On September 8, Spyre Therapeutics (NASDAQ:SYRE) announced that SPY003, its anti-IL-23 antibody, hit its primary endpoint in Part A of the Phase 2 SKYLINE trial, posting a 10.0-point reduction in Robart’s Histopathology Index score at Week 12 with a p-value below 0.0001. That result matters because it closes out a run of three straight readouts. Spyre has now shown proof-of-concept for all three molecules behind its inflammatory bowel disease combination strategy in a five-month stretch.
Three Shots, Three Makes
The pattern across SPY001, SPY002, and SPY003 is what stands out. Each posted a double-digit reduction in RHI score during Part A of SKYLINE: 9.2 points, 10.7 points, and 10.0 points, respectively. Secondary endpoints followed the same script. SPY003 delivered a 20% clinical remission rate and 30% endoscopic improvement, while SPY001 and SPY002 posted even stronger remission rates of 40% and 33%. All three monotherapies were described as well tolerated, with safety profiles consistent with their respective drug classes and no drug-related serious adverse events reported for SPY001 or SPY002.
The company is not short on runway to chase this thesis. As of June 30, Spyre held $1.1 billion in cash, cash equivalents, and marketable securities, a position built in part on a $435.2 million stock offering in April. Management pegs that as enough to fund operations into the second half of 2029. That buys time for a busy catalyst calendar, including SKYWAY data in rheumatoid arthritis expected in September, psoriatic arthritis and axial spondyloarthritis readouts due in the fourth quarter of 2026, and the real test, SKYLINE Part B combination data, in 2027.
The Combination Bet Is Still Unproven
Every result so far comes from Part A of SKYLINE, an open-label study testing a single dose of each drug alone, not the randomized, placebo-controlled design that will actually judge these therapies. The SPY003 cohort included just 44 subjects. Nineteen of them experienced a treatment-emergent adverse event, and three had serious adverse events, including hospitalization for a UC flare, hemorrhoid thrombosis, and acute cholecystitis, all attributed to causes other than the drug.
The bigger question is whether pairing these antibodies actually beats using them alone. Spyre’s entire strategy rests on that premise, but Part B, which tests the pairwise combinations SPY120, SPY130, and SPY230 against placebo, is still enrolling, and topline induction data will not arrive until 2027. In the meantime, the company keeps burning cash. It used $69.9 million in operating activities in the second quarter of 2026 alone and posted a net loss of $36.2 million for the quarter, a number barely changed from the $36.7 million loss a year earlier despite the flurry of positive trial news.
A Crowded Short Base
Hedge fund ownership climbed from 36 funds to 57 heading into this readout, a jump that points to institutions building conviction ahead of the data. At the same time, short interest sits at 14.38% of float, a level that reflects real organized skepticism rather than routine hedging. That combination sets up a tug of war between investors betting on the combination thesis and those still waiting for proof it works.
Proof, Not Yet Payoff
Spyre has done what it set out to do in Part A: show that each piece of its IBD puzzle works on its own. What it has not yet shown is that the pieces work better together, and that answer will not come until 2027. For the bulls, three consistent double-digit RHI reductions across three mechanisms is a rare kind of execution. For the skeptics, an open-label design, a small sample, and a widening short base are reasons to wait for Part B before believing the combination story. Both camps are, for now, watching the same calendar.
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