A phase 2 asthma study of Upstream Bio’s TSLP receptor agonist has hit its primary endpoint. But, with only the 12-week regimen achieving a Tezspire-like reduction in the annualized asthma exacerbation rate (AAER), the readout fell short of the best-case scenario and left room for rivals to deliver better data.
The study randomized adults with severe asthma to receive one of three verekitug regimens or placebo. Verekitug blocks the TSLP receptor, setting it apart from Amgen and AstraZeneca’s ligand-targeting TSLP drug Tezspire.
While Tezspire is given every four weeks, Upstream has used its potentially more potent design to explore the effects of giving verekitug every 12 or 24 weeks. Upstream reported a statistically significant 56% reduction in AAER in patients who received 100 mg verekitug every 12 weeks.
“This result directly achieves management’s base case scenario, creating a target product profile with an easy autoinjector once every three months and similar efficacy to Tezspire,” William Blair analysts wrote in a note to investors.
Patients who received 100 mg or 400 mg of verekitug every 24 weeks also had statistically significant declines in AAER, but the regimens numerically underperformed 12-week dosing. The biotech tracked a 39% reduction in AAER in the 400-mg cohort. Upstream said the 100-mg, 24-week regimen had a statistically significant effect on AAER, too, but added that the regimen failed to provide consistent improvements in other endpoints.
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Writing in a note to investors last week, TD Cowen analysts set the efficacy bar at a 50%-55% drop in AAER, reflecting data on Tezspire. The key question, the analysts said, was whether both the 12- and 24-week regimens could clear the bar. The analysts predicted Upstream’s stock could surge up to 100% if the 24-week regimen succeeded, but warned the market could react badly to a 12-week win.
“If only Q12W succeeds, the stock could be flat or down 10%-20% as Upstream will need to raise capital, has few stock-moving near-term catalysts after asthma and faces competition from other long-acting TSLP agents,” the analysts said.
That scenario came to pass, with Upstream’s stock price falling 23% to drop below $23 in premarket trading Wednesday from a Tuesday closing price of $27.81. Yet, while investors pulled back, Upstream CEO Rand Sutherland, M.D., said in a statement that the phase 2 findings “strengthen verekitug’s potential to advance the standard of care with a highly competitive efficacy profile and less frequent dosing.”
Sutherland’s statement is consistent with comments he made at the J.P. Morgan Healthcare Conference in January, when the Upstream CEO said a “50% or so” reduction in AAER in the 12-week cohort would be “a great outcome.”
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“We know from our market research and from a lot of conversations with physicians that dosing frequency really matters,” Sutherland said. “If you can deliver best-in-class efficacy and do that with far less dosing, no loading dose, a broad population—that’s the potential for a very meaningful value creation exercise.”
Upstream is now reviewing the data to inform decisions about dose selection and trial design for phase 3. TD Cowen analysts predicted Upstream will only take one dose into late-phase development. Sutherland provided a clue as to how Upstream will proceed last month, telling JPM attendees “we would not make a choice to move something forward solely for dosing convenience.” The goal is robust, durable efficacy.
TD Cowen analysts said a 12-week regimen should support blockbuster sales, provided other long-acting TSLP drugs are unable to offer competitive efficacy with six-monthly dosing.
Generate Biomedicines is starting a pair of phase 3 trials of a molecule that targets the TSLP ligand and is dosed every six months. Meanwhile, GSK has a candidate in phase 2, and Windward Bio started a phase 2 trial of a long-acting inhibitor of the TSLP ligand last year.
