Theravance Biopharma CYPPRESS Misses Endpoint

Theravance Biopharma Inc. said on March 3, 2026, that its Phase 3 CYPRESS study of ampreloxetine failed to meet the primary endpoint, prompting a wind-down of the program, an accelerated strategic review with Lazard, and a restructuring to cut costs and refocus on YUPELRI.

CYPRESS Miss and Program Wind-Down

The CYPRESS study (NCT05696717) was a multi-center randomized-withdrawal trial testing ampreloxetine in patients with symptomatic neurogenic orthostatic hypotension due to multiple-system atrophy. The primary endpoint, change in the Orthostatic Hypotension Symptom Assessment (OHSA) composite score at Week 8, did not reach statistical significance, and secondary endpoints showed similar non-significant trends. The company reported a confirmed pressor effect on blood pressure, heart rate, and norepinephrine, and said the drug was well tolerated with no supine hypertension signal.

Theravance has begun winding down the ampreloxetine program and will conduct additional analyses of CYPRESS and Phase 3 data with external experts to evaluate potential regulatory pathways, though it cautioned there is no assurance of regulatory success. The company disclosed these developments in a press release at 8:30 a.m. ET and filed an 8-K later the same day reporting material events.

Strategic Review, Cash Position, and Restructuring

Theravance’s Strategic Review Committee, formed in 2024, said it is accelerating its review of alternatives to maximize shareholder value and has engaged Lazard to explore options that could include a sale, while providing no assurance a transaction will occur.

The company reported cash and cash equivalents of $326.5 million as of December 31, 2025, with no debt. It received a $25 million YUPELRI milestone payment from Viatris in January 2026 and a $50 million payment from Royalty Pharma in February 2026, leaving it with roughly $400 million expected at the end of the first quarter. Management expressed high confidence in a separate $100 million TRELEGY milestone contingent on Royalty Pharma receiving minimum royalties tied to GSK global net sales of at least $3.51 billion for fiscal 2026.

As part of the restructuring, Theravance plans to wind down ampreloxetine development and reduce general and administrative expenses by about 60%, targeting roughly $70 million in full run-rate savings by the third quarter of 2026 compared with a preliminary 2025 operating expense base of $110 million. The company projects post-restructuring annualized cash flow of $60 million to $70 million starting in the third quarter, comprising $45 million to $55 million of income from operations excluding non-cash stock-based compensation, plus interest and other income. This projection excludes the TRELEGY milestone.

Theravance holds a 35% profit-and-loss interest in YUPELRI (revefenacin), a nebulized long-acting muscarinic antagonist for chronic obstructive pulmonary disease. Viatris-recognized U.S. net sales for YUPELRI were $70.6 million in the fourth quarter of 2025, up 6% year-over-year, and $266.6 million for fiscal 2025, up 12%. The product’s intellectual property protection extends through 2039. Management identified YUPELRI as the source of durable cash flow as the company executes its strategic review and cost reductions.

The combined steps—winding down the late-stage ampreloxetine program, accelerating the strategic review, and cutting costs while relying on YUPELRI revenues and near-term milestones—shift Theravance’s near-term profile from late-stage development to commercial cash-flow preservation as it explores options to maximize shareholder value.

"The Committee is accelerating its ongoing review of alternatives to maximize value for shareholders," the Strategic Review Committee said.