[Translation] An open-label Phase I study to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of Eplontersen after a single subcutaneous injection in healthy Chinese subjects

主要目的是研究中国健康受试者接受45mg eplontersen单次皮下给药后的药代动力学（PK）特征，次要目的是研究中国健康受试者接受45 mg eplontersen单次皮下给药后的药效学（PD）特征，安全性目的是评价中国健康受试者接受45mg eplontersen单次皮下给药后的安全性和耐受性，探索性目的是评价中国健康受试者接受45mg eplontersen单次皮下给药后的免疫原性

[Translation]

The primary objective is to study the pharmacokinetic (PK) characteristics of 45 mg eplontersen after a single subcutaneous administration in healthy Chinese subjects. The secondary objective is to study the pharmacodynamic (PD) characteristics of 45 mg eplontersen after a single subcutaneous administration in healthy Chinese subjects. The safety objective is to evaluate the safety and tolerability of 45 mg eplontersen after a single subcutaneous administration in healthy Chinese subjects. The exploratory objective is to evaluate the immunogenicity of 45 mg eplontersen after a single subcutaneous administration in healthy Chinese subjects.

Start Date06 Aug 2024

Sponsor / Collaborator

AstraZeneca Global R&D (China) Co., Ltd.

[+2]

NCT06527755 / CompletedPhase 1

A Phase 1, Open-Label Study to Assess the Pharmacokinetics (PK), Pharmacodynamics (PD), Safety and Tolerability of Eplontersen Following Subcutaneous Administration of a Single Dose in Healthy Chinese Volunteers

This is a Phase 1 study to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of eplontersen following single dosing in healthy Chinese participants. The objectives of the study are: to characterize the pharmacokinetic (PK) profiles and the pharmacodynamic (PD) profiles, and to evaluate the safety and tolerability and the immunogenicity of eplontersen following subcutaneous administration of a single 45 mg dose in healthy Chinese participants.

Start Date06 Aug 2024

Sponsor / Collaborator

AstraZeneca PLC

NCT06194825 / Active, not recruitingPhase 3

A Phase 3, Randomized Study, With Initial 24-week, Double-Blind and Placebo-Controlled Treatment Phase, Followed by An 80-week Open-label Extension Treatment Phase to Evaluate the Effect of Eplontersen on the Transthyretin Reduction and Long-Term Safety in Chinese Participants With Transthyretin Amyloid Cardiomyopathy (EPIC-ATTR)

The purpose of this study is to investigate the effect of eplontersen compared to placebo on the reduction of serum TTR concentration and long-term safety in Chinese participants with hereditary or wild-type transthyretin amyloid cardiomyopathy.

Start Date01 Dec 2023

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with Eplontersen

100 Translational Medicine associated with Eplontersen

100 Patents (Medical) associated with Eplontersen

Literatures (Medical) associated with Eplontersen

01 Jan 2025·MUSCLE & NERVE

Estimating Meaningful Differences in Measures of Neuropathic Impairment, Health‐Related Quality of Life, and Nutritional Status in Patients With Hereditary Transthyretin Amyloidosis

Article

Author: Maurer, Mathew S. ; Wixner, Jonas ; Chen, Jersey ; Gertz, Morie ; Cruz, Márcia Waddington ; Reicher, Barry ; Folkvaljon, Folke ; Yarlas, Aaron ; Gillmore, Julian D. ; Masri, Ahmad ; Khella, Sami ; Berk, John L. ; Kwoh, Jesse

ABSTRACT:

Introduction/Aims:

The degree of change in neuropathic impairment and quality of life (QoL) that is clinically meaningful to patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN) is not established. This study aimed to estimate the magnitude of treatment differences that are meaningful to patients in measures of neuropathy and QoL and to determine whether eplontersen achieved a meaningful improvement versus placebo.

Methods:

Data from the NEURO‐TTRansform trial on patients with ATTRv‐PN treated with eplontersen (n = 141) or historical placebo (n = 59) were used. Anchor‐based approaches were used to estimate thresholds for meaningful differences in the modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk QoL‐Diabetic Neuropathy (Norfolk QoL‐DN) total score, Neuropathy Symptoms and Change (NSC) total score, and modified body mass index (mBMI). Differences between the least squares means of the treatment groups were analyzed.

Results:

Meaningful improvement in mNIS+7 was estimated as −4.0 points and deterioration as 1.8 points. The estimated ranges of meaningful improvement and deterioration in Norfolk QoL‐DN were −12.8 to −4.0 points, and 5.9 to 14.7 points, respectively. For NSC, ranges were −2.4 to −1.3 points for meaningful improvement, and 0.6 to 5.8 points for deterioration. The estimated meaningful improvement in mBMI was 9.8 kg/m2 × g/L and deterioration was −40.9 kg/m2 × g/L. Improvements in each measure with eplontersen versus placebo were greater than the estimates of meaningful differences.

Discussion:

Eplontersen demonstrated a clinically meaningful effect on neuropathic impairment, QoL, and nutritional status. Such estimates have implications for clinical practice and trials.

04 Oct 2024·European Heart Journal-Cardiovascular Pharmacotherapy

Pharmacological management of transthyretin amyloid cardiomyopathy: a scoping review

Review

Author: Ibrahim, Ramzi ; Raza, Shahzad ; Asif, Mohammad Shahzad ; Ahmad, Fahad ; Masthan, Shameera Shaik ; Pham, Hoang Nhat ; Anwar, Zain ; Safdar, Ahmad ; Rehman, Shafi ; Hassan, Danial ; William, Preethi

Abstract:

Aims:

Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the accumulation of transthyretin (TTR) protein in the myocardium. The aim of this scoping review is to provide a descriptive summary of the clinical trials and observational studies that evaluated the clinical efficacy and safety of various agents used in ATTR-CM, with a goal of identifying the contemporary gaps in literature and to reveal future research opportunities.

Methods and results:

The search was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search using several databases for observational and clinical trials investigating the treatment modalities for ATTR-CM was undertaken. We extracted data including study characteristics, primary endpoints, and adverse events from each study. A total of 19 studies were included in our scoping review. Out of which, 8 were clinical trials and 11 were observational analyses. The drugs evaluated included tafamadis, acoramidis, revusiran, doxycycline and tauroursodeoxycholic acid and doxycycline, diflusinil, inotersan, eplontersen, and patisiran. Tafamidis has shown to be efficacious in the management of ATTR-CM, particularly when initiated at earlier stages. RNA interference and antisense oligonucleotide drugs have shown promising impacts on quality of life. Additionally, this review identified gaps in the literature, particularly among long-term outcomes, comparative effectiveness, and the translation of research into economic contexts.

Conclusion:

Multiple pharmacological options are potential disease-modifying therapies for ATTR-CM. However, many gaps exist in the understanding of these various drug therapies, warranting further research. The future directions for management of ATTR-CM are promising in regard to improving prognostic implications.

01 Oct 2024·JOURNAL OF NEUROLOGY

Switching from inotersen to eplontersen in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: analysis from NEURO-TTRansform

Article

Author: Kwoh, T Jesse ; Masri, Ahmad ; Weiler, Markus ; Conceição, Isabel ; Attarian, Shahram ; Jung, Shiangtung W ; Kowacs, Pedro A ; Chen, Jersey ; Dasgupta, Noel R ; Chao, Chi-Chao ; Coelho, Teresa ; Cruz, Márcia Waddington ; Berk, John L ; Gertz, Morie ; Viney, Nicholas J ; Khella, Sami ; Yu, Rosie Z

Abstract:

Background:

The phase 3 NEURO-TTRansform trial showed eplontersen treatment for 65 weeks reduced transthyretin (TTR), halted progression of neuropathy impairment, and improved quality of life (QoL) in adult patients with hereditary TTR-mediated amyloidosis with polyneuropathy (ATTRv-PN), vs. historical placebo.

Methods:

NEURO-TTRansform enrolled patients with ATTRv-PN. A subset of patients were randomized to receive subcutaneous inotersen 300 mg weekly (Weeks 1–34) and subsequently switched to subcutaneous eplontersen 45 mg every 4 weeks (Weeks 37–81). Change in serum TTR and treatment-emergent adverse events (TEAEs) were evaluated through Week 85. Effects on neuropathy impairment, QoL, and nutritional status were also evaluated.

Results:

Of 24 patients randomized to inotersen, 20 (83%) switched to eplontersen at Week 37 and four discontinued due to AEs/investigator decision. Absolute change in serum TTR was greater after switching from inotersen (−74.3%; Week 35) to eplontersen (−80.6%; Week 85). From the end of inotersen treatment, neuropathy impairment and QoL were stable (i.e., did not progress) while on eplontersen, and there was no deterioration in nutritional status. TEAEs were fewer with eplontersen (Weeks 37–85; 19/20 [95%] patients) compared with inotersen (up to Week 35; 24/24 [100%] patients). Mean platelet counts decreased during inotersen treatment (mean nadir reduction ‒40.7%) and returned to baseline during eplontersen treatment (mean nadir reduction, ‒3.2%).

Conclusions:

Switching from inotersen to eplontersen further reduced serum TTR, halted disease progression, stabilized QoL, restored platelet count, and improved tolerability, without deterioration in nutritional status. This supports a positive benefit-risk profile for patients with ATTRv-PN who switch from inotersen to eplontersen.

News (Medical) associated with Eplontersen

25 Nov 2024

·medcitynews.com

FDA Nod for BridgeBio Brings New Competition to Blockbuster Pfizer Cardio Drug - MedCity News

A BridgeBio Pharma drug developed for an increasingly prevalent cardiovascular condition has won FDA approval, marking a comeback for a company and a molecule with a turbulent history. But BridgeBio’s challenges aren’t over. The biotech’s new product must now compete against a blockbuster Pfizer medication already well established as the standard of care and fend off new competition on the way. The late Friday approval for the drug, acoramidis, covers the treatment of adults with cardiomyopathy caused by transthyretin-mediated amyloidosis, or ATTR. The disease stems from a genetic mutation though it can also develop as a consequence of aging. The FDA approval covers both types. BridgeBio’s twice-daily pill will be marketed under the brand name Attruby. In ATTR, abnormal versions of a liver protein called transthyretin lead to a buildup of amyloid protein in tissues and organs. When this buildup affects the heart, it can lead to cardiomyopathy, making it harder for the organ to pump blood. Attruby is a small molecule designed to bind to the abnormal TTR, stabilizing the protein and preventing it from leading to the amyloid buildup characterized by the disease. Pfizer’s ATTR cardiomyopathy drug, tafamidis, approved in 2019 and marketed as the four-times daily capsule Vyndaqel and the once-daily capsule Vyndamax, is also a TTR stabilizer. But Palo Alto, California-based BridgeBio set out to show its drug is the better stabilizer. That effort was almost derailed. Health IT Reducing Clinical and Staff Burnout with AI Automation As technology advances, AI-powered tools will increasingly reduce the administrative burdens on healthcare providers. By Dr. Michael Blackman, Chief Medical Officer at Greenway Health Nearly three years ago, BridgeBio reported preliminary data showing its drug failed to beat a placebo in the first part of a Phase 3 clinical trial, which assessed patients after 12 months. The company attributed the failure to a high placebo response. The disappointing results sank shares of the biotech by more than 70%. But the study’s design included a second part that would assess patients after 30 months of treatment. BridgeBio opted to continue the study, hoping longer treatment would lead to better outcomes. FDA approval of Attruby is based on the 30-month data from the Phase 3 study, which enrolled 632 patients with ATTR cardiomyopathy. Results showed the drug met the main goal of showing statistically significant improvement on a composite endpoint comprised of four measures of the disease. The results were published in the New England Journal of Medicine early this year. Speaking during a Friday evening webcast, BridgeBio CEO Neil Kumar drew distinctions between Attruby and Pfizer’s product. “This is the only oral stabilizer with the verbiage ‘near-complete stabilization’ in the label,” he said. “Almost all of benefits described downstream in the label stem from this near-complete stabilization. As early as three months, the earliest time point that we know of, this medicine begins to take action against a composite endpoint of cardiovascular hospitalization and death.” BridgeBio estimates 500,000 patients in the U.S. and European Union have ATTR cardiomyopathy, which represents a market opportunity of $15 billion to $20 billion. Right now, that market is dominated by Pfizer, which reported $3.9 billion in tafamidis sales in the first nine months of 2024, a more than 65% increase compared to the same period in 2023. But this market could soon be split among several products. Consumer / Employer Health Executives on Digital Transformation in Healthcare Hear executives from Quantum Health, Surescripts, EY, Clinical Architecture and Personify Health share their views on digital transformation in healthcare. By MedCity News Alnylam Pharmaceuticals develops drugs that silence genes, preventing them from causing disease-causing proteins. The biotech already markets Amvuttra for treating polyneuropathy caused by ATTR. But Alnylam has also tested Amvuttra, administered as a subcutaneous injection every three months, as a treatment for ATTR cardiomyopathy. On Monday, Alnylam announced the FDA accepted the company’s supplemental new drug application in this indication, setting a March 23, 2025 target date for a regulatory decision. Meanwhile, partners AstraZeneca and Ionis Pharmaceuticals market antisense oligonucleotide drug eplontersen, brand name Wainua, for treating polyneuropathy caused by ATTR. A Phase 3 trial is underway testing the drug in ATTR cardiomyopathy. In a note sent to investors, Leerink Partners analyst Mani Foroohar said Attruby’s label was the best-case scenario as the indication statement includes cardiovascular mortality and hospitalization, consistent with Pfizer’s product. Furthermore, Attruby can stake the claim of being the first and only product with a label specifying near-complete stabilization of TTR. That said, cracking Pfizer’s established market presence will be difficult. In results of a Leerink survey released in September, the Pfizer drug was physicians’ treatment of choice for cardiomyopathy caused by ATTR, given long their long experience with the product. There was an uptick in preference for gene silencing therapies, but mainly for treating polyneuropathy caused by the disease, the survey showed. Many physicians stated they would switch to another product only if a patient’s condition is not well controlled by the Pfizer drug. William Blair analyst Myles Minter said language in Attruby’s label stating the drug’s ability to reduce cardiovascular death is “a clear win for BridgeBio.” But Minter noted the absence on the label of any standalone all-cause mortality data, which is different than the Pfizer product’s label. Attruby did not lead to a statistically significant benefit on all-cause mortality compared to a placebo in its pivotal study. Minter said clinicians the firm spoke with at recent cardiovascular conferences continue to suggest the importance of not only the magnitude of cardiovascular event risk reduction, but also the timing of the onset of the drug’s effect given that cardiomyopathy can progress rapidly. He added that TTR-silencing drugs are best positioned for market differentiation. “We continue to view a reduction in all-cause mortality on label as a necessary distinction to gain major market share in ATTR-CM alongside Pfizer’s tafamidis,” Minter said. “Given the lack of all-cause mortality data included in the Attruby label, we believe Pfizer could start marketing more specifically around mortality benefit claims.” BridgeBio set Attruby’s wholesale price at $18,759.12 for a 28-day supply, which works out to about $244,500 annually. That’s a slight discount to Pfizer’s product, priced at $267,987 annually. But it’s still well above the $13,600 to $39,000 cost-effectiveness price range calculated by the Institute for Clinical and Economic Review, a non-profit organization that researches the value of drugs in order to determine what would be a fair price. Kumar said all patients who participated in Attruby’s Phase 3 study will continue to receive the drug for free for the rest of their lives. Attruby is still under review in Europe with a regulatory decision expected in 2025. Under a deal struck earlier this year, Bayer has exclusive rights to market the drug in Europe for ATTR cardiomyopathy. Bayer shelled out $310 million in upfront and near-term milestone payments; additional sales-based milestones were not disclosed. BridgeBio will also earn royalties from Bayer’s sales of the product. Image: Magicmine, Getty Images

Phase 3Clinical ResultDrug Approval

06 Nov 2024

·www.prnewswire.com

Ionis Announces Pivotal Phase 3 Trial Design for ION582 in Angelman Syndrome

Positive End of Phase 2 discussion with FDA, including alignment on Phase 3 design Bayley-4 expressive communication selected as Phase 3 study primary endpoint Initiation of ION582 Phase 3 study planned for H1 2025 Ionis to share ION582 program update at the FAST Global Science Summit in November CARLSBAD, Calif., Nov. 6, 2024 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced the pivotal Phase 3 study design following successful alignment with the U.S. Food and Drug Administration (FDA) on ION582, an investigational medicine for the treatment of people living with Angelman syndrome (AS). AS typically presents in infancy and is characterized by profound intellectual disability, impaired verbal abilities and severe motor impairment. "Following positive results for ION582 in the Phase 2 HALOS trial, we are pleased to have alignment with the FDA on the design of our Phase 3 REVEAL trial, which will address clinical endpoints that reflect the most pressing and meaningful outcomes for people living with AS and their caregivers," said Brett Monia, Ph.D., chief executive officer of Ionis. "We will enroll a broad group of individuals living with AS in the global pivotal Phase 3 trial, planned to begin in the first half of 2025. We look forward to working with the community to advance a potential new treatment targeting the underlying cause of disease in this debilitating neurological condition that has no approved medicines." The planned global, randomized, placebo-controlled Phase 3 study will enroll approximately 200 children and adults with AS that have a maternal UBE3A gene deletion or mutation. The primary analysis will occur after approximately one year of treatment, followed by all patients transitioning into an open-label long-term extension (LTE) phase of the study. Patients will be randomized 2:1 to active therapy or placebo, and ION582 will be evaluated at two dose levels which will be dosed quarterly without a loading regimen. The primary endpoint will be improvement in expressive communication as assessed by the Bayley Scales for Infant and Toddler Development-4 (Bayley-4), an objective and direct clinician-administered assessment of clinical functioning. Deficits in expressive communication are reported to be the symptoms most challenging to caregivers of people with AS. The study will evaluate several secondary endpoints including overall disease severity, cognition, communication, sleep, motor functioning and daily living skills, in addition to other exploratory endpoints. The End of Phase 2 meeting was supported by data from the Phase 2 open-label HALOS study. In the recently completed multiple ascending dose (MAD) portion of the study, ION582 treatment provided strong evidence of clinically meaningful improvement on all functional domains including communication, cognition and motor function. Overall, 97% of people in the medium and high dose groups assessed in the study saw an improvement in overall AS symptoms as measured by the Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale, which evaluates clinicians' impressions. ION582 showed favorable safety and tolerability at all dose levels in the study. At the FAST Global Science Summit this weekend (November 8-9), Ionis will provide an update to the community on the Phase 3 program and review data from the MAD portion of the HALOS trial. About ION582 ION582 is an investigational antisense medicine designed to inhibit the expression of the UBE3A antisense transcript (UBE3A-ATS) and increase production of UBE3A protein, for the potential treatment of Angelman syndrome (AS). In 2022, the U.S. Food and Drug Administration (FDA) granted ION582 Orphan Drug designation and Rare Pediatric designation. About Angelman Syndrome (AS) AS is a rare, genetic neurological disease caused by the loss of function of the maternally inherited UBE3A gene. AS typically presents in infancy and is characterized by profound intellectual disability, balance issues, motor impairment and debilitating seizures. Most patients are unable to speak. Individuals with AS have a normal lifespan but require complete care from a caregiver. Some symptoms can be managed with existing medicines; however, there are no approved disease modifying therapies. About Ionis' Neurology Franchise Ionis has been at the forefront of discovering and developing leading neurological disease medicines, including SPINRAZA® (nusinersen), the first approved treatment for spinal muscular atrophy, WAINUA™ (eplontersen), a medicine to treat hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), and QALSODY® (tofersen) for SOD1-ALS. The clinical-stage portfolio includes 11 therapies, of which five are wholly owned by Ionis. Ionis' investigational portfolio includes medicines for which there are few or no disease modifying treatments, such as rare diseases including Prion disease and Alexander disease and more common conditions such as Alzheimer's and Parkinson's disease. About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has five marketed medicines and a leading pipeline in neurology, cardiology, and other 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 Ionis' commercial medicines, ION582 and Ionis' additional medicines in development and technologies. 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 but not limited to those related to our commercial products and the medicines in our pipeline, and particularly 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 Dec. 31, 2023, and most recent Form 10-Q, which are on file with the SEC. Copies of these and other documents are available at . 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 registered trademark of Ionis Pharmaceuticals, Inc. ION582 is an investigational medicine that has not been approved for the treatment of any disease by regulatory authorities. Ionis Pharmaceuticals Investor Contact: D. Wade Walke, Ph D. - [email protected] - 760-603-2331 Ionis Pharmaceuticals Media Contact: Hayley Soffer - [email protected] - 760-603-4679 SOURCE Ionis Pharmaceuticals, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Clinical ResultPhase 2Phase 3Orphan DrugDrug Approval

06 Nov 2024

·www.prnewswire.com

Ionis reports third quarter 2024 financial results

WAINUATM U.S. launch progressing well; approved in UK; positive CHMP opinion Olezarsen FCS PDUFA December 19, 2024 Donidalorsen HAE PDUFA August 21, 2025; EU regulatory submission in process On track to achieve 2024 P&L financial guidance; increased 2024 cash guidance CARLSBAD, Calif., Nov. 6, 2024 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company") today reported financial results for the third quarter of 2024. "Today, we stand on the cusp of a new era for Ionis, with our first co-commercialization launch proceeding well with WAINUA, our first planned independent launch fast approaching and continued strong progress across our rich pipeline. With an upcoming December FDA action date, we are ready to independently bring olezarsen to people with familial chylomicronemia syndrome, a serious rare disease with no approved treatments in the U.S. We are similarly well positioned for our second independent launch for donidalorsen, which we believe could become a preferred treatment choice for people with hereditary angioedema, with an FDA action date of August 21, 2025," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "In parallel, we are making great progress across the rest of our rich Phase 3 pipeline. We expect Phase 3 results supporting olezarsen's second indication in severe hypertriglyceridemia and pelacarsen in Lp(a)-driven cardiovascular disease next year, as well as Phase 3 results supporting eplontersen's second indication in ATTR cardiomyopathy in the second half of 2026. We are also advancing our next wave of potentially transformational wholly owned medicines, including ION582 for Angelman syndrome, which we expect to enter Phase 3 development in the first half of next year following our positive end of Phase 2 discussion with the FDA. Our recent achievements, together with our advancing and expanding pipeline, position Ionis to deliver on our goal to bring a steady cadence of transformational medicines to people with serious diseases." Third Quarter 2024 Summary Financial Results(1): Financial Highlights Revenue for the three and nine months ended September 30, 2024 decreased by 7% and increased by 3% compared to the same periods last year, respectively. Ionis continued to generate revenue from diverse sources, including a new source of royalty revenue with the launch of WAINUA in the U.S in the first quarter Operating expenses for the three and nine months ended September 30, 2024 increased as planned compared to the same periods last year, excluding certain one-time costs in 2023, reflecting continued investments in late-stage development, including WAINUA for ATTR cardiomyopathy (ATTR-CM) and olezarsen for severe hypertriglyceridemia (sHTG), and commercialization efforts for WAINUA, olezarsen and donidalorsen Reaffirmed 2024 P&L financial guidance, increased cash guidance to $2.2 billion reflecting proceeds from equity offering Recent Marketed Medicines Highlights WAINUA (WAINZUA in Europe) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) achieved multiple commercial and regulatory milestones: Generated sales of $23 million and $44 million resulting in royalty revenue of $5 million and $10 million in the three and nine months ended September 30, 2024, respectively Received positive Committee for Medicinal Products for Human Use (CHMP) opinion from European Medicines Agency (EMA) for the treatment of hereditary transthyretin-mediated amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy Approved in UK by the Medicines and Healthcare products Regulatory Agency (MHRA) with an accelerated National Institute for Health and Care Excellence (NICE) recommendation; earning $30 million from AstraZeneca Launch underway in Canada, following approval and reimbursement from Health Canada SPINRAZA® (nusinersen) for the treatment of spinal muscular atrophy (SMA) generated global sales of $381 million and $1.2 billion resulting in royalty revenue of $57 million and $152 million in the three and nine months ended September 30, 2024, respectively Positive Phase 2/3 DEVOTE study data presented from higher dose nusinersen; global regulatory applications planned QALSODY® (tofersen) granted marketing approval in China for the treatment of SOD1-ALS Recent Late-Stage Pipeline Highlights Olezarsen positioned to potentially treat two patient populations with urgent unmet need, familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (sHTG): NDA for patients with FCS under FDA Priority Review with a PDUFA date of December 19, 2024 Marketing authorization application (MAA) under regulatory review by the EMA Ongoing pivotal development program for sHTG on track for data in H2:2025 Donidalorsen Phase 3 data position it to potentially launch next year as the first RNA-targeted prophylactic treatment for people with hereditary angioedema (HAE): FDA accepted the NDA for patients with HAE with a PDUFA date of August 21, 2025; Otsuka, Europe and Asia Pacific partner, preparing to submit MAA Presented positive Phase 2 open label extension (OLE) study data in patients treated up to three years with every four weeks or every eight weeks dosing Zilganersen Phase 3 study fully enrolled as a potential treatment for Alexander disease; on track for data in 2025 Granted Fast Track designation by the FDA ION582 achieved important clinical and regulatory milestones enabling initiation of Phase 3 development in Angelman syndrome (AS) in H1:2025: Presented positive Phase 1/2 data in patients with AS at Angelman Syndrome Foundation (ASF) Family Conference Completed positive End-of-Phase 2 discussion with FDA, included alignment on Phase 3 design Reported positive data from the Phase 2 study of IONIS-FB-LRx in patients with immunoglobulin A nephropathy (IgAN); Roche continues to advance IONIS-FB-LRx in the Phase 3 IMAGINATION study Recent Other Pipeline Updates Sapablursen for the treatment of polycythemia vera granted orphan drug designation by FDA; enrollment complete in Phase 2 IMPRSSION study with data expected in 2025 IONIS-MAPTRx (BIIB080) enrollment complete in Phase 2 CELIA study in patients with early Alzheimer's disease (AD); data expected in 2026 Initiated first in human studies with multiple medicines from neurological disease pipeline: Phase 1/2 Orbit study of ION356 (PLP1) in patients with Pelizaeus-Merzbacher disease (PMD) Phase 1/2 HERO study of ION269 (APP), for the potential treatment of Alzheimer's disease (AD), which is initially being evaluated in patients with Down syndrome (DS) who have a genetic risk for developing AD Phase 1/2 ATTUNE study of ION440 (MECP2) in patients with MECP2 duplication syndrome Third Quarter 2024 Financial Results "This year has been marked by strong delivery on our pipeline and business goals, which position Ionis to deliver on our vision of bringing a steady cadence of innovative medicines to patients in need. Fully realizing these significant opportunities requires substantial investment. As a result, we recently executed an equity offering that extends our cash runway, enabling us to continue to invest in the numerous attractive opportunities ahead of us, including our near-term commercial launches with multi-billion-dollar revenue potential and our rich late and mid-stage pipeline," said Elizabeth L. Hougen, chief financial officer of Ionis. "Looking beyond this year, we will continue to invest in go-to-market preparations for our planned olezarsen and donidalorsen launches. Additionally, with our increased confidence in the potential of WAINUA and olezarsen to address broader patient populations, we plan to scale our capabilities in line with the significant potential of these important medicines. At the same time, we are investing in our next wave of medicines, including pre-commercialization activities and Phase 3 development for ION582 for Angelman syndrome and zilganersen for Alexander disease. We expect our investments today will position Ionis for sustainable growth for years to come." Revenue Ionis' revenue was comprised of the following: Commercial revenue for the three and nine months ended September 30, 2024 included a new source of royalty revenue with the launch of WAINUA in the U.S. in late January 2024. Ionis' commercial revenue for the three and nine months ended September 30, 2024 and 2023 also included royalties from the net sales of QALSODY, which Biogen launched in the U.S. in the second quarter of 2023 and in the EU in the second quarter of 2024. SPINRAZA product sales for the three months ended September 30, 2024 compared to the same period last year increased slightly in the U.S. and decreased outside of the U.S. primarily due to an annual order from a single country that did not recur in 2024. R&D revenue was relatively consistent for the three months ended September 30, 2024 compared to the same period last year. R&D revenue increased for the nine months ended September 30, 2024 compared to the same period last year primarily due to the amortization of upfront payments from the new collaborations with Roche and Novartis that Ionis entered into during the second half of last year. In addition, license fees increased year over year as a result of new collaborations Ionis entered into during the second quarter of 2024, including the expanded donidalorsen licensing agreement with Otsuka, which now includes the Asia-Pacific region in addition to Europe. These increases were partially offset by the decrease in WAINUA joint development revenue, which decreased as development activities relating to ATTRv-PN wound down with the launch of WAINUA for this indication. Operating Expenses Ionis' operating expenses, excluding one-time costs associated with a lease exit in the third quarter of 2023, increased for the three and nine months ended September 30, 2024 compared to the same periods in 2023, consistent with expectations. SG&A expenses increased year over year primarily due to the launch of WAINUA in the U.S. and launch preparation activities for olezarsen and donidalorsen, including establishing the field team for olezarsen in the second quarter of 2024. R&D expenses were essentially flat for the three and nine months ended September 30, 2024 compared to the same periods last year as several late-stage studies have ended. Balance Sheet As of September 30, 2024, Ionis' cash, cash equivalents and short-term investments increased to $2.5 billion compared to $2.3 billion at December 31, 2023. In September 2024, Ionis issued 11.5 million shares of its common stock at a public offering price of $43.50 per share that generated gross proceeds of $500 million, before deducting underwriting discounts and commissions and other offering expenses payable by Ionis. The Company plans to continue deploying its capital resources toward growth opportunities, and projects to end 2024 with $2.2 billion in cash, cash equivalents and short-term investments. Ionis' working capital also increased over the same period primarily due to the Company's higher cash and short-term investments balance. As a result of Ionis' advancing pipeline that has delivered several positive data readouts, Ionis expects to make increased investments in the years ahead with the goal to realize the value of these opportunities, with a focus on its wholly owned late-stage and next wave of innovative medicines. Webcast Management will host a conference call and webcast to discuss Ionis' third quarter 2024 results at 11:30 a.m. Eastern time on Wednesday, November 6, 2024. 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 2024 earnings slides click here. For more information about SPINRAZA and QALSODY, visit and , 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). 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. About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has five marketed medicines and a leading pipeline in neurology, cardiology, and other 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 and technologies. 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, 2023, 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 registered trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics® is a registered trademark of Akcea Therapeutics, Inc. TEGSEDI® is a registered trademark of Akcea Therapeutics, Inc. WAYLIVRA® is a registered trademark of Akcea Therapeutics, Inc. SPINRAZA® and QALSODY® are registered trademarks of Biogen. WAINUATM is a registered trademark of the AstraZeneca group of companies. Ionis Investor Contact: D. Wade Walke, Ph.DD. [email protected] 760-603-2331 Ionis Media Contact: Hayley Soffer [email protected] 760-603-4679 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. Key 2024 Value Driving Events(1) SOURCE Ionis Pharmaceuticals, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Clinical ResultPhase 3Drug Approval

100 Deals associated with Eplontersen

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R&D Status

Approved

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Indication	Country/Location	Organization	Date
Transthyretin-related (ATTR) familial amyloid polyneuropathy	US	AstraZeneca AB	21 Dec 2023

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Amyloidosis, Hereditary, Transthyretin-Related	NDA/BLA	EU	AstraZeneca AB	17 Oct 2024
Transthyretin Amyloid Cardiomyopathy	NDA/BLA	CN	AstraZeneca Global R&D (China) Co., Ltd.	29 Sep 2024
Transthyretin Amyloid Cardiomyopathy	NDA/BLA	CN	Vetter Pharma-Fertigung GmbH & Co. KG	29 Sep 2024
Transthyretin Amyloid Cardiomyopathy	NDA/BLA	CN	AstraZeneca AB	29 Sep 2024
Transthyretin cardiac amyloidosis	Phase 3	US	AstraZeneca PLC	07 Dec 2021

Clinical Result

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04136184 (NEURO-TTRansform, CTgov)	Phase 3	Transthyretin-related (ATTR) familial amyloid polyneuropathy	168	Eplontersen	ugfdtwwprw(woedmivjwg) = hkapfmhulb ifsfcozvfc (ubeyvrpyjv, kkyjnbdikr - mpncwejjbs) View more	-	10 Dec 2024
NCT04136184 \| NCT01737398 (FDA) Manual	Phase 2/3	Transthyretin-related (ATTR) familial amyloid polyneuropathy	204	WAINUA	spnkwfrdbc(lrrdidwvzf) = gloahrhmfo pdssbjgntm (wdxowubsip, 1.9) View more	Positive	21 Dec 2023
				placebo	spnkwfrdbc(lrrdidwvzf) = gvdkqmdjah pdssbjgntm (wdxowubsip, 1.9) View more
NCT04136184 \| EUCTR2019-001698-10-CY (Pubmed \| JAMA)	Phase 3	Amyloid Neuropathies, Familial	-	Eplontersen 45 mg	msdbddazhr(kjwtydrepx) = Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. jpuzefkgue (uhjayukfgw ) View more	-	17 Oct 2023
				Placebo
NCT03728634 (CTgov)	Phase 1/2	Amyloidosis, Hereditary, Transthyretin-Related	47	Placebo (Multiple Dose Cohort: Placebo)	qfubxjfgwi(fitfaqyuse) = vgrutoctrv bmtataltjq (pkfzvzycrm, osvazuqzqk - ocuytvbytx) View more	-	19 Dec 2022
				Vitamin A+ION-682884 (Multiple Dose Cohort A: ION-682884 45 mg)	qfubxjfgwi(fitfaqyuse) = llkaafbkby bmtataltjq (pkfzvzycrm, wzfgiisryi - iiohmvnruj) View more
NCT04136184 (NEURO-TTRansform, Corporate Publications) Manual	Phase 3	Amyloidosis	168	Eplontersen	jlpttzexeb(pwhpmjxkxf): P-Value = <0.0001 View more	Positive	07 Sep 2022
				Placebo
NCT04302064 \| NCT03728634 (Pubmed \| Br J Clin Pharmacol)	Phase 1	Amyloidosis, Hereditary, Transthyretin-Related	-	Eplontersen	yxgtbqmvrp(fjogrkouaz) = proglxbkwt kddbwzkrjd (oqtlmflznh, 13.3) View more	-	22 Jul 2022

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