RegulationFast Track (United States), Orphan Drug (United States), Orphan Drug (South Korea), Overseas New Drugs Urgently Needed in Clinical Settings (China), Orphan Drug (Japan)

Structure/Sequence

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Sequence Code 29854605

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Clinical Trials associated with Nusinersen sodium

NCT07047144

/ RecruitingPhase 2

A Phase 2, Double-Blind Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Apitegromab in Subjects <2 Years Old With Spinal Muscular Atrophy (SMA)

This double-blind, Phase 2, multiple-dose study will be conducted to evaluate the PK/PD, efficacy, safety, and tolerability of apitegromab in subjects <2 years old with 5q autosomal recessive SMA who have delayed motor milestones for their age attributed to SMA at the discretion of the Investigator or a Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score <55.

Start Date01 Sep 2025

Sponsor / Collaborator

Scholar Rock, Inc.

NCT06555419

/ RecruitingPhase 1

An Open Label, Single Cohort Study to Assess the Pharmacokinetic Profile of Nusinersen (BIIB058) Administered Via the ThecaFlex DRx™ System (PIERRE-PK)

In this PIERRE-PK study, researchers will learn how the body processes nusinersen when it is given through the ThecaFlex DRx™ System, compared to when nusinersen is given by lumbar puncture (LP). The ThecaFlex DRx system is an investigational implantable medical device developed by Alcyone Therapeutics, Inc. It consists of a catheter, which is a flexible tube, connected to a port which is placed under the skin. Alcyone Therapeutics, Inc. has an ongoing study called PIERRE to test the ThecaFlex DRx system. Participants with spinal muscular atrophy (SMA) in the PIERRE study may be enrolled in the PIERRE-PK study.
The main objective of the PIERRE-PK study is to learn how the body processes nusinersen when given by the ThecaFlex DRx system compared to a lumbar puncture. The main questions researchers want to answer are:
* What is the highest amount of nusinersen found in the blood after dosing?
* How much nusinersen is found in the blood over the first 24 hours after dosing?
The PIERRE-PK study will be done as follows:
* Participants will be screened to check if they can join the study. The screening period will be up to 30 days for this study and may overlap with the PIERRE study.
* Participants will receive a dose of nusinersen by lumbar puncture.
* The ThecaFlex DRx system will be implanted after the lumbar puncture, as part of the PIERRE study.
* Participants will receive a dose of nusinersen by the ThecaFlex DRx system, as part of the PIERRE study.
* Researchers will take blood samples before and after each dose. The last blood sample will be taken 24 hours after the dose.
* The total study duration for each participant in the PIERRE-PK study will be approximately 5 months. This period will overlap with the participant's first 5 months in the PIERRE study.

Start Date16 Jan 2025

Sponsor / Collaborator

Biogen, Inc.

[+1]

NCT06978985

/ RecruitingNot ApplicableIIT

Adult SMA REACH: Development and Implementation of a Standardised Data Set and Data Collection Research Study in the UK Adult SMA Population

Adult SMA REACH is a data collection study aiming to gain a better understanding of the impact of standards of care and new treatments on the natural history of Spinal Muscular Atrophy (SMA). This study is sponsored by The Newcastle upon Tyne Hospitals NHS Foundation Trust. Adult SMA REACH is funded by Biogen and Roche.
Currently, there are three drug treatments available for SMA in the UK: Zolgensma, Nusinersen and Risdiplam. Zolgensma is the only approved drug - Nusinersen and Risdiplam are currently available as part of Managed Access Agreements (MAA).

Start Date29 Jul 2022

Sponsor / Collaborator

The Newcastle upon Tyne Hospitals NHS Foundation Trust

[+3]

100 Clinical Results associated with Nusinersen sodium

100 Translational Medicine associated with Nusinersen sodium

100 Patents (Medical) associated with Nusinersen sodium

820

Literatures (Medical) associated with Nusinersen sodium

01 Jan 2026·Methods in molecular biology (Clifton, N.J.)

DG9-Conjugated Morpholino Rescues Phenotype in Spinal Muscular Atrophy Mice

Article

Author: Haque, Umme Sabrina ; Yokota, Toshifumi ; Kohut, Melissa

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease characterized by decreased expression of the survival of motor neuron 1 (SMN1) gene. Antisense oligonucleotide (ASO)-based therapies have been developed recently as a means of increasing the production of functional SMN protein by targeting the SMN2 gene. Nusinersen, an FDA-approved ASO, has shown success in SMA treatment. However, it faces several challenges that limit its therapeutic potential. One of the main challenges is the administration route, as nusinersen requires intrathecal injection, which involves direct delivery into the cerebrospinal fluid (CSF). This invasive method can be burdensome for patients and may pose accessibility and practicality issues. Another challenge is the limited ability of nusinersen to efficiently penetrate the blood-brain barrier (BBB). The BBB restricts the passage of molecules to bodywide tissues. Cost and affordability are significant challenges associated with nusinersen. The therapy is expensive, which can limit its accessibility for all patients who could benefit from it. Overcoming these challenges is crucial to optimize the therapeutic benefits of ASOs and broaden their availability to a larger population of SMA patients. To address these challenges, phosphorodiamidate morpholino oligomer (PMO)-based ASOs have emerged as a potential solution. However, PMO's inability to cross the BBB remains a significant hurdle. Recent advancements include the development of DG9 conjugated to PMO, which has demonstrated CNS distribution following subcutaneous injection. DG9-PMO treatment shows promise in increasing survival rates, improving motor coordination, mitigating muscle pathology, and enhancing neuromuscular junction characteristics, compared to the molecule equivalent to nusinersen and a benchmark cell-penetrating peptide R6G-conjugated PMO. Importantly, it also leads to a significant increase in full-length SMN2 expression in both CNS and systemic tissues. This chapter describes the methodologies employed to evaluate the efficacy and safety of DG9-PMO in a severe SMA mouse model. These methodologies include systemic ASO injection, quantitative RT-PCR, western blotting, histology, ELISA-based quantification of DG9-PMO, functional tests, and toxicology analysis. By addressing challenges related to administration route, BBB penetration, and cost, overcoming these obstacles is essential to optimize the therapeutic benefits of ASO and broaden its accessibility to a larger population of SMA patients. The advancements in DG9-PMO offer promising prospects for the development of ASO-based therapeutics.

31 Dec 2025·ANNALS OF MEDICINE

Unlocking the potential: advancements and applications of gene therapy in severe disorders

Review

Author: M. Elossaily, Gehan ; Makhijani, Shivani ; Ansari, Mohd Nazam ; Ingle, Rahul G.

INTRODUCTION:

Several severe disorders, such as inherited diseases (e.g. cystic fibrosis and beta thalassemia), genetic diseases (e.g. malignant tumors and diabetes), and infectious diseases (e.g. HIV) are pose significant challenges to human health.

BACKGROUND:

Over the past few decades, researchers have been working on gene therapies, and currently, terrible dreams have come true. To date, the Food and Drug Administration (FDA) has approved multiple gene therapies such as Kynamro for familial hypercholesterolaemia, Exondys51 for duchenne muscular dystrophy, Spinraza for spinal muscular atrophy, etc., rest for cancer, infectious diseases, and rare diseases.

DISCUSSION:

The authors have summarized recent advances in gene therapy, its background, molecular basis (e.g. viral and non-viral vectors), gene-editing techniques (e.g. CRISPR/Cas9, TALEN, ZFN), and its foremost applications in severe disorders, such as cancer, monogenic disorders (e.g. spinal muscular atrophy), polygenic disorders (e.g. autism), neurogenic disorders (e.g. Parkinson disease and Alzheimer's disease), and infectious diseases (e.g. HIV).

CHALLENGES:

In addition, we explored the major challenges faced by gene therapies during targeted delivery, immunogenicity, efficacy, and safety.

CONCLUSION:

To date, most of the promising approaches, such as different vectors, target cell populations, and both in vivo and ex vivo have paved the foundation for applications of gene therapies. Additionally, advances in enhancing the immune system that would certainly lower the healthcare costs. This review highlights the translatory potential of gene therapy in revolutionizing the treatment landscape for severe disorders.

01 Nov 2025·EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY

Value of creatine kinase and creatinine as biomarkers in nusinersen-treated children with spinal muscular atrophy

Article

Author: Feng, Yijie ; Huang, Siyi ; Mao, Shanshan ; Ren, Jielu ; Jiang, Liya ; Yan, Yue ; Zou, Xinli ; Jin, Jianing ; Yu, Yicheng ; Zhu, Danhui ; Gao, Feng

BACKGROUND:

The search for convenient and effective biomarkers is a critical and pressing need for spinal muscular atrophy (SMA) in the era of disease-modifying treatment.

METHODS:

Data from 65 SMA children treated with nusinersen and followed up for 18 months were retrospectively collected. Motor function was assessed at baseline, 6, 10, 14 and 18 months using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), the Hammersmith Functional Motor Scale Expanded (HFMSE), and the Revised Upper Limb Module (RULM). Serum creatine kinase (CK) and creatinine (Crn) levels were measured, and the correlations were further analyzed.

RESULTS:

Significant differences in CK and Crn levels were found among different types before treatment. Baseline CK levels in children with SMA type 3 were higher than those with types 1 and 2 (P = 0.008 and 0.042, respectively), while baseline Crn levels were higher in type 3 than in type 2 (P < 0.001). During the follow-up, baseline Crn levels in types 2 and 3 patients with clinically meaningful improvements in HFMSE scores were higher than those without such improvements (P = 0.013). Additionally, a correlation was observed between HFMSE scores and CK and Crn levels in types 2 and 3 patients (CK: P < 0.001, ρ = 0.473; Crn: P < 0.001, ρ = 0.642). RULM scores were correlated with Crn levels (P < 0.001, ρ = 0.642).

CONCLUSIONS:

Serum CK and Crn levels appear to correlate with clinical severity in later-onset SMA. Moreover, baseline serum Crn may serve as a potential biomarker for predicting the degree of motor function improvement under nusinersen treatment in children with later-onset SMA.

366

News (Medical) associated with Nusinersen sodium

29 Oct 2025

·ir.ionispharma.com

Ionis reports third quarter 2025 financial results and highlights progress on key programs

- TRYNGOLZA® generated $32 million in net product sales in the third quarter 2025 - - DAWNZERA™ (donidalorsen) launch off to encouraging start - - Olezarsen significantly reduced triglycerides and acute pancreatitis events in severe hypertriglyceridemia (sHTG) in landmark Phase 3 studies; sNDA submission on track by year-end – - Positive pivotal zilganersen results in Alexander disease position Ionis for first independent neurology launch in 2026 - - Increasing 2025 financial guidance driven by continued strength across the business – CARLSBAD, Calif. --(BUSINESS WIRE)--Oct. 29, 2025-- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the “Company”) today reported financial results and provided key updates for the third quarter ended September 30, 2025 . "The third quarter was a watershed moment for Ionis, as we made important progress advancing our Ionis-owned medicines. With two independent launches now underway, and two more anticipated in 2026, we are delivering on our goal to bring a steady cadence of new medicines to people in need,” said Brett P. Monia , Ph.D., chief executive officer of Ionis. “Last month, we announced groundbreaking, positive topline Phase 3 results for olezarsen in severe hypertriglyceridemia and for zilganersen in Alexander disease, with regulatory filings planned in the coming months. Our approved and late-stage portfolio continues to deliver — positioning Ionis for substantial growth while, most importantly, offering the opportunity to profoundly improve the lives of people with serious diseases." Third Quarter 2025 Summary Financial Results(1): Three months ended Nine months ended September 30 , September 30 , 2025 2024 2025 2024 (amounts in millions) Total revenue $ 157 $ 134 $ 740 $ 479 Operating expenses $ 317 $ 282 $ 907 $ 843 Operating expenses on a non-GAAP basis $ 286 $ 250 $ 816 $ 749 Loss from operations ($ 160 ) ($ 148 ) ($ 167 ) ($ 364 ) Loss from operations on a non-GAAP basis ($ 129 ) ($ 116 ) ($ 76 ) ($ 270 ) (1) Reconciliation of GAAP to non-GAAP basis contained later in this release. Recent Financial Highlights Revenue increased 17% in the third quarter of 2025 and increased 55% in the nine months ended September 30, 2025 , compared to the same periods last year, driven by the continued successful launch of TRYNGOLZA and increased royalty revenues. Contributing to the year-to-date increase, Ionis earned a $280 million upfront payment for the global license of sapablursen to Ono Pharmaceutical Co., Ltd. in the second quarter of 2025 Operating expenses on a non-GAAP basis increased 14% in the third quarter of 2025 and increased 9% in the nine months ended September 30, 2025 , compared to the same periods last year, primarily due to investments related to commercialization efforts for TRYNGOLZA, DAWNZERA and WAINUA Increasing 2025 financial guidance reflects strong overall revenue performance experienced year-to-date and fourth quarter outlook, including strong momentum seen with TRYNGOLZA revenues: Full Year 2025 Guidance Previous Guidance New Guidance Total Revenue $825-850 million $875-900 million TRYNGOLZA product sales, net $75-80 million $85-95 million Operating loss on a non-GAAP basis $300-325 million $275-300 million Cash, cash equivalents and short-term investments ~$2.0 billion > $2.1 billion Third Quarter 2025 Financial Results "In the third quarter of 2025, we delivered strong revenue performance, highlighted by TRYNGOLZA’s nearly 70% increase over the prior quarter. As a result of this strength and our fourth quarter outlook, we are increasing our financial guidance again for 2025," said Elizabeth L. Hougen , chief financial officer of Ionis. "Looking ahead, we expect the 2026 independent launches of olezarsen in severe hypertriglyceridemia and zilganersen in Alexander disease to further strengthen our commercial portfolio. We anticipate that growth in our product revenues coupled with additional partner revenues will position Ionis to achieve cash flow breakeven in 2028 and generate substantial and sustainable positive cash flow for years to come." Recent Highlights - Wholly Owned Medicines TRYNGOLZA® (olezarsen), the first and only FDA approved treatment for adults living with familial chylomicronemia syndrome (FCS) as an adjunct to diet Generated net product sales of $32 million in the third quarter of 2025, its third full quarter on the market, a nearly 70% increase over the prior quarter, and $57 million in the nine months ended September 30, 2025 Approved in the European Union (EU) as an adjunct to diet in adult patients for the treatment of genetically confirmed FCS ; Sobi anticipates launching in the fourth quarter 2025 Olezarsen demonstrated positive topline results in the pivotal Phase 3 CORE and CORE2 studies in sHTG 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 sNDA submission on track for the end of 2025 with approval anticipated in the fourth quarter of 2026 Detailed data to be presented at the American Heart Association Conference on November 8, 2025 , in a late-breaking session DAWNZERA™ (donidalorsen) was approved on August 21, 2025 , by the FDA for prophylaxis to prevent attacks of hereditary angioedema ( HAE) in adult and pediatric patients 12 years of age and older First and only RNA-targeted prophylactic therapy that has the potential to offer durable efficacy, a favorable safety and tolerability profile, and the longest available dosing interval, with self-administration via autoinjector every four or eight weeks U.S. launch underway and off to an encouraging start Currently under regulatory review in the EU Zilganersen demonstrated positive results in the pivotal study in children and adults with Alexander disease (AxD), a rare, progressive, and often fatal neurological disorder with no approved disease-modifying treatments Zilganersen 50 mg demonstrated statistically significant and clinically meaningful stabilization on the primary endpoint of gait speed as assessed by the 10-Meter Walk Test (10MWT), compared to control at week 61 (mean difference 33.3%) with favorable safety and tolerability Additional data from the pivotal study in children and adults living with Alexander disease were presented at the Child Neurology Society Annual Meeting in October 2025 NDA submission planned for the first quarter of 2026 with approval anticipated next year ION582 granted Breakthrough Therapy designation from FDA for the treatment of Angelman syndrome Phase 3 REVEAL study expected to be fully enrolled in 2026 Phase 2 HALOS study showed continued improvement across multiple functional measures versus natural history through 18 months including expressive communication Generated net product sales of $32 million in the third quarter of 2025, its third full quarter on the market, a nearly 70% increase over the prior quarter, and $57 million in the nine months ended September 30, 2025 Approved in the European Union (EU) as an adjunct to diet in adult patients for the treatment of genetically confirmed FCS ; Sobi anticipates launching in the fourth quarter 2025 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 sNDA submission on track for the end of 2025 with approval anticipated in the fourth quarter of 2026 Detailed data to be presented at the American Heart Association Conference on November 8, 2025 , in a late-breaking session First and only RNA-targeted prophylactic therapy that has the potential to offer durable efficacy, a favorable safety and tolerability profile, and the longest available dosing interval, with self-administration via autoinjector every four or eight weeks U.S. launch underway and off to an encouraging start Currently under regulatory review in the EU Zilganersen 50 mg demonstrated statistically significant and clinically meaningful stabilization on the primary endpoint of gait speed as assessed by the 10-Meter Walk Test (10MWT), compared to control at week 61 (mean difference 33.3%) with favorable safety and tolerability Additional data from the pivotal study in children and adults living with Alexander disease were presented at the Child Neurology Society Annual Meeting in October 2025 NDA submission planned for the first quarter of 2026 with approval anticipated next year Phase 3 REVEAL study expected to be fully enrolled in 2026 Phase 2 HALOS study showed continued improvement across multiple functional measures versus natural history through 18 months including expressive communication Recent Highlights – Partnered Medicines WAINUA® (eplontersen) (WAINZUA in EU) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) generated sales of $59 million and $143 million resulting in royalty revenue of $13 million and $33 million in the third quarter and the nine months ended September 30, 2025 , respectively Launches underway in numerous regions, including the EU; additional submissions in progress to expand WAINUA access globally SPINRAZA® (nusinersen) for the treatment of spinal muscular atrophy (SMA) generated global sales of $374 million and $1.2 billion resulting in royalty revenue of $56 million and $158 million in the third quarter and the nine months ended September 30, 2025 , respectively Launches underway in numerous regions, including the EU; additional submissions in progress to expand WAINUA access globally Revenue Ionis’ revenue was comprised of the following: Three months ended Nine months ended September 30 , September 30 , 2025 2024 2025 2024 Revenue: (amounts in millions) Commercial revenue: Product sales, net: TRYNGOLZA sales, net $ 32 $ - $ 57 $ - Total product sales, net 32 - 57 - Royalty revenue: SPINRAZA royalties 56 57 158 152 WAINUA royalties 13 5 33 10 Other royalties 7 5 19 18 Total royalty revenue 76 67 210 180 Other commercial revenue 8 9 27 27 Total commercial revenue 116 76 294 207 Research and development revenue: Collaborative agreement revenue 31 45 414 237 WAINUA joint development revenue 10 13 32 35 Total research and development revenue 41 58 446 272 Total revenue $ 157 $ 134 $ 740 $ 479 Commercial revenue for the third quarter and the nine months ended September 30, 2025 , increased 53% and 42%, respectively, compared to the same periods in 2024. This increase was primarily driven by TRYNGOLZA product sales. Higher royalty revenue also contributed to the year over year increase. The remainder of the Company’s revenue came from programs under its R&D collaborations, including a $280 million upfront payment for the global license of sapablursen to Ono Pharmaceutical Co., Ltd. in the second quarter of 2025, reflecting the value that Ionis’ pipeline and technology continues to generate. Operating Expenses SG&A expenses increased as anticipated for the third quarter and the nine months ended September 30, 2025 , compared to the same periods in 2024, primarily due to the launches of TRYNGOLZA, DAWNZERA and WAINUA. This increase was partially offset by a decrease in R&D expenses as several late-stage studies ended. Overall, this led to a modest year-over-year increase in total operating expenses, which was in line with expectations. Balance Sheet As of September 30, 2025 , Ionis’ cash, cash equivalents and short-term investments were $2.2 billion , compared to $2.3 billion on December 31, 2024 . Ionis’ working capital decreased over the same period primarily due to the reclassification of the Company’s 0% convertible notes as a current liability. Webcast and Other Updates Management will host a conference call and webcast to discuss Ionis’ third quarter 2025 results at 11:30 a.m. Eastern time on Wednesday, October 29, 2025 . Interested parties may access the webcast here. A webcast replay will be available for a limited time at the same address. To access the Company’s third quarter 2025 earnings slides click here. Ionis’ Marketed Medicines INDICATION for TRYNGOLZA® (olezarsen) TRYNGOLZA® (olezarsen) was approved by the U.S. Food and Drug Administration as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to TRYNGOLZA or any of the excipients in TRYNGOLZA. Hypersensitivity reactions requiring medical treatment have occurred. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills and myalgias) have been reported in patients treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. ADVERSE REACTIONS The most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count and arthralgia. Please see full Prescribing Information for TRYNGOLZA. INDICATION for DAWNZERATM (donidalorsen) DAWNZERA™ (donidalorsen) was approved by the U.S. Food and Drug Administration for prophylaxis to prevent attacks of hereditary angioedema ( HAE) in adult and pediatric patients 12 years of age and older. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS DAWNZERA is contraindicated in patients with a history of serious hypersensitivity reactions, including anaphylaxis, to donidalorsen or any of the excipients in DAWNZERA. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with DAWNZERA. If signs and symptoms of serious hypersensitivity reactions occur, discontinue DAWNZERA and institute appropriate therapy. ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 5%) are injection site reactions, upper respiratory tract infection, urinary tract infection, and abdominal discomfort. Please see full Prescribing Information for DAWNZERA. INDICATION for WAINUA® (eplontersen) WAINUA injection, for subcutaneous use, 45 mg is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. IMPORTANT SAFETY INFORMATION for WAINUA® (eplontersen) WARNINGS AND PRECAUTIONS Reduced Serum Vitamin A Levels and Recommended Supplementation WAINUA leads to a decrease in serum vitamin A levels. Supplement with recommended daily allowance of vitamin A. Refer patient to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. ADVERSE REACTIONS Most common adverse reactions (≥9% in WAINUA-treated patients) were vitamin A decreased (15%) and vomiting (9%). Please see link to U.S. Full Prescribing Information for WAINUA. For more information about SPINRAZA and QALSODY, visit https://www.spinraza.com/ and https://www.qalsody.com/, respectively. QALSODY is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL) observed in patients treated with QALSODY. Continued approval may be contingent upon verification of clinical benefit in confirmatory trial(s). 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 Statement This press release includes forward-looking statements regarding Ionis’ business, financial guidance and the therapeutic and commercial potential of our commercial medicines, additional medicines in development, 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. IONIS® is a registered trademark of Ionis Pharmaceuticals, Inc. TRYNGOLZA® is a registered trademark of Ionis Pharmaceuticals, Inc. DAWNZERATM is a trademark of Ionis Pharmaceuticals, Inc. AKCEATM is a trademark of Akcea Therapeutics, Inc. TEGSEDITM is a trademark of Akcea Therapeutics, Inc. WAYLIVRATM is a trademark of Akcea Therapeutics, Inc. SPINRAZA® and QALSODY® are registered trademarks of Biogen. WAINUA® is a registered trademark of the AstraZeneca group of companies. IONIS PHARMACEUTICALS, INC. SELECTED FINANCIAL INFORMATION Condensed Consolidated Statements of Operations (In Millions, Except Per Share Data) Three months ended Nine months ended September 30 , September 30 , 2025 2024 2025 2024 (unaudited) Revenue: Commercial revenue: Product sales, net $ 32 $ - $ 57 $ - Royalty revenue 76 67 210 180 Other commercial revenue 8 9 27 27 Total commercial revenue 116 76 294 207 Research and development revenue: Collaborative agreement revenue 31 45 414 237 WAINUA joint development revenue 10 13 32 35 Total research and development revenue 41 58 446 272 Total revenue 157 134 740 479 Expenses: Cost of sales 2 1 8 7 Research, development and patent 218 220 636 656 Selling, general and administrative 97 61 263 180 Total operating expenses 317 282 907 843 Loss from operations (160 ) (148 ) (167 ) (364 ) Other income (expense): Interest expense related to the sale of future royalties (18 ) (19 ) (55 ) (55 ) Other income, net 49 23 70 66 Loss before income tax benefit (129 ) (144 ) (152 ) (353 ) Income tax benefit - 4 - 3 Net loss ($ 129 ) ($ 140 ) ($ 152 ) ($ 350 ) Basic and diluted net loss per share ($ 0.80 ) ($ 0.95 ) ($ 0.95 ) ($ 2.38 ) Shares used in computing basic and diluted net loss per share 160 149 159 147 IONIS PHARMACEUTICALS, INC. Reconciliation of GAAP to Non-GAAP Basis: Condensed Consolidated Operating Expenses, Loss From Operations, and Net Loss (In Millions) Three months ended September 30 , Nine months ended September 30 , 2025 2024 2025 2024 (unaudited) As reported research, development and patent expenses according to GAAP $ 218 $ 220 $ 636 $ 656 Excluding compensation expense related to equity awards (21 ) (22 ) (61 ) (67 ) Non-GAAP research, development and patent expenses $ 197 $ 198 $ 575 $ 589 As reported selling, general and administrative expenses according to GAAP $ 97 $ 61 $ 263 $ 180 Excluding compensation expense related to equity awards (10 ) (10 ) (29 ) (26 ) Non-GAAP selling, general and administrative expenses $ 87 $ 51 $ 234 $ 154 As reported operating expenses according to GAAP $ 317 $ 282 $ 907 $ 843 Excluding compensation expense related to equity awards (31 ) (32 ) (91 ) (94 ) Non-GAAP operating expenses $ 286 $ 250 $ 816 $ 749 As reported loss from operations according to GAAP ($ 160 ) ($ 148 ) ($ 167 ) ($ 364 ) Excluding compensation expense related to equity awards (31 ) (32 ) (91 ) (94 ) Non-GAAP loss from operations ($ 129 ) ($ 116 ) ($ 76 ) ($ 270 ) As reported net loss according to GAAP ($ 129 ) ($ 140 ) ($ 152 ) ($ 350 ) Excluding compensation expense related to equity awards and related tax effects (31 ) (32 ) (91 ) (94 ) Non-GAAP net loss ($ 98 ) ($ 108 ) ($ 61 ) ($ 256 ) Reconciliation of GAAP to Non-GAAP Basis As illustrated in the Selected Financial Information in this press release, non-GAAP operating expenses, non-GAAP loss from operations, and non-GAAP net loss were adjusted from GAAP to exclude compensation expense related to equity awards and the related tax effects. Compensation expense related to equity awards are non-cash. These measures are provided as supplementary information and are not a substitute for financial measures calculated in accordance with GAAP. Ionis reports these non-GAAP results to better enable financial statement users to assess and compare its historical performance and project its future operating results and cash flows. Further, the presentation of Ionis’ non-GAAP results is consistent with how Ionis’ management internally evaluates the performance of its operations. IONIS PHARMACEUTICALS, INC. Condensed Consolidated Balance Sheets (In Millions) September 30 , December 31 , 2025 2024 (unaudited) Assets: Cash, cash equivalents and short-term investments $ 2,240 $ 2,298 Contracts receivable 25 92 Other current assets 254 230 Property, plant and equipment, net 106 94 Right-of-use assets 242 162 Other assets 166 127 Total assets $ 3,033 $ 3,003 Liabilities and stockholders’ equity: Current portion of deferred contract revenue $ 77 $ 79 0% convertible senior notes, net – current 631 - Other current liabilities 195 229 1.75% convertible senior notes, net 567 565 0% convertible senior notes, net - 629 Liability related to sale of future royalties, net 545 542 Long-term lease liabilities 263 162 Long-term obligations, less current portion 29 52 Long-term deferred contract revenue 108 157 Total stockholders’ equity 618 588 Total liabilities and stockholders’ equity $ 3,033 $ 3,003 Key 2025 and 2026 Value Driving Events(1) New Product Launches Program Indication 2025 2026 DAWNZERA ( U.S. ) HAE Achieved TRYNGOLZA ( U.S. ) FCS Achieved WAINZUA (EU) ATTRv-PN Achieved Olezarsen ( U.S. ) sHTG • Zilganersen ( U.S. ) Alexander disease • Regulatory Actions Program Indication Regulatory Action 2025 2026 Donidalorsen HAE U.S. approval decision Achieved EU approval decision • TRYNGOLZA FCS EU approval decision Achieved Olezarsen sHTG U.S. submission • U.S. approval decision • Zilganersen Alexander disease U.S. submission • U.S. approval decision • Nusinersen (higher dose) SMA U.S. and EU submissions Achieved U.S. approval decision Refiling process on track WAINZUA ATTRv-PN EU approval decision Achieved Pelacarsen Lp(a)- CVD U.S. submission • Bepirovirsen HBV Regulatory submission(s) • Regulatory decision(s) • Key Phase 3 Clinical Events Program Indication Event 2025 2026 Olezarsen sHTG CORE, CORE2 data Achieved Essence data Achieved Zilganersen Alexander disease Phase 3 data Achieved ION582 Angelman syndrome Phase 3 study start Achieved Phase 3 enrollment completion • Pelacarsen Lp(a)-CVD Lp(a) HORIZON data • Bepirovirsen HBV B-Well data • Eplontersen ATTR-CM CARDIO-TTRansform data • Sefaxersen IgAN IMAGINATION data • Ulefnersen FUS-ALS FUSION data • Timing expectations based on current assumptions and subject to change. Indicates that the milestone is anticipated in the respective year. View source version on businesswire.com: https://www.businesswire.com/news/home/20251029676166/en/ 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 Source: Ionis Pharmaceuticals, Inc.

Drug ApprovalClinical ResultPhase 3Financial StatementBreakthrough Therapy

09 Oct 2025

·firstwordpharma.com

Xspray's Dasynoc is latest drug shot down by FDA due to manufacturing issues

Xspray Pharma said Wednesday that its application for Dasynoc (dasatinib) to treat chronic myeloid leukaemia and acute lymphoblastic leukaemia was rejected by the FDA due to good manufacturing practice (GMP) observations at the drugmaker's contract manufacturing organisation (CMO). improved version of Sprycel, a second-generation tyrosine kinase inhibitor.Dasynoc is an improved version of second-generation tyrosine kinase inhibitor Sprycel that's designed to not interact with antacids and have greater uptake. No issues were identified at Xspray's own production line, but the FDA is pausing approvals of products made at the CMO's facility "while corrective actions are being implemented," the company said. The manufacturer has implemented a remediation plan and plans to meet with the US regulator in December. In the complete response letter (CRL), the FDA also requested information from Xspray to ensure "the discussed product information is appropriate.""It is unfortunate that manufacturing-related issues beyond our control are delaying our launch. We have made significant progress in the regulatory review and maintained discussions with the FDA regarding the product information for Dasynoc up to the PDUFA date," said Per Andersson, Xspray's chief executive. "We will now work closely with both the manufacturer and the FDA to expedite the process and enable a resubmission as soon as the corrective actions have been completed."Xspray is the latest in a series of drugmakers to receive a CRL prompted by manufacturing issues. Earlier this month, Fortress Biotech said FDA declined to approve CUTX-101 (copper histidinate) to treat paediatric patients with Menkes disease due to GMP deficiencies, and Biogen's high-dose Spinraza was hit with a similar complaint last month.After the US regulator released hundreds of CRLs in July, a FirstWord analysis found that issues related to chemistry, manufacturing and controls are the most frequent reason the FDA didn't approve a drug, with deficiencies at manufacturing facilities or subpar quality of the manufactured drug product leading to a combined 60% of all rejections (see – Vital Signs: What we learned from the FDA's CRL data dump).

Drug ApprovalAccelerated Approval

01 Oct 2025

·firstwordpharma.com

Fortress says manufacturing issues triggered CRL for Menkes disease drug

The FDA has declined to approve CUTX-101 (copper histidinate) to treat Menkes disease in paediatric patients, Fortress Biotech and its subsidiary Cyprium Therapeutics said on Wednesday. In late 2023, Cyprium sold commercial and developmental rights for CUTX-101 to Sentynl Therapeutics, a subsidiary of Zydus Life Sciences, for $4.5 million upfront. Under the deal, Cyprium was eligible for up to $129 million in development and sales milestones, plus tiered royalties; the company will also retain a priority review voucher if issued by the FDA upon approval of CUTX-101.According to Fortress, the complete response letter (CRL) was due to current Good Manufacturing Practice (cGMP) deficiencies at the facility where CUTX-101 is manufactured. The unnamed site has provided responses to a re-inspection in September.Issues related to chemistry, manufacturing and controls are the most frequent reason for an FDA rejection, a recent FirstWord analysis found; Biogen's high-dose Spinraza was hit with a similar complaint last month. The US regulator in July posted a batch of CRLs associated with more than 200 new drug applications, and deficiencies at manufacturing facilities or subpar quality of the manufactured drug product led to a combined 60% of all rejections (see – Vital Signs: What we learned from the FDA's CRL data dump).The CRL for CUTX-101 didn't flag any issues with the efficacy or safety, and Sentynl is planning to meet with the FDA to discuss resubmitting its application for the drug.The agency had granted the initial filing a priority review in January based on data showing that CUTX-101 led to a median overall survival of 177.1 months in patients with Menkes disease, a statistically significant result compared with the 16.1 months seen for an untreated historical control cohort.

Priority Review

100 Deals associated with Nusinersen sodium

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KEGG	Wiki	ATC	Drug Bank
D10791	Nusinersen sodium	M09AX07	DB13161

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Spinal Muscular Atrophy	United States	Biogen, Inc.	23 Dec 2016

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	United States	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	Japan	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	Australia	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	Belgium	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	Canada	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	France	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	Germany	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	Italy	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	Spain	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	Sweden	Biogen, Inc.	19 Aug 2014

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02386553 (NURTURE, CTgov)	Phase 2	Spinal Muscular Atrophy	25	nusinersen (ISIS 396443 2 SMN2 Copies)	qqziavnalp(xgqzpqvebu) = lvqumdahwp wtnbjtqvav (mcjiwdvihe, ojqauckgqt - wjoxkpiale) View more	-	20 Oct 2025
				nusinersen (ISIS 396443 3 SMN2 Copies)	oeswaudjwl = ddkqflfpkp djatwgfbgz (ritgxjufqc, yoelflzdyv - pkbhjnkswe) View more
NCT04089566 (DEVOTE, Company_Website) Manual	Phase 3	Spinal Muscular Atrophy	38	Nusinersen (received one loading dose (50 mg) and two maintenance doses (28 mg each))	gyvoaynjwj(rhpfjbtnzv) = qlkisnmunk rsmhmhkxkm (xtfglnyhnd, 0.49 - 4.56) View more	Positive	27 Jun 2025
NCT02386553 (NURTURE, Company_Website) Manual	Phase 2	Spinal Muscular Atrophy	25	SPINRAZA 12mg	yegxsszhbz(ywkfxpyznf) = tmucfqkznz hoqfiyrrbl (tumxvpyadp ) View more	Positive	27 Jun 2025
NCT04089566 (DEVOTE, MDA2025)	Phase 2/3	Spinal Muscular Atrophy	145	50/28mg regimen	aifrrvpqqm(bsdwkeicha): Difference = 26.19, P-Value = <0.0001	Positive	16 Mar 2025
				50/28mg regimen (Part C)
NCT04488133 (RESPOND, MDA2025)	Phase 2	Spinal Muscular Atrophy	46	Nusinersen (age ≤9 mo with 2 SMN2 copies)	cmcydftour(hjioddligy) = Three (7%) children had a nusinersen-related mild AE (proteinuria). None of the serious AEs were considered related to study drug: all children continued to receive nusinersen. rbdfmcjtod (uryhqierbk )	Positive	16 Mar 2025
				Nusinersen (age >9 mo with 2 copies)
NCT02594124 (SHINE Study (1692) \| SHINE, CTgov)	Phase 3	Spinal Muscular Atrophy	292	nusinersen (Infantile SMA Onset CS3A)	guhbozhgfs = fuhejfbzhg qsgwudlwxm (kfwkqwmykx, kmesnbpwzn - nudeljouqx) View more	-	22 Oct 2024
				nusinersen (Infantile SMA Onset CS3B Previous Control)	guhbozhgfs = ghsthjufye qsgwudlwxm (kfwkqwmykx, rpfpukltjf - tjybhiqgsn) View more
NCT04089566 (DEVOTE, NEWS) Manual	Phase 2/3	Spinal Muscular Atrophy	75	Spinraza 50/28 mg Active Treatment Group	ictbbpjzsl(gguzdbsfer) = Biogen on Wednesday said that an experimental, higher dose of its spinal muscular atrophy drug Spinraza met the primary endpoint of a clinical trial comparing it with a historical control group. bckwpnemdr (pteowsfwor ) Met View more	Positive	04 Sep 2024
				Spinraza 28/28 Milligram (mg) Safety Group
NCT04419233 (PANDA, Pubmed \| Adv Ther)	Phase 4	Spinal Muscular Atrophy	50	Nusinersen	pmzgbffgdj(ixverjegck) = xgmdgcbumi chpznwifga (zxqfbvwrrq )	Positive	01 Jul 2024
NCT04488133 (RESPOND, GlobeNewswire) Manual	Phase 4	Spinal Muscular Atrophy Nfl	29	SPINRAZA	uvminqyali(ujbgrneuic) = sqdfqkpiut epqjdluxlp (nwedlzawzr ) View more	Negative	06 Mar 2024
NCT02386553 (NURTURE, MDA2023) Manual	Phase 2	Spinal Muscular Atrophy SMN2 copies	15	Nusinersen (2 SMN2 copies)	aramqcodch(qgppoqokcx) = qvflxxqjlz mrtlvnhhjk (ssnxugfmcg ) View more	Positive	19 Mar 2023
				Nusinersen ( 2 SMN2 copies who did not have CMAP <2 mV )	aramqcodch(qgppoqokcx) = wptzgkaidx mrtlvnhhjk (ssnxugfmcg ) View more

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