Last updated: August 11, 2026
Sionna Therapeutics’ SION-719 failed to move sweat chloride as an add on to Trikafta in a Phase 2a trial, with a placebo adjusted change of minus 1.0 mmol/L (p=0.7). Sionna discontinued the add on program and refocused on its SION-451 dual combination.
This page covers the August 10 readouts from Sionna Therapeutics, Tenax Therapeutics, and Silence Therapeutics, plus the FDA advisory committee date set for Grail’s Galleri cancer detection test.
What happened in Sionna’s cystic fibrosis trial?
Sionna Therapeutics reported that SION-719, an NBD1 stabilizer, produced no meaningful sweat chloride reduction when added to Trikafta in its Phase 2a PreciSION CF trial. The placebo adjusted change was minus 1.0 mmol/L with a p value of 0.7, and the company discontinued the add on approach.
PreciSION CF was a randomized, double blind, placebo controlled crossover study in 15 adults with cystic fibrosis homozygous for the F508del mutation, all on stable dosing of Vertex Pharmaceuticals’ Trikafta (elexacaftor/tezacaftor/ivacaftor). Sweat chloride, a direct readout of CFTR protein function, was the key activity measure. A drug that improves CFTR function should push sweat chloride down. SION-719 did not.
| PreciSION CF Phase 2a | Result |
|---|---|
| Design | Randomized, double blind, placebo controlled crossover |
| Participants | 15 adults with CF, homozygous F508del, on stable Trikafta |
| Sweat chloride, placebo adjusted | Minus 1.0 mmol/L (p=0.7) |
| Safety | Generally well tolerated; no serious adverse events; no meaningful liver function trends |
| Outcome | SION-719 discontinued as an add on to Trikafta |
Sionna pointed to greater than expected variability in individual sweat chloride measurements and to differences in Trikafta exposure between the crossover periods as confounding factors. Chief executive Mike Cloonan called the results unexpected and disappointing. Market reports put the single day share price decline at roughly 92 percent, a figure the market set and the company has no reason to confirm.
Why was this trial considered so important?
Sionna’s entire scientific thesis rests on stabilizing NBD1, the first nucleotide binding domain of the CFTR protein, which the field has long considered the root defect in F508del cystic fibrosis and a target that decades of chemistry failed to crack. PreciSION CF was the first clinical test of that thesis on top of the standard of care.
The bull case was that even Trikafta, which has transformed cystic fibrosis care, leaves patients short of normal CFTR function, and that a true NBD1 stabilizer layered on top could close the gap. A clean sweat chloride signal in 15 patients would have validated the mechanism and set up larger trials. The flat result means the central question of whether NBD1 stabilization adds benefit on top of triple combination therapy remains unanswered in patients.
What does Sionna do now?
Sionna moves to its dual combination strategy. A Phase 1 trial in 120 healthy volunteers identified SION-451 plus SION-2222 as the preferred pairing, meeting its safety, tolerability, and pharmacokinetic objectives with exposures in the range the company defined before the study began.
The dual combination is a different bet: instead of adding an NBD1 stabilizer to Vertex’s regimen, Sionna would assemble its own CFTR modulator combination. The company reported $268.3 million in cash, cash equivalents, and marketable securities at the end of the second quarter and said it will take capital preservation actions while it works out next steps for the combination program.
What does Sionna’s failure mean for Vertex?
Vertex keeps its cystic fibrosis franchise unchallenged for now. The most visible near term attempt to improve on Trikafta from outside Vertex has been removed, and any Sionna challenge now runs through a longer, earlier stage combination path rather than an add on shortcut.
Trade coverage from BioPharma Dive and Endpoints framed the readout as removing the nearest threat to Trikafta. The strategic point for the field is that displacing an entrenched, highly effective standard of care requires either clearly better efficacy or a fundamentally different mechanism, and the bar for demonstrating either keeps rising as the standard improves.
What happened in the Tenax LEVEL trial?
Tenax Therapeutics’ Phase 3 LEVEL trial of TNX-103, an oral formulation of levosimendan, missed its primary endpoint in pulmonary hypertension with heart failure with preserved ejection fraction. Patients on drug gained 14.0 meters on the six minute walk test at week 12 versus 10.4 meters on placebo, a 3.5 meter difference (p=0.63).
| LEVEL Phase 3 measure | TNX-103 | Placebo | Significance |
|---|---|---|---|
| Six minute walk distance, week 12 | +14.0 m | +10.4 m | p=0.63, not significant |
| KCCQ total symptom score | +6.6 | +6.5 | Not met |
| Subgroup: baseline walk under 333 m | +26.3 m vs placebo | p=0.0112, prespecified | |
| Subgroup: age 71 and older | +27.1 m vs placebo | p=0.0021, prespecified | |
| NT-proBNP (exploratory) | 49 percent reduction vs placebo | p<0.0001 | |
| Right ventricular systolic pressure (exploratory) | 3.5 mmHg reduction | p=0.0045 | |
The trial randomized 241 patients across 41 sites in the United States and Canada, dosing 1 mg twice daily titrated to three times daily over a 12 week double blind period. Adverse events were more frequent on drug (86.7 percent versus 71.9 percent), while serious adverse events were balanced. Orion, which licensed levosimendan to Tenax, issued its own release confirming the miss.
Is there a path forward for oral levosimendan?
Tenax plans a Type C meeting with the FDA and a parallel consultation with the European Medicines Agency, built around a population enrichment strategy targeting the sicker, older patients where prespecified subgroups showed benefit. That is a legitimate scientific direction, but it almost certainly requires another trial.
The honest read: subgroup wins inside a failed trial generate hypotheses, not approvals. The biomarker data cut in the drug’s favor, with a 49 percent NT-proBNP reduction that is hard to dismiss as noise, and the walk distance effect concentrated in patients with the least functional reserve. Regulators have accepted enrichment strategies before, but they will want the enriched population tested prospectively.
What did Silence Therapeutics report in polycythemia vera?
Silence Therapeutics’ divesiran hit its primary endpoint in the Phase 2 SANRECO trial, with 88 percent of patients responding versus 19 percent on placebo (p<0.0001). Patients on divesiran needed 0.2 phlebotomies each versus 2.1 on placebo, and the company plans a Phase 3 start in the first half of 2027.
| SANRECO Phase 2 measure | Divesiran | Placebo |
|---|---|---|
| Primary endpoint response rate | 88 percent (p<0.0001) | 19 percent |
| Every 6 weeks dosing arm | 93.8 percent | n/a |
| Every 12 weeks dosing arm | 81.3 percent | n/a |
| Phlebotomies per patient | 0.2 (p<0.0001) | 2.1 |
SANRECO was a 36 week, randomized, double blind, placebo controlled study in 48 phlebotomy dependent polycythemia vera patients, testing divesiran at 6 mg/kg subcutaneously every six or every twelve weeks. The drug was well tolerated, with infrequent, self limiting injection site reactions and two cases of grade 1 anemia. Hematocrit control, iron markers, and symptom scores also improved.
Divesiran is an siRNA that silences TMPRSS6 in the liver, raising the body’s own hepcidin production. Higher hepcidin restricts the iron supply that bone marrow needs to overproduce red blood cells, which is the core problem in polycythemia vera. The Phase 3 will test the every twelve weeks dose against placebo.
How does divesiran compare with Takeda’s rusfertide?
Both drugs raise hepcidin signaling to control red blood cell overproduction, but rusfertide is a peptide mimetic dosed frequently and is already under FDA priority review with a decision expected this quarter, while divesiran is an siRNA dosed as infrequently as every twelve weeks and is a Phase 3 start away from registration.
| Rusfertide (Takeda/Protagonist) | Divesiran (Silence) | |
|---|---|---|
| Modality | Hepcidin mimetic peptide | siRNA silencing TMPRSS6, raising native hepcidin |
| Stage | NDA under FDA priority review; PDUFA target Q3 2026 | Phase 2 complete; Phase 3 planned H1 2027 |
| Pivotal data | VERIFY Phase 3, 293 patients; primary and all four key secondary endpoints met | SANRECO Phase 2, 48 patients; 88 percent vs 19 percent response |
| Dosing | Subcutaneous, frequent administration | Subcutaneous every 6 or every 12 weeks |
Rusfertide’s VERIFY readout more than doubled clinical response rates versus standard care, per Takeda, and the FDA accepted the application with priority review in March. If approved on schedule, rusfertide would define the hepcidin pathway market years before divesiran can reach it. Silence’s counterargument is durability and convenience: four to eight injections a year instead of frequent dosing, if Phase 3 confirms the Phase 2 profile.
What is polycythemia vera and why does phlebotomy matter?
Polycythemia vera is a chronic blood cancer in which bone marrow produces too many red blood cells, thickening the blood and raising clot and cardiovascular risk. Standard management includes regular therapeutic phlebotomy, essentially scheduled blood draws, to keep hematocrit below 45 percent.
Phlebotomy dependence is burdensome and control between procedures is imperfect, which is why both hepcidin pathway drugs measure success largely by eliminating the need for it. A therapy that keeps hematocrit controlled for months at a time addresses the day to day reality of the disease, not just a lab value.
When will the FDA decide on Grail’s Galleri test?
The FDA has scheduled its Molecular and Clinical Genetics Panel advisory committee meeting for September 23, 2026 to review Grail’s premarket approval application for the Galleri multi cancer early detection blood test. Grail announced the date on August 7; a panel recommendation is advisory, with the FDA decision to follow.
| Galleri regulatory milestone | Date |
|---|---|
| Breakthrough Device designation | 2018 |
| PMA submission completed | January 29, 2026 |
| FDA advisory committee (Molecular and Clinical Genetics Panel) | September 23, 2026 |
The application rests on PATHFINDER 2 data from 25,490 consented participants with one year of follow up, supported by data from more than 70,000 participants in the prevalent screening round of the NHS-Galleri trial in the United Kingdom. Galleri looks for cancer specific methylation patterns in blood and, when it finds a cancer signal, predicts the tissue of origin to direct the diagnostic workup.
Why does the Galleri advisory panel matter beyond Grail?
This is the first multi cancer early detection test to reach an FDA advisory panel with a completed premarket approval application, so the questions the panel asks and the evidence bar it sets will become the template for the entire MCED category, including every competitor behind Grail.
Grail chief executive Josh Ofman’s framing is the category’s core argument: 70 to 80 percent of cancer deaths occur in cancers with no recommended screening at all. The counterweight the panel must wrestle with is what happens after a positive signal, including false positives, incidental findings, and whether earlier detection at population scale actually changes outcomes. Whatever standard emerges on September 23 becomes the de facto rulebook for blood based cancer screening.
Frequently asked questions
Why did Sionna Therapeutics’ stock drop?
Its lead program, SION-719, showed no meaningful activity as an add on to Trikafta in a Phase 2a cystic fibrosis trial, with sweat chloride essentially unchanged versus placebo. Market reports put the single day decline at roughly 92 percent.
What is SION-719?
An oral small molecule designed to stabilize NBD1, the first nucleotide binding domain of the CFTR protein, which is misfolded in people with the F508del mutation that causes most cystic fibrosis.
Is Sionna Therapeutics shutting down?
No. The company discontinued SION-719 as a Trikafta add on, reported $268.3 million in cash and equivalents at the end of the second quarter, and is prioritizing a dual combination of SION-451 and SION-2222 while taking capital preservation actions.
What is sweat chloride and why is it used in CF trials?
Sweat chloride directly reflects CFTR protein function, the underlying defect in cystic fibrosis. Effective CFTR modulators lower it. It responds quickly and objectively, which makes it a standard early stage activity readout.
Does Sionna’s failure affect people taking Trikafta?
No. Trikafta’s efficacy and availability are unaffected. The trial tested whether an experimental add on could improve on Trikafta, and it did not.
What is TNX-103?
An oral formulation of levosimendan, a calcium sensitizer long used intravenously in acute heart failure in some markets. Tenax licensed it from Orion and developed it for pulmonary hypertension with heart failure with preserved ejection fraction.
Did the LEVEL trial show any benefit at all?
The overall trial missed, but prespecified subgroups of sicker patients (baseline walk distance under 333 meters) and older patients (71 and up) improved significantly, and NT-proBNP fell 49 percent versus placebo on an exploratory basis.
What happens next for Tenax Therapeutics?
The company plans a Type C meeting with the FDA and a consultation with the European Medicines Agency to discuss a population enrichment strategy focused on the subgroups that responded.
What is divesiran?
An siRNA therapeutic from Silence Therapeutics that silences the TMPRSS6 gene in the liver, raising natural hepcidin levels to restrict the iron supply bone marrow uses to overproduce red blood cells in polycythemia vera.
How is divesiran different from rusfertide?
Rusfertide is a synthetic peptide that mimics hepcidin and requires frequent injections; divesiran raises the body’s own hepcidin through gene silencing and was dosed every six or twelve weeks in Phase 2. Rusfertide is years ahead in development, with an FDA decision expected in the third quarter of 2026.
When could divesiran reach the market?
Phase 3 is planned to begin in the first half of 2027, which puts any approval several years out, assuming the trial succeeds.
What is the Galleri test?
A blood test from Grail that screens for methylation patterns shared across many cancer types, aiming to detect cancers before symptoms appear and predict where the cancer originated. It is intended to supplement recommended screenings, not replace them.
What will the FDA panel review on September 23?
The Molecular and Clinical Genetics Panel will review Grail’s premarket approval application for Galleri, drawing on PATHFINDER 2 and NHS-Galleri data. The panel’s vote is advisory; the FDA makes the final approval decision afterward.
Would panel support make Galleri a covered screening test?
Not by itself. FDA approval and insurance coverage are separate steps, and screening coverage typically also involves guideline bodies. Approval would, however, be the category’s first and a major step toward routine use.
Sources
Primary sources
- Sionna Therapeutics press release, August 10, 2026 (topline PreciSION CF and Phase 1 dual combination data, corporate update)
- Tenax Therapeutics press release, August 10, 2026 (Phase 3 LEVEL topline results); Orion Corporation release, same date
- Silence Therapeutics press release, August 10, 2026 (Phase 2 SANRECO topline results)
- Grail press release, August 7, 2026 (FDA advisory committee meeting for Galleri PMA)
- Takeda press release, March 2, 2026 (FDA acceptance and priority review of rusfertide NDA)
Corroborating coverage
- STAT, BioPharma Dive, Endpoints News, BioSpace, Yahoo Finance, August 10, 2026
