# EDGAR Filing Document

**Accession Number:** 0000874015
**File Stem:** 0001140361-25-033541
**Filing Date:** 2025-9
**Character Count:** 20931
**Document Hash:** 5782153b2902f23ad53780d038842e03
**Contains OCR:** False
**Source Format:** 

## Filing Content

## Filing Summary
**0001140361-25-033541.hdr.sgml**: 20250902

**ACCESSION NUMBER**: 0001140361-25-033541

**CONFORMED SUBMISSION TYPE**: 8-K

**PUBLIC DOCUMENT COUNT**: 14

**CONFORMED PERIOD OF REPORT**: 20250902

**ITEM INFORMATION**: Regulation FD Disclosure

**ITEM INFORMATION**: Other Events

**ITEM INFORMATION**: Financial Statements and Exhibits

**FILED AS OF DATE**: 20250902

**DATE AS OF CHANGE**: 20250902

**FILER**: 

**COMPANY DATA:**
- **COMPANY CONFORMED NAME:** IONIS PHARMACEUTICALS INC
- **CENTRAL INDEX KEY:** 0000874015
- **STANDARD INDUSTRIAL CLASSIFICATION:** PHARMACEUTICAL PREPARATIONS [2834]
- **ORGANIZATION NAME:** 03 Life Sciences
- **EIN:** 330336973
- **STATE OF INCORPORATION:** CA
- **FISCAL YEAR END:** 1231

**FILING VALUES:**
- **FORM TYPE:** 8-K
- **SEC ACT:** 1934 Act
- **SEC FILE NUMBER:** 000-19125
- **FILM NUMBER:** 251282925

**BUSINESS ADDRESS:**
- **STREET 1:** 2855 GAZELLE COURT
- **CITY:** CARLSBAD
- **STATE:** CA
- **ZIP:** 92010
- **BUSINESS PHONE:** 7609319200

**MAIL ADDRESS:**
- **STREET 1:** 2855 GAZELLE COURT
- **CITY:** CARLSBAD
- **STATE:** CA
- **ZIP:** 92010

**FORMER COMPANY:**
- **FORMER CONFORMED NAME:** ISIS PHARMACEUTICALS INC
- **DATE OF NAME CHANGE:** 19930328

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### 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): September 2, 2025

## IONIS PHARMACEUTICALS, INC.
(Exact Name of Registrant as Specified in Charter)

#### Delaware
(State or Other Jurisdiction of Incorporation)

---

| | |
|:---|:---|
| **000-19125**<br>| **33-0336973**<br>|
| (Commission File No.) | (IRS Employer Identification No.) |

---

#### 2855 Gazelle Court

#### Carlsbad, CA 92010
(Address of Principal Executive Offices and Zip Code)

Registrant's telephone number, including area code: **(760) 931-9200**

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Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

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| | | |
|:---|:---|:---|
| Title of each class | Trading symbol | Name of each exchange on which registered |
| Common Stock, $.001 Par Value<br>| "IONS" | The Nasdaq Stock Market, LLC<br>|

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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 Rule 12b-2 of the Securities Exchange Act of 1934 (Section 240.12b-2 of this chapter).

Emerging growth company&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; ☐

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| | |
|:---|:---|
| **Item 7.01** | **Regulation FD Disclosure.** |

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On September 2, 2025, Ionis Pharmaceuticals, Inc. ("Ionis," "we," "us" or "our company") issued a press release announcing positive topline results from the pivotal Phase 3 CORE and CORE2 studies of olezarsen in people with severe hypertriglyceridemia ("sHTG"). 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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| | |
|:---|:---|
| **Item 8.01** | **Other Events.** |

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On September 2, 2025, we announced positive topline results from the pivotal Phase 3 CORE and CORE2 studies of olezarsen in people with sHTG. In the studies, olezarsen demonstrated a highly statistically significant placebo-adjusted mean reduction in fasting triglycerides of up to 72% and a highly statistically significant reduction in acute pancreatitis events of 85% with favorable safety and tolerability. CORE and CORE2 make up the largest pivotal program for sHTG, with nearly 1,100 patients who were required to be on standard of care lipid-lowering therapy throughout the treatment period.

The CORE and CORE2 studies met the primary endpoint, with both 80 mg and 50 mg monthly doses of olezarsen demonstrating a highly statistically significant placebo-adjusted mean reduction in fasting triglyceride levels at six months:

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| | | | |
|:---|:---|:---|:---|
|  | **Olezarsen 80 mg** | **Olezarsen 50 mg** | **Placebo** |
| **CORE** |  |  |  |
| Percent reduction from baseline<sup>1</sup> | 73% | 63% | 0.5% |
| **Percent placebo-adjusted reduction<sup>2</sup>** | **72%** | **63%** |  |
| P-value<sup>3</sup> | p<0.0001 | p<0.0001 |  |
| **CORE2** |  |  |  |
| Percent reduction from baseline<sup>1</sup> | 68% | 63% | 14% |
| **Percent placebo-adjusted reduction<sup>2</sup>** | **55%** | **49%** |  |
| P-value<sup>3</sup> | p<0.0001 | p<0.0001 |  |

---

1. Least-squares mean. 2. Least-squares mean difference of percent reduction in fasting triglycerides. 3. P-values are based on comparison between each olezarsen group and placebo group in percent reduction in fasting triglycerides.

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Additionally, the studies met the secondary endpoint of reduction in acute pancreatitis events. Olezarsen demonstrated a highly statistically significant 85% reduction in events (p=0.0002) compared to placebo. This was a prespecified analysis of pooled olezarsen groups compared to pooled placebo groups across both studies at 12 months.

Olezarsen demonstrated a favorable safety and tolerability profile. Adverse events were generally balanced across treatment groups, and serious adverse events occurred less frequently in the olezarsen groups compared to placebo. Injection site reactions, which were mostly mild, were the most common adverse event and occurred more frequently in the olezarsen groups compared to placebo. More than 90% of patients who completed CORE and CORE2 chose to continue into the open-label extension study.

We plan to submit a supplemental new drug application (sNDA) to the U.S. Food and Drug Administration by end of year. Detailed data will be presented at an upcoming medical conference.

#### Forward-Looking Statements
Certain statements contained in this report are forward-looking statements that involve a number of risks and uncertainties. Such forward-looking statements include, without limitation, statements regarding Ionis' business, the therapeutic and commercial potential of olezarsen, our commercial medicines, additional medicines in development and technologies, and Ionis' expectations regarding development and regulatory milestones. Words such as "anticipate," "believe," "could," "continue," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "will," "would" and similar expressions are intended to identify forward-looking statements, though not all forward-looking statements necessarily contain these identifying words. For such statements, Ionis claims the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. Actual events or results may differ materially from Ionis' expectations. Factors that could cause actual results to differ materially from the forward-looking statements include, but are not limited to, 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. Additional factors that could cause actual results to differ materially from those stated or implied by Ionis' forward-looking statements are disclosed in Ionis' filings with the Securities and Exchange Commission, including in the section captioned "Risk Factors" in Ionis' most recent Annual Report on Form 10-K and subsequently filed Quarterly Reports on Form 10-Q. These forward-looking statements represent Ionis' judgment as of the time of this report. Ionis disclaims any intent or obligation to update these forward-looking statements, other than as may be required under applicable law.

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| | |
|:---|:---|
| **Item 9.01** | **Financial Statements and Exhibits.** |

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(d) Exhibits.

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| | |
|:---|:---|
| **<u>Exhibit No.</u>** | **<u>Description</u>** |
| [99.1](ef20054942_ex99-1.htm) | Press Release dated September 2, 2025. |
| 104 | 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.** | **Ionis Pharmaceuticals, Inc.** |
| Dated: September 2, 2025 | By: <br>| /s/ Patrick R. O'Neil |
|  |  | **Patrick R. O'Neil** |
|  |  | Executive Vice President, Chief Legal Officer and General Counsel |

---

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## Exhibit 99.1

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**Exhibit 99.1**<br>

![](image00001.jpg)

#### Olezarsen significantly reduces triglycerides and acute pancreatitis events in landmark pivotal studies for people with severe hypertriglyceridemia (sHTG)

#### – Up to 72% (p<0.0001) placebo-adjusted mean reduction in fasting triglycerides –

#### – 85% (p=0.0002) reduction in acute pancreatitis events, the first and only time achieved for the treatment of sHTG –

#### – Favorable safety and tolerability profile –

#### – sNDA submission planned by end of year –

#### – Ionis to host webcast today at 8:30 a.m. ET –

CARLSBAD, Calif., Sept. 2, 2025 -- <u>Ionis Pharmaceuticals, Inc.</u> (Nasdaq: IONS) today announced positive topline results from the pivotal Phase 3 CORE and CORE2 studies of olezarsen in people with severe hypertriglyceridemia (sHTG). In the studies, olezarsen demonstrated a highly statistically significant placebo-adjusted mean reduction in fasting triglycerides of up to 72% and a highly statistically significant reduction in acute pancreatitis events of 85% with favorable safety and tolerability. CORE and CORE2 make up the largest pivotal program for sHTG, with nearly 1,100 patients who were required to be on standard of care lipid-lowering therapy throughout the treatment period.

"These data are groundbreaking, demonstrating that olezarsen is the first therapy for sHTG to significantly reduce acute pancreatitis events," said Sam Tsimikas, M.D., senior vice president, global cardiovascular development, Ionis. "Despite current standard of care and lifestyle changes, people with sHTG – who could have triglyceride levels reaching into the thousands – remain vulnerable to unpredictable and life-threatening acute pancreatitis attacks. These results reinforce our confidence that olezarsen has the potential to change the sHTG treatment paradigm."

The CORE and CORE2 studies met the primary endpoint, with both 80 mg and 50 mg monthly doses of olezarsen demonstrating a highly statistically significant placebo-adjusted mean reduction in fasting triglyceride levels at six months:

---

| | | | |
|:---|:---|:---|:---|
|  | **Olezarsen 80 mg** | **Olezarsen 50 mg** | **Placebo** |
| **CORE** |  |  |  |
| Percent reduction from baseline<sup>1</sup> | 73% | 63% | 0.5% |
| **Percent placebo-adjusted reduction<sup>2</sup>** | **72%** | **63%** |  |
| P-value<sup>3</sup> | p<0.0001 | p<0.0001 |  |
| **CORE2** |  |  |  |
| Percent reduction from baseline<sup>1</sup> | 68% | 63% | 14% |
| **Percent placebo-adjusted reduction<sup>2</sup>** | **55%** | **49%** |  |
| P-value<sup>3</sup> | p<0.0001 | p<0.0001 |  |

---

1. Least-squares mean. 2. Least-squares mean difference of percent reduction in fasting triglycerides. 3. P-values are based on comparison between each olezarsen group and placebo group in percent reduction in fasting triglycerides.

------

![](image00001.jpg)<br>

Additionally, the studies met the secondary endpoint of reduction in acute pancreatitis events. Olezarsen demonstrated a highly statistically significant 85% reduction in events (p=0.0002) compared to placebo. This was a prespecified analysis of pooled olezarsen groups compared to pooled placebo groups across both studies at 12 months.

"Building on our success in familial chylomicronemia syndrome, the exceptional CORE and CORE2 results position Ionis to set a new treatment standard for the many people with sHTG who are at risk of debilitating acute pancreatitis attacks," said Brett P. Monia, Ph.D., chief executive officer, Ionis. "If approved, olezarsen for sHTG will mark our third independent launch in under two years and our first launch in a prevalent population, marking a major step forward in delivering transformative care to those who need it most."

Olezarsen demonstrated a favorable safety and tolerability profile. Adverse events were generally balanced across treatment groups, and serious adverse events occurred less frequently in the olezarsen groups compared to placebo. Injection site reactions, which were mostly mild, were the most common adverse event and occurred more frequently in the olezarsen groups compared to placebo. More than 90% of patients who completed CORE and CORE2 chose to continue into the open-label extension study.

Ionis plans to submit a supplemental new drug application (sNDA) to the U.S. Food and Drug Administration by end of year. Detailed data will be presented at an upcoming medical conference.

#### Essence study data published in NEJM and presented at ESC Congress
Detailed data from the Phase 3 Essence study evaluating olezarsen in people with moderate hypertriglyceridemia (fasting triglycerides ≥150 mg/dL) and elevated cardiovascular risk were recently published in *The New England Journal of Medicine* (NEJM) and presented during a hot line session at the European Society of Cardiology (ESC) Congress. Olezarsen met the primary endpoint, demonstrating a statistically significant reduction in fasting triglyceride levels at six months, and all key secondary endpoints. Olezarsen demonstrated a favorable safety and tolerability profile, and the approximately 1,500-person study supports the olezarsen safety database.

#### Webcast
Ionis will host a webcast to discuss the topline results from the CORE and CORE2 studies on Tuesday, September 2 at 8:30 a.m. ET. Interested parties may access the webcast here. A webcast replay will be available for a limited time.

#### About the CORE and CORE2 Studies
CORE (<u>NCT05079919</u>; n=617) and CORE2 (<u>NCT05552326</u>; n=446), conducted with The TIMI Study Group, are Phase 3 global, multicenter, randomized, double-blind, placebo-controlled trials investigating the safety and efficacy of olezarsen for severe hypertriglyceridemia (sHTG). Participants aged 18 and older with triglyceride levels ≥500 mg/dL were enrolled. Participants were required to be on standard of care therapies for elevated triglycerides throughout the treatment period. At baseline, 47% and 37% of participants had baseline fasting triglycerides ≥880 mg/dL in CORE and CORE2, respectively. Participants were randomized to receive 50 mg or 80 mg of olezarsen or placebo every 4 weeks via subcutaneous injection for 12 months. The primary endpoint is the percent change from baseline in fasting triglycerides at six months compared to placebo.

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![](image00001.jpg)<br>

#### About Severe Hypertriglyceridemia
Severe hypertriglyceridemia (sHTG) is defined by severely high triglycerides (≥500 mg/dL) and characterized by an increased risk of acute pancreatitis and other morbidities. Considered a medical emergency, acute pancreatitis causes debilitating abdominal pain that often requires prolonged hospitalization, can lead to permanent organ damage and can become life-threatening. Preventing the first attack is key. In people with a history of acute pancreatitis episodes, the risk of future attacks is even greater. Current standard of care therapies for sHTG and lifestyle modifications (such as diet and exercise) do not sufficiently or consistently lower triglyceride levels or reduce the risks of sHTG in all patients. Approximately 3 million people are living with sHTG in the U.S., including more than 1 million who are considered high risk. High-risk sHTG includes those with triglycerides ≥880 mg/dL or triglycerides ≥500 mg/dL and a history of acute pancreatitis.

#### About Olezarsen
Olezarsen is an investigational RNA-targeted medicine being evaluated for the treatment of sHTG. Olezarsen is designed to lower the body's production of apoC-III, a protein produced in the liver that regulates triglyceride metabolism in the blood. Olezarsen is approved in the U.S. as TRYNGOLZA® as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia (FCS).

#### 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 <u>Ionis.com</u> and follow us on <u>X (Twitter)</u>, <u>LinkedIn</u> and <u>Instagram</u>.

#### Ionis Forward-looking Statements
This press release includes forward-looking statements regarding Ionis' business, the therapeutic and commercial potential of our commercial medicines, olezarsen, additional medicines in development and technologies, and our expectations regarding development and regulatory milestones. 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, 2024, 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.

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![](image00001.jpg)<br>

Ionis Pharmaceuticals<sup>®</sup> and TRYNGOLZA<sup>®</sup> are trademarks of Ionis Pharmaceuticals, Inc.

**Ionis Investor Contact:**<br> D. Wade Walke, Ph.D.<br> <u>IR@ionis.com</u> 760-603-2331

**Ionis Media Contact:**<br> Hayley Soffer<br> <u>media@ionis.com</u> 760-603-4679

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