyond Jakafi.

For Jakafi itself, the extended-release version doesn’t have much commercial impact, the William Blair team argued. But an approval for the once-daily formulation would be “an important step” toward Incyte’s proposed fixed-dose combinations of Jakafi with other novel agents, Incyte’s chief medical officer Steven Stein told investors on the company’s fourth-quarter earnings call.

Under an umbrella clinical development program dubbed LIMBER, Incyte is exploring using once-daily Jakafi with other once-daily drugs, namely, PI3K inhibitor parsaclisib, ALK2 inhibitor zilurgisertib and BET inhibitor INCB57643, in myelofibrosis.

While Jakafi itself will likely face generics at the end of 2028, its fixed-dose combos would enjoy longer patent protections, the William Blair team noted.

Even before the FDA rejection, Incyte’s LIMBER program already suffered a serious blow. Earlier this month, Incyte stopped the phase 3 LIMBER-304 study combining Jakafi with parsaclisib in previously treated myelofibrosis patients. That decision came after an independent data monitoring committee found that the study was unlikely to meet its goals.

Because Incyte’s entire combination plan rests on the new Jakafi formulation, the William Blair team suggested the FDA rejection was even a bigger blow than the parsaclisib trial flop.

Meanwhile, the studies for the BET and ALK2 programs are still in early stages, which could give Incyte enough time to address the complete response letter. “But if modifications to the extended-release formulation or additional clinical studies are required” for long-acting Jakafi, that could cause delays, the analysts said.

Alternatively, the team said, Incyte could postpone fixed-dosing regimens and pursue separate dosing, like it’s doing for the parsaclisib combo trials.

RELATED: Incyte's LIMBER lumbers to early end as analysis shows Jakafi cancer combo destined to fail

In the meantime, rivals are advancing. GSK is awaiting an FDA decision in myelofibrosis for its rival once-daily JAK inhibitor momelotinib by June 16, and GSK has an internal BET inhibitor of its own. Bristol Myers Squibb’s once-daily Inrebic entered the myelofibrosis ring with an FDA approval in 2019, and the New York pharma is working on BET inhibitor trotabresib.

Lately, Jakafi has taken a smaller place in Incyte investors’ minds. The Novartis-shared JAK inhibitor pulled in $2.41 billion in revenue for Incyte in 2022, up 13% year over year.

Some focus has shifted to atopic dermatitis and vitiligo treatment Opzelura, a cream version of ruxolitinib. Setbacks in the LIMBER program will likely place even greater scrutiny on Opzelura’s launch, the William Blair team said.