Ionis Pharmaceuticals (IONS) Phase 3 eplontersen trial in ATTR-CM fails primary goal
Filing Impact
Filing Sentiment
Form Type
8-K
Rhea-AI Filing Summary
Ionis Pharmaceuticals reported that the CARDIO-TTRansform Phase 3 trial of eplontersen in transthyretin-mediated amyloid cardiomyopathy did not meet its primary endpoint, a composite of cardiovascular death and recurrent cardiovascular events through Week 140 versus placebo.
In patients receiving contemporary standard of care, including many on TTR stabilizers, adding eplontersen did not show a statistically significant benefit on this main outcome. A prespecified subgroup on eplontersen monotherapy showed a nominally significant hazard ratio of 0.71 for the same composite. Secondary imaging and biomarker measures generally favored eplontersen, and the drug showed large, sustained reductions in transthyretin with a safety profile consistent with prior studies. Ionis and AstraZeneca plan to present full results at the European Society of Cardiology Congress in August 2026.
Positive
- None.
Negative
- CARDIO-TTRansform primary endpoint missed: The Phase 3 trial of eplontersen in transthyretin-mediated amyloid cardiomyopathy did not show a statistically significant benefit on the primary composite of cardiovascular mortality and recurrent cardiovascular events versus placebo.
Insights
Key Phase 3 trial missed its primary endpoint, tempering expectations for eplontersen in ATTR-CM.
The CARDIO-TTRansform trial in ATTR-CM failed its primary composite endpoint of cardiovascular mortality and recurrent events through Week 140 when eplontersen was added to contemporary standard of care. This is a pivotal outcome for the cardiomyopathy indication.
A nominally significant hazard ratio of 0.71 in the monotherapy subgroup, plus favorable secondary imaging and biomarker trends and strong transthyretin suppression, suggest biological activity but not definitive clinical benefit in the overall population, especially where many patients received stabilizers.
Ionis highlights its broader, wholly owned portfolio and existing eplontersen commercial use in hereditary polyneuropathy, aiming for cash flow breakeven by 2028. The ultimate commercial impact for ATTR-CM will depend on detailed data to be presented at the ESC Congress in August 2026 and on any regulatory or guideline reactions.
8-K Event Classification
3 items: 7.01, 8.01, 9.01
3 items
Item 7.01
Regulation FD Disclosure
Disclosure
Material non-public information disclosed under Regulation Fair Disclosure, often investor presentations or guidance.
Item 8.01
Other Events
Other
Voluntary disclosure of events the company deems important to shareholders but not covered by other items.
Item 9.01
Financial Statements and Exhibits
Exhibits
Financial statements, pro forma financial information, and exhibit attachments filed with this report.
Key Figures
Monotherapy hazard ratio: 0.71 hazard ratio
Trial duration for primary endpoint: Week 140
Stabilizer use at baseline: 57% of patients
+5 more
8 metrics
Monotherapy hazard ratio
0.71 hazard ratio
Prespecified subgroup on eplontersen monotherapy vs placebo for composite CV outcome
Trial duration for primary endpoint
Week 140
Composite of CV mortality and recurrent CV clinical events measured through Week 140
Stabilizer use at baseline
57% of patients
Patients in each arm receiving stabilizer treatment at baseline
Stabilizer initiated during trial
24% of patients
Patients in each arm who started stabilizer therapy during the trial
Participants enrolled
1,432 participants
Adults with wild-type or hereditary ATTR-CM in CARDIO-TTRansform
Study sites
130 sites
Global multicenter trial across 20 countries
Dose level
45 mg
Eplontersen subcutaneous dose every four weeks
Cash flow target year
2028
Ionis aim to achieve cash flow breakeven by 2028
Key Terms
transthyretin-mediated amyloid cardiomyopathy, composite outcome, hazard ratio, RNA-targeted silencer, +2 more
6 terms
transthyretin-mediated amyloid cardiomyopathy medical
"trial for eplontersen in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) did not meet the primary"
A progressive heart condition in which the blood protein transthyretin misfolds and forms sticky deposits in the heart, making the heart muscle stiff and less able to pump. Think of it like scale building up inside pipes that reduces flow; over time this can cause breathlessness, fatigue and heart failure. It matters to investors because it creates demand for diagnostics, treatments and related healthcare services, affecting companies that develop drugs, tests, or care for these patients.
composite outcome medical
"primary efficacy endpoint of the composite outcome of cardiovascular (CV) mortality and recurrent CV clinical events"
hazard ratio financial
"a nominally significant hazard ratio of 0.71 was observed on the composite outcome"
A hazard ratio is a way scientists compare the chance of something happening over time between two groups, like patients taking different medicines. If the ratio is high, it means one group is more likely to experience the event sooner or more often, which helps determine how effective a treatment is or how risky a situation might be.
RNA-targeted silencer medical
"Eplontersen is a once-monthly RNA-targeted silencer that can be self-administered"
Phase 3, multicenter, randomized, double-blinded, placebo-controlled study medical
"CARDIO-TTRansform is a Phase 3, multicenter, randomized, double-blinded, placebo-controlled study to evaluate the safety"
stabilizer treatment medical
"57% of patients in each arm received a stabilizer treatment at baseline"
FAQ
What did Ionis Pharmaceuticals (IONS) announce about the CARDIO-TTRansform trial?
Ionis announced that the CARDIO-TTRansform Phase 3 trial of eplontersen in ATTR-CM did not meet its primary efficacy endpoint. The composite of cardiovascular mortality and recurrent cardiovascular events through Week 140 showed no statistically significant benefit versus placebo in the overall study population.
Were there any positive signals for eplontersen in the Ionis (IONS) ATTR-CM study?
Yes. A prespecified monotherapy subgroup showed a nominally significant hazard ratio of 0.71 on the composite cardiovascular outcome. Additionally, secondary imaging and biomarker analyses generally favored eplontersen, and the drug produced large, sustained transthyretin reductions with a favorable safety profile.
How did background stabilizer therapy affect eplontersen results in CARDIO-TTRansform?
In this trial, 57% of patients in each arm received a TTR stabilizer at baseline and another 24% initiated one during the study. Among patients on stabilizer therapy at baseline, no treatment effect for eplontersen on the primary composite outcome was observed compared with placebo.
How large was the Ionis (IONS) CARDIO-TTRansform Phase 3 trial?
CARDIO-TTRansform enrolled 1,432 adults with wild-type or hereditary ATTR-CM across 130 study sites in 20 countries. Participants were randomized 1:1 to receive eplontersen 45 mg or placebo by subcutaneous injection every four weeks, alongside standard of care treatments.
What is the primary endpoint in the CARDIO-TTRansform ATTR-CM study?
The primary endpoint is a composite of cardiovascular mortality and recurrent cardiovascular clinical events through Week 140. This combined measure evaluates both deaths and repeat cardiovascular problems over time, providing a broad view of how eplontersen affects serious heart-related outcomes in ATTR-CM.
When will more detailed eplontersen ATTR-CM data from Ionis (IONS) be presented?
Ionis and AstraZeneca plan to share the full CARDIO-TTRansform data set with the scientific community at the European Society of Cardiology Congress in August 2026. That presentation is expected to provide more detail on subgroups, secondary endpoints and safety findings.
UNITED STATES SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
PURSUANT TO SECTION 13 OR 15(d) OF THE
SECURITIES EXCHANGE ACT OF 1934
Date of report (Date of earliest event reported): July 9, 2026
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Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
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Securities registered pursuant to Section 12(b) of the Act:
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (Section 230.405 of this chapter) or
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Emerging growth company ☐
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| Item 7.01 |
Regulation FD Disclosure.
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On July 9, 2026, Ionis Pharmaceuticals, Inc. (“Ionis”) issued a press release announcing that the
CARDIO-TTRansform Phase 3 trial for eplontersen in patients with transthyretin-mediated amyloid cardiomyopathy (“ATTR-CM”) did not meet the primary efficacy endpoint of the composite outcome
of cardiovascular (“CV”) mortality and recurrent CV clinical events up to Week 140 compared with placebo. A copy of the press release is furnished as Exhibit 99.1 to this Current Report on
Form 8-K.
The information in this Item 7.01 and the exhibit attached hereto shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as
amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as
amended, or the Exchange Act, regardless of any general incorporation language in such filing.
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Other Events.
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On July 9, 2026, Ionis announced that the CARDIO-TTRansform Phase 3 trial for eplontersen in patients with ATTR-CM did not meet the primary efficacy endpoint of the
composite outcome of CV mortality and recurrent CV clinical events up to Week 140 compared with placebo. In this contemporary patient population treated with standard of care, including a majority on a stabilizer, adding eplontersen did not provide a
statistically significant benefit.
In a prespecified subgroup analysis of patients treated with eplontersen monotherapy compared to placebo, a nominally significant hazard ratio of 0.71 was observed on
the composite outcome of CV mortality and recurrent CV events. In patients who were on stabilizer therapy at baseline, no treatment effect was observed.
In the overall population, multiple secondary, imaging and biomarker analyses favored eplontersen versus placebo. Large and
sustained reductions in transthyretin were observed, consistent with the silencer class for ATTR. Eplontersen was well tolerated, with a favorable safety profile consistent with previous results.
CARDIO-TTRansform is a Phase 3, multicenter, randomized, double-blinded, placebo-controlled study to evaluate the safety and efficacy of eplontersen compared to placebo
in participants with ATTR-CM receiving available standard of care: 57% of patients in each arm received a stabilizer treatment at baseline, and a further 24% in each arm initiated a stabilizer during the trial.
Ionis and AstraZeneca will continue to analyze the full data set, and results will be shared with the scientific community at the European Society of Cardiology Congress
in August 2026.
Forward-Looking Statements
This report includes forward-looking statements regarding Ionis’ business and the therapeutic and commercial potential of eplontersen, Ionis’ technologies and other
products in development . Any statement describing Ionis’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain
risks and uncertainties including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines.
Ionis’ forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis’
forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking
statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis’ programs are described in additional detail in Ionis’ annual report on Form 10-K for the year ended
December 31, 2025, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission. Copies of these and other documents are available from the Company. In this report, unless the context requires otherwise, “Ionis,”
“Company,” “we,” “our” and “us” all refer to Ionis Pharmaceuticals and its subsidiaries.
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Financial Statements and Exhibits.
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(d) Exhibits.
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Exhibit No.
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Description
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99.1
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Press Release dated July 9, 2026.
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104
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Cover Page Interactive Data File (embedded within the Inline XBRL document).
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SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf
by the undersigned, thereunto duly authorized.
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Ionis Pharmaceuticals, Inc.
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Dated: July 9, 2026
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By:
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/s/ Patrick R. O’Neil
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Patrick R. O’Neil
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Executive Vice President, Chief Legal Officer and General Counsel
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Exhibit 99.1
Update on CARDIO-TTRansform Phase 3 trial of eplontersen in adults with transthyretin-mediated amyloid cardiomyopathy
– Study missed primary endpoint of composite outcome of cardiovascular
(CV) mortality and recurrent CV events; in a pre-specified subgroup analysis, a nominally significant result was observed with eplontersen monotherapy –
– Favorable safety profile consistent with previous results –
CARLSBAD, Calif., July 9, 2026 -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) and partner AstraZeneca today
announced that the CARDIO-TTRansform Phase 3 trial for eplontersen in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) did not meet the primary efficacy endpoint
of the composite outcome of cardiovascular (CV) mortality and recurrent CV clinical events up to Week 140 compared with placebo. In this contemporary patient population treated with standard of care, including a majority on a stabilizer, adding
eplontersen did not provide a statistically significant benefit.
In a prespecified subgroup analysis of patients treated with eplontersen monotherapy compared to placebo, a nominally significant hazard ratio of 0.71 was
observed on the composite outcome of CV mortality and recurrent CV events. In patients who were on stabilizer therapy at baseline, no treatment effect was observed.
In the overall population, multiple secondary, imaging
and biomarker analyses favored eplontersen versus placebo. Large and sustained reductions in transthyretin (TTR) were observed, consistent with the silencer class for ATTR. Eplontersen was
well tolerated, with a favorable safety profile consistent with previous results.
“We believe these findings reflect the rapidly evolving treatment landscape, in which contemporary ATTR-CM patients are widely treated with stabilizers,”
said Brett P. Monia, Ph.D., chief executive officer, Ionis. “Although we are disappointed that the study did not meet the primary endpoint, these results have the potential to guide the treatment
landscape for ATTR-CM and contribute to advancing future care for patients. We extend our sincere gratitude to the patients, families and
investigators whose participation helped progress the science of ATTR-CM treatment.”
CARDIO-TTRansform is a Phase 3, multicenter, randomized, double-blinded, placebo-controlled study to evaluate the safety and efficacy of eplontersen compared to placebo in
participants with ATTR-CM receiving available standard of care: 57% of patients in each arm received a stabilizer treatment at baseline, and a further 24% in each arm initiated a stabilizer during
the trial.
“Ionis continues to be well positioned to create substantial value in both the near and long
term, driven primarily by the strength of our wholly owned portfolio,” said Monia. “We have multiple successful independent launches underway, including TRYNGOLZA, our first in a prevalent population, and we continue
to advance a robust pipeline of potentially transformational medicines. We remain on track to deliver a steady cadence of new medicines to patients and achieve cash flow breakeven by 2028.”
“Over the last decade, multiple advances and increased awareness of ATTR-CM have driven
earlier diagnosis, improved management and better outcomes for patients,” said Mathew Maurer, M.D., primary investigator, Arnold and Arlene Goldstein professor of cardiology, Columbia University Irving Medical
Center. “These data from the largest enrolled study of a contemporary ATTR-CM patient population provide important clarity for the field that will help inform future treatment decisions in ATTR-CM.”
Ionis and AstraZeneca will continue to analyze the full data set, and results will be shared with the scientific community at the European Society of Cardiology (ESC) Congress in August 2026.
Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)
ATTR-CM is a systemic, progressive, debilitating and fatal disease that predominantly affects the heart and is an underrecognized cause of heart failure (HF). ATTR-CM, which can be inherited (hereditary, ATTRv) or develop with age (wild-type, ATTRwt), and occurs when amyloid fibrils consisting of misfolded TTR protein build up in the heart, disrupting
cardiac structure and function and making it harder for the heart to pump blood throughout the body. Patients commonly present with non-specific symptoms such as shortness of breath, swelling, heart palpitations, dizziness, weakness and fatigue,
which can contribute to misdiagnosis and delays in care. With an estimated 300,000 to 500,000 people living with ATTR-CM worldwide, greater awareness, earlier diagnosis and appropriate targeted treatment are critical to improving outcomes and quality
of life for patients.
About the CARDIO-TTRansform Trial
CARDIO-TTRansform is a global, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy and safety of eplontersen in adults with wild-type or
hereditary ATTR-CM who are receiving available standard of care therapy. As the largest enrolled ATTR-CM trial to date, CARDIO-TTRansform enrolled 1,432 participants across 130 study sites in 20 countries, who were randomized 1:1 to receive
eplontersen 45 mg or placebo by subcutaneous injection every four weeks. The primary endpoint is a composite of CV mortality and recurrent CV clinical events through Week 140. Secondary endpoints include changes from baseline in the 6-Minute Walk
Test and Kansas City Cardiomyopathy Questionnaire overall summary score at Week 140, total recurrent CV clinical events up to Week 140, all-cause mortality up to Weeks 140 and 160, the primary endpoint in the subgroup of patients receiving a TTR
stabilizer at baseline and CV mortality through Weeks 140 and 160.
About Eplontersen
Eplontersen is a once-monthly RNA-targeted silencer that can be self-administered via an autoinjector or as a pre-filled syringe by healthcare professional administration
in the U.S. It reduces production of TTR protein at its source in the liver. WAINUA® (eplontersen) has now been approved for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults, commonly referred
to as hATTR-PN or ATTRv-PN in over 20 countries, including in the EU as Wainzua.
As part of a global development and commercialization agreement, AstraZeneca and Ionis are jointly developing and commercializing eplontersen in the US. Outside the US,
AstraZeneca has exclusive rest of world commercialization and development rights.
About Ionis Pharmaceuticals, Inc.
For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has marketed medicines and a leading pipeline in
neurology, cardiometabolic disease and select areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of
disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit Ionis.com and follow us on X (Twitter), LinkedIn and Instagram.
Ionis Forward-looking Statements
This press release includes forward-looking statements regarding Ionis’ business and the therapeutic and commercial potential of eplontersen, Ionis’ technologies and other
products in development. Any statement describing Ionis’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain
risks and uncertainties including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines.
Ionis’ forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis’
forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking
statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis’ programs are described in additional detail in Ionis’ annual report on Form 10-K for the year ended
December 31, 2025, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission. Copies of these and other documents are available from the Company. In this press release, unless the context requires otherwise, “Ionis,”
“Company,” “we,” “our” and “us” all refer to Ionis Pharmaceuticals and its subsidiaries.
Ionis Pharmaceuticals® is a trademark of Ionis Pharmaceuticals, Inc. WAINUA® is a registered trademark of AstraZeneca plc.
Ionis Investor Contact:
D. Wade Walke, Ph.D.
IR@ionis.com 760-603-2331
Ionis Media Contact:
Hayley Soffer
media@ionis.com 760-603-4679
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