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

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 up to 5 months. This period will overlap with the participant's first 5 months in the PIERRE study.

Start Date16 Dec 2024

Sponsor / Collaborator

Biogen, Inc.

CTR20232342 / Active, not recruitingPhase 3

一项在既往参加过诺西那生钠试验性研究的脊髓性肌萎缩症受试者中给予高剂量诺西那生钠 (BIIB058) 的长期扩展研究

[Translation] A long-term extension study of high-dose nusinersen (BIIB058) in subjects with spinal muscular atrophy who had previously participated in a pilot study of nusinersen

1. 评价既往参加过研究 203 的 SMA 受试者鞘内注射更高剂量诺西那生钠的长期安全性和耐受性 2. 评价既往参加过研究 203 的 SMA 受试者鞘内注射更高剂量诺西那生钠的长期疗效 3. 研究以较高剂量向先前参加研究 203 的SMA 受试者鞘内注射诺西那生钠的 PK（脑脊液和血浆） 4. 研究以较高剂量向先前参加研究 203 的SMA 受试者鞘内给予诺西那生钠后诺西那生钠治疗对 pNF-H 水平（脑脊液和血浆）的影响

[Translation]

1. To evaluate the long-term safety and tolerability of higher doses of intrathecal nusinersen in SMA subjects who had previously participated in Study 203 2. To evaluate the long-term efficacy of higher doses of intrathecal nusinersen in SMA subjects who had previously participated in Study 203 3. To investigate the PK (cerebrospinal fluid and plasma) of intrathecal nusinersen at higher doses in SMA subjects who had previously participated in Study 203 4. To investigate the effect of nusinersen treatment on pNF-H levels (cerebrospinal fluid and plasma) after intrathecal administration of higher doses of nusinersen to SMA subjects who had previously participated in Study 203

Start Date14 Aug 2023

Sponsor / Collaborator

Biogen Idec Research Ltd.

[+2]

ChiCTR2200064655 / SuspendedNot ApplicableIIT

Ultrasound-guided nusinersen administration for spinal muscular atrophy patients with scoliosis: median transverse positioning approach versus paramedian sagittal positioning approach

Start Date20 Oct 2022

Sponsor / Collaborator-

100 Clinical Results associated with Nusinersen sodium

100 Translational Medicine associated with Nusinersen sodium

100 Patents (Medical) associated with Nusinersen sodium

644

Literatures (Medical) associated with Nusinersen sodium

01 Feb 2025·NEUROIMAGING CLINICS OF NORTH AMERICA

Lumbar Transforaminal Injections of Nusinersen in Spinal Muscular Atrophy Patients

Review

Author: Monroe, Eric J. ; Monroe, Eric J

Following a review of spinal muscular atrophy pathogenesis and current therapeutics, a comprehensive review of transforaminal lumbar injections is provided. Patient preparation, special considerations, procedural technique, complications, and alternative approaches are discussed.

01 Dec 2024·Lancet Regional Health-Europe

Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region: a population-based observational study

Article

Background:

Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH).

Methods:

This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status.

Findings:

343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0-90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups.

Interpretation:

Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio.

Funding:

The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

01 Dec 2024·MUSCLE & NERVE

Outcomes of early‐treated infants with spinal muscular atrophy: A multicenter, retrospective cohort study

Article

Author: Lee, Bo Hoon ; Hamid, Omer Abdul ; Farah, Hiba ; Herbert, Karen ; King, Kiana ; Kuntz, Nancy L. ; Zaidman, Craig M. ; Fisher, Mark ; Gibbons, Melissa ; Lakhotia, Arpita ; Parsons, Julie ; Rehborg, Rebecca ; Rogers, Amanda ; Goedeker, Natalie L. ; Kichula, Elizabeth ; Harmelink, Matthew ; Veerapaniyan, Aravindhan ; Brandsema, John F. ; Felker, Marcia V. ; Farrar, Michelle A. ; Arya, Kapil

Abstract:

Introduction/Aims:

While prompt identification and treatment of infants with spinal muscular atrophy (SMA) can ameliorate outcomes, variability persists. This study assessed management and outcomes of early‐treated infants with SMA.

Methods:

We analyzed retrospective data at 12 centers on infants with SMA treated at age ≤6 weeks from August 2018 to December 2023.

Results:

Sixty‐six patients, 35 with two SMN2 copies and 31 with ≥3 SMN2 copies, were included. Twenty‐five (38%, 22 with two SMN2 copies), had SMA findings before initial treatment which was onasemnogene abeparvovec in 47 (71%) and nusinersen in 19 (29%). Thirty‐two received sequential or combination treatments, including 16 adding nusinersen or risdiplam due to SMA findings following onasemnogene abeparvovec. All sat independently. Compared to children with ≥3 SMN2 copies, those with two SMN2 copies were less likely to walk (23/34 [68%] vs. 31/31 [100%], p < .001) and less likely to walk on time (9/34 [26%] vs. 29/31 [94%], p < .001); one non‐ambulatory child was <18 months old and was excluded from this analysis. No patients required permanent ventilation or exclusively enteral nutrition; six required nocturnal non‐invasive ventilation and four utilized supplemental enteral nutrition, all with two SMN2 copies.

Discussion:

Early treatment of infants with SMA can improve outcomes as indicated by our cohort, all of whom sat independently and are without permanent ventilation. However, our study demonstrates ongoing disability in most children with two SMN2 copies despite early monotherapy and emphasizes the need for additional research, including earlier monotherapy, initial combination therapy, prenatal treatment, and non‐SMN modifying treatments.

186

News (Medical) associated with Nusinersen sodium

12 Nov 2024

·www.businesswire.com

Scholar Rock Reports Third Quarter 2024 Financial Results and Highlights Business Progress

CAMBRIDGE, Mass.--( BUSINESS WIRE )--Scholar Rock (NASDAQ: SRRK), a late-stage biopharmaceutical company focused on advancing innovative treatments for spinal muscular atrophy (SMA), cardiometabolic disorders, and other serious diseases where protein growth factors play a fundamental role, today reported financial results and corporate updates for the third quarter ended September 30, 2024. “ We were thrilled to announce positive and statistically significant topline data from the pivotal Phase 3 SAPPHIRE trial, a major achievement that underscores apitegromab’s potential to redefine the standard of care for patients with SMA,” said Jay Backstrom, M.D., MPH, President and Chief Executive Officer of Scholar Rock. “ The positive SAPPHIRE trial validates our approach to targeting pro-and latent myostatin and demonstrates apitegromab’s potentially transformative benefit. Based on these results, we plan to submit a BLA and MAA in the first quarter of 2025 and are working diligently to prepare for the commercial launch of apitegromab, and if approved, to deliver the potentially transformative benefits of apitegromab to children and adults living with SMA.” Dr. Backstrom continued, “ The robust results from SAPPHIRE also reinforce the broader potential of our selective myostatin inhibition strategy across our pipeline, with potential readthrough to our cardiometabolic program as we evaluate apitegromab in obesity in our Phase 2 EMBRAZE proof-of-concept trial. We were pleased to announce in September that the EMBRAZE trial is fully enrolled, and we expect to report initial data in the second quarter of next year.” Company Highlights and Upcoming Milestones SMA Program Apitegromab is an investigational, fully human monoclonal antibody that inhibits myostatin activation by selectively binding the pro- and latent forms of myostatin in skeletal muscle and is being developed as a potential first muscle-targeted therapy for the treatment of SMA. Apitegromab is the first muscle-targeted therapy to show clinical proof-of-concept in SMA. Reported positive topline data from Phase 3 SAPPHIRE clinical trial . The study achieved its primary endpoint demonstrating a statistically significant and clinically meaningful improvement for apitegromab versus placebo in motor function as measured by the gold standard HFMSE in SMA patients on chronic dosing of standard of care therapies (either nusinersen or risdiplam). In the main efficacy population (ages 2-12), the mean difference in change from baseline in HFMSE was 1.8 points (p=0.0192) for all patients receiving apitegromab 10 mg/kg and 20 mg/kg (n=106) compared to placebo (n=50). Patients receiving 20 mg/kg of apitegromab (n=53) showed a 1.4 point mean difference compared to placebo (p=0.1149). The prespecified analysis of the 10 mg/kg dose showed that patients receiving 10 mg/kg of apitegromab (n=53) showed a mean difference in change from baseline in HFMSE of 2.2 points compared to placebo (nominal p=0.0121). Based upon PK/PD data from the SAPPHIRE trial, similar levels of target engagement were observed for the 10 mg/kg and 20 mg/kg dose groups. Scholar Rock plans to submit a U.S. BLA and a European Union MAA in 1Q 2025. Presented preliminary baseline characteristics from SAPPHIRE during a poster presentation at the 29 th Annual Congress of the World Muscle Society in October in Prague, Czech Republic. Analyses of the full Phase 3 SAPPHIRE data are ongoing, and Scholar Rock plans to present detailed results at an upcoming medical conference in early 2025. The ONYX open-label, multi-center extension study remains ongoing. The study is evaluating the long-term safety and efficacy of apitegromab in patients who completed the TOPAZ or SAPPHIRE trials. More than 90 percent of patients on combination therapy in the TOPAZ trial have completed 4 years of apitegromab treatment and enrolled into ONYX. Following trial completion, 98 percent of SAPPHIRE patients (185/188) enrolled in the ongoing ONYX open-label expansion study. On track to initiate OPAL clinical trial in SMA patients under two years old in mid-2025. Cardiometabolic Program SRK-439 is a novel, preclinical, investigational myostatin inhibitor that binds to pro- and latent myostatin with high affinity and is selective for myostatin (i.e., no GDF11 or Activin A binding), and is initially being developed for the treatment of obesity. Based on preclinical data, SRK-439 has the potential to support healthier weight management by preserving lean mass during weight loss. Completed enrollment of Phase 2 EMBRAZE proof-of-concept trial with apitegromab in combination with a GLP-1 receptor agonist (GLP-1 RA) in obesity in September. The Phase 2 trial is a randomized, double-blind, placebo-controlled, multi-center study evaluating the safety and efficacy of apitegromab, a highly selective investigational myostatin inhibitor, to preserve muscle mass as an adjunctive therapy in overweight and obese adults who are taking a GLP-1 RA. Data are expected in the second quarter of 2025 and will be used to guide clinical development of SRK-439. The Company plans to file an IND for SRK-439 for the treatment of obesity in 2025. Immuno-Oncology Program SRK-181 is an investigational selective inhibitor of latent TGFβ1 activation and is being developed with the aim of overcoming resistance to checkpoint therapy, such as anti-PD-(L)1 antibodies, in patients with advanced cancer. New SRK-181 data from the Phase 1 DRAGON proof-of-concept trial presented at the SITC 39 th Annual Meeting in November. The presentation, “ DRAGON Trial: Durable remission rate with the latent TGFβ1 inhibitor linavonkibart (SRK-181) and pembrolizumab in patients with immune checkpoint inhibitor resistant advanced cancers,” highlighted new clinical and biomarker results. Highlights since the Company’s last update on the DRAGON trial include one additional complete response, seen in the clear cell renal cell (ccRCC) cohort (ORR=23.3%) and durable responses in multiple cohorts. Additionally, biomarker results continue to support proof of mechanism; new data shows suppressed granulocytic myeloid-derived suppressor cells (gMDSC) levels in the tumor microenvironment of responders. Notably new biomarker data in the ccRCC cohort supports a potential patient selection strategy with positive correlations between clinical response and baseline CD8+ infiltration status, elevated baseline Treg levels, and elevated baseline TGFβ1 levels in the tumor compartment. Enrollment of the DRAGON trial was completed in December 2023, and patients who remain on the study continue to be treated. Other Corporate Updates Appointed Beth Shafer, Ph.D., to the newly created role of Chief Business Officer. Ms. Shafer brings over 20 years of biopharmaceutical industry leadership and expertise to Scholar Rock, where she will drive the Company’s long-term corporate and business development strategy. Raised $345 million in upsized follow-on offering. In October, the Company completed an upsized follow-on offering raising aggregate gross proceeds of $345 million. Third Quarter 2024 Financial Results For the quarter ended September 30, 2024, net loss was $64.5 million or $0.66 per share compared to a net loss of $42.4 million or $0.53 per share for the quarter ended September 30, 2023. The Company did not record any revenue for the quarter ended September 30, 2024, or for the quarter ended September 30, 2023. Research and development expense was $48.7 million for the quarter ended September 30, 2024, compared to $30.3 million for the quarter ended September 30, 2023. The increase was primarily attributable to costs associated with the ONYX and EMBRAZE trials, and the development of SRK-439. General and administrative expenses were $16.1 million for the quarter ended September 30, 2024, compared to $13.3 million for the quarter ended September 30, 2023. The increase was due to employee-related costs. As of September 30, 2024, Scholar Rock had cash, cash equivalents and marketable securities of approximately $139.1 million ($463.5 million, on a pro forma basis, including the approximately $324.4 million raised in the October 2024 equity offering). Along with cash available to the Company, runway is extended into 4Q 2026. “ Supported by our recent upsized public offering on the heels of successful SAPPHIRE data, Scholar Rock is advancing our mission from a position of strength as we move forward with preparations for our first commercial launch in the fourth quarter of 2025,” said Ted Myles, Chief Operating Officer and Chief Financial Officer of Scholar Rock. “ We are working tirelessly to obtain approval for apitegromab and deliver it to patients with SMA as soon as possible, as well as continuing to advance our portfolio of highly selective myostatin inhibition programs.” Conference Call Information Management will provide an update on the Company and discuss third quarter 2024 results via conference call on Tuesday, November 12 at 8:15 am ET. To access the live conference call, participants may register here . The live audio webcast of the call will be available under “Events and Presentations” in the Investor Relations section of the Scholar Rock website at http://investors.scholarrock.com . To participate via telephone, please register in advance here . Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. An archived replay of the webcast will be available on the Company’s website for approximately 90 days. About Scholar Rock Scholar Rock is a biopharmaceutical company that discovers, develops, and delivers life-changing therapies for people with serious diseases that have high unmet need. As a global leader in the biology of the transforming growth factor beta (TGFβ) superfamily of cell proteins and named for the visual resemblance of a scholar rock to protein structures, the clinical-stage company is focused on advancing innovative treatments where protein growth factors are fundamental. Over the past decade, Scholar Rock has created a pipeline with the potential to advance the standard of care for neuromuscular disease, cardiometabolic disorders, cancer, and other conditions where growth factor-targeted drugs can play a transformational role. This commitment to unlocking fundamentally different therapeutic approaches is powered by broad application of a proprietary platform, which has developed novel monoclonal antibodies to modulate protein growth factors with extraordinary selectivity. By harnessing cutting-edge science in disease spaces that are historically under-addressed through traditional therapies, Scholar Rock works every day to create new possibilities for patients. The efficacy and safety of apitegromab, SRK-181, and SRK-439 have not been established and apitegromab, SRK-181, and SRK-439 have not been approved for any use by the FDA or any other regulatory agency. Scholar Rock ® is a registered trademark of Scholar Rock, Inc. Availability of Other Information About Scholar Rock Investors and others should note that we communicate with our investors and the public using our company website www.scholarrock.com , including, but not limited to, company disclosures, investor presentations and FAQs, Securities and Exchange Commission filings, press releases, public conference call transcripts and webcast transcripts, as well as on Twitter and LinkedIn. The information we post on our website, Twitter or LinkedIn could be deemed material information. As a result, we encourage investors, the media and others interested to review the information we post there regularly. The contents of our website or social media shall not be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended. Forward-Looking Statements This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding Scholar Rock’s future expectations, plans and prospects, including without limitation, Scholar Rock’s expectations regarding its growth, strategy, progress and timing of its clinical trials for apitegromab and SRK-181 and its preclinical programs, including SRK-439, and indication selection and development timing, including the timing of any regulatory submissions, the therapeutic potential, clinical benefits and safety of any product candidates, expectations regarding timing, success and data announcements of current ongoing preclinical and clinical trials, its cash runway, expectations relating to commercial launch in the US in the fourth quarter of 2025, expectations regarding the achievement of important milestones, the ability of any product candidate to perform in humans in a manner consistent with earlier nonclinical, preclinical or clinical trial data, and the potential of its product candidates and proprietary platform. The use of words such as “may,” “might,” “could,” “will,” “should,” “expect,” “plan,” “anticipate,” “believe,” “estimate,” “project,” “intend,” “future,” “potential,” or “continue,” and other similar expressions are intended to identify such forward-looking statements. All such forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, without limitation, that preclinical and clinical data, including the results from the Phase 3 SAPPHIRE trial will be sufficient to support regulatory approval, that the full results from the Phase 3 SAPPHIRE trial may differ from the topline data, that preclinical and clinical data, including the results from the Phase 2 or Phase 3 clinical trial of apitegromab, or Part A or Part B of the Phase 1 clinical trial of SRK-181, are not predictive of, may be inconsistent with, or more favorable than, data generated from future or ongoing clinical trials of the same product candidates; the data generated from Scholar Rock’s nonclinical and preclinical studies and clinical trials; Scholar Rock’s ability to provide the financial support, resources and expertise necessary to identify and develop product candidates on the expected timeline; the data generated from Scholar Rock’s nonclinical and preclinical studies and clinical trials; information provided or decisions made by regulatory authorities; competition from third parties that are developing products for similar uses; Scholar Rock’s ability to obtain, maintain and protect its intellectual property; Scholar Rock’s dependence on third parties for development and manufacture of product candidates including, without limitation, to supply any clinical trials; and Scholar Rock’s ability to manage expenses and to obtain additional funding when needed to support its business activities and establish and maintain strategic business alliances and new business initiatives, and as well as those risks more fully discussed in the section entitled "Risk Factors" in Scholar Rock’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, as well as discussions of potential risks, uncertainties, and other important factors in Scholar Rock’s subsequent filings with the Securities and Exchange Commission. Any forward-looking statements represent Scholar Rock’s views only as of today and should not be relied upon as representing its views as of any subsequent date. All information in this press release is as of the date of the release, and Scholar Rock undertakes no duty to update this information unless required by law. Scholar Rock Holding Corporation Condensed Consolidated Statements of Operations (unaudited) (in thousands, except share and per share data) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Operating expenses Research and development $ 48,719 $ 30,337 $ 134,185 $ 86,939 General and administrative 16,061 13,335 48,512 36,324 Total operating expenses 64,780 43,672 182,697 123,263 Loss from operations (64,780 ) (43,672 ) (182,697 ) (123,263 ) Other income (expense), net 301 1,313 2,857 3,600 Net loss $ (64,479 ) $ (42,359 ) $ (179,840 ) $ (119,663 ) Net loss per share, basic and diluted $ (0,66 ) $ (0,53 ) $ (1,86 ) $ (1,49 ) Weighted average common shares outstanding, basic and diluted 97,050,637 80,606,438 96,587,149 80,115,143 Scholar Rock Holding Corporation Condensed Consolidated Balance Sheets (unaudited) (in thousands) September 30, 2024 December 31, 2023 Assets Cash, cash equivalents and marketable securities $ 139,065 $ 279,938 Other current assets 13,862 8,256 Total current assets 152,927 288,194 Other assets 26,206 22,841 Total assets $ 179,133 $ 311,035 Liabilities and Stockholders' Equity Current liabilities $ 39,372 $ 32,741 Long-term liabilities 60,565 53,076 Total liabilities 99,937 85,817 Total stockholders' equity 79,196 225,218 Total liabilities and stockholders' equity $ 179,133 $ 311,035

Phase 2Clinical ResultPhase 1Phase 3Financial Statement

11 Nov 2024

·www.globenewswire.com

Climb Bio Appoints Douglas E. Williams, Ph.D., as Chair of the Board

WELLESLEY, Mass., Nov. 11, 2024 (GLOBE NEWSWIRE) -- Climb Bio, Inc. (Nasdaq: CLYM) today announced the appointment of Douglas E. Williams, Ph.D., as Climb Bio’s Chair of its Board of Directors. Dr. Williams will assume the role of Chair of the Board, succeeding Andrew Levin, who will remain on the Board as a director, while Liam Ratcliffe will step down from his position as a director. Dr. Williams has over 30 years of executive leadership experience in the biotechnology sector. Throughout his career, Dr. Williams has held leadership roles in research and development, contributing significantly to the creation of drugs such as Leukine®, Enbrel®, Adcetris®, Tecfidera®, Alprolix®, Eloctate® and Spinraza®. As a CEO, he has successfully guided both private and public companies from development to commercialization and has overseen multiple successful mergers. “I am thrilled to welcome Dr. Doug Williams to Climb Bio. As our incoming Chair of the Board, Doug’s experiences over his 30 plus year career building and leading a range of biotechnology and pharmaceutical companies will offer critical perspective as we grow Climb Bio,” said Aoife Brennan, President and CEO of Climb Bio. “In particular, Doug’s expertise in immunology drug development will be very valuable as we pursue our mission to develop better treatments for the approximately 50 million patients in the U.S. and many more globally living with immune-mediated diseases.” Dr. Williams previously served as the President of Research and Development at Sana Biotechnology and was CEO of Codiak BioSciences. He has also served as Executive Vice President of Research and Development at Biogen. Prior to Biogen he was CEO at ZymoGenetics and led its acquisition by Bristol Myers Squibb. He has also held a variety of leadership positions, including Chief Scientific Officer and Executive Vice President of Research and Development at Seattle Genetics (acquired by Pfizer in 2023), Senior Vice President and Washington Site Leader at Amgen and Executive Vice President and Chief Technology Officer and a member of the Board of Directors at Immunex (acquired by Amgen in 2021). Dr. Williams has served as a board member of more than a dozen public and private biotechnology companies and is currently Chair of the Board of AC Immune SA and a Director of Stablix. He holds a Ph.D. from the State University of New York at Buffalo, Roswell Park Division and completed a postdoctoral fellowship at Indiana University School of Medicine. Dr. Williams added: “I am honored to be joining Climb Bio’s Board at this exciting time as they work to advance budoprutug and build a leading immune-mediated disease focused company. I believe budoprutug has potential across a broad range of B-cell mediated diseases and provides a cornerstone for the company to expand. I look forward to working with the talented Climb Bio team and the board to help them advance their mission to develop therapeutics for patients with immune-mediated diseases.” “I look forward to continuing to work with Aoife, the Climb Bio team, and other board members,” stated Andrew Levin, a member of Climb Bio’s Board and former Chair of the Board. “In the short time since acquiring Tenet Medicines, we have achieved a great deal. With the tremendous opportunity ahead, I am excited to transition the Chair role to Doug while remaining on the Board. Doug has incredible experience and a proven track record in building successful biotechnology companies and will be invaluable in guiding Climb Bio going forward. In addition, on behalf of the Board, I would also like to thank Liam for his valuable contributions and commitment to the Company through its transition.” About Climb Bio, Inc. Climb Bio, Inc. is a clinical-stage biotechnology company developing therapeutics for patients with immune-mediated diseases. The Company’s lead product candidate, budoprutug, is an anti-CD19 monoclonal antibody that has demonstrated B-cell depletion and has potential to treat a broad range of B-cell mediated diseases. For more information, please visit climbbio.com. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including without limitation statements regarding: future expectations, plans and prospects for Climb Bio; the anticipated benefits of the acquisition of Tenet Medicines, Inc.; expectations regarding budoprutug’s therapeutic benefits, clinical potential and clinical development; plans to optimize the administration of budoprutug; and other statements containing the words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “would,” “will,” “working” and similar expressions. Forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. Climb Bio may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. These risks and uncertainties include, but are not limited to, important risks and uncertainties associated with: the ability of Climb Bio to timely and successfully achieve or recognize the anticipated benefits of its acquisition of Tenet Medicines, Inc.; changes in applicable laws or regulation; the possibility that Climb Bio may be adversely affected by other economic, business and/or competitive factors; Climb Bio’s ability to advance budoprutug on the timelines expected or at all and to obtain and maintain necessary approvals from the U.S. Food and Drug Administration and other regulatory authorities; obtaining and maintaining the necessary approvals from investigational review boards at clinical trial sites and independent data safety monitoring boards; replicating in clinical trials positive results found in early-stage clinical trials of budoprutug; competing successfully with other companies that are seeking to develop treatments for primary membranous nephropathy, immune thrombocytopenia and systemic lupus erythematosus and other immune-mediated diseases; maintaining or protecting intellectual property rights related to budoprutug and/or its other product candidates; managing expenses; and raising the substantial additional capital needed, on the timeline necessary, to continue development of budoprutug and any other product candidates Climb Bio may develop. For a discussion of other risks and uncertainties, and other important factors, any of which could cause Climb Bio’s actual results to differ materially from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties and other important factors, in Climb Bio’s most recent filings with the U.S. Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent Climb Bio’s views as of the date hereof and should not be relied upon as representing Climb Bio’s views as of any date subsequent to the date hereof. Climb Bio anticipates that subsequent events and developments will cause Climb Bio’s views to change. However, while Climb Bio may elect to update these forward-looking statements at some point in the future, Climb Bio specifically disclaims any obligation to do so, except as required by law. InvestorsChris Brinzey ICR Healthcarechris.brinzey@icrhealthcare.com 339-970-2843 MediaJon YuICR Healthcarejon.yu@icrhealthcare.com475-395-5375

Executive ChangeAcquisition

06 Nov 2024

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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

100 Deals associated with Nusinersen sodium

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KEGG	Wiki	ATC	Drug Bank
D10791	Nusinersen sodium	M09AX07	DB13161

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Approved

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Indication	Country/Location	Organization	Date
Neuromuscular Diseases	CN	Biogen Netherlands BV	22 Feb 2019
Spinal Muscular Atrophy	US	Biogen, Inc.	23 Dec 2016

Developing

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Indication	Highest Phase	Country/Location	Organization	Date
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	US	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	JP	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	AU	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	BE	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	CA	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	FR	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	DE	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	IT	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	KR	Biogen, Inc.	19 Aug 2014
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 3	ES	Biogen, Inc.	19 Aug 2014

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02594124 (SHINE Study (1692) \| SHINE, CTgov)	Phase 3	Spinal Muscular Atrophy	292	nusinersen (Infantile SMA Onset CS3A)	peraamjybi(wjkphqwffm) = dgwxljkyuk iplulhrsxj (kozanucqvn, qpzcmdbtyn - nsyzxdbgag) View more	-	22 Oct 2024
				nusinersen (Infantile SMA Onset CS3B Previous Control)	peraamjybi(wjkphqwffm) = khyiwgmxag iplulhrsxj (kozanucqvn, qwazfdjbrt - tjaymkrtad) View more
NCT04089566 (DEVOTE, NEWS) Manual	Phase 2/3	Spinal Muscular Atrophy	75	Spinraza 50/28 mg Active Treatment Group	ownppfetox(yuhrlnvalt) = 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. qzyqtiejyw (domxdkictw ) Met View more	Positive	04 Sep 2024
				Spinraza 28/28 Milligram (mg) Safety Group
RESPOND (GlobeNewswire) Manual	Phase 4	Spinal Muscular Atrophy Neurofilament Light Chain	29	SPINRAZA	cxeuerqnwy(hejmdsaxgv) = tjzcvdvqwg yznfmumdpu (yxgwpifkyl ) View more	Negative	06 Mar 2024
MDA2024	Not Applicable	Spinal Muscular Atrophy	-	Nusinersen	hfkwlqeaez(ywyzhpbcev) = iqjupasyqu tvadiefnxj (vgovtalonm ) View more	Positive	03 Mar 2024
				Risdiplam	hfkwlqeaez(ywyzhpbcev) = mkapeajmuq tvadiefnxj (vgovtalonm ) View more
MDA2024	Not Applicable	Spinal Muscular Atrophy	-	Nusinersen	wkaurjavtj(uctydwldli) = tbwrhhzexm bvazixrxve (uvotnuqpfm )	-	03 Mar 2024
MDA2024	Not Applicable	Spinal Muscular Atrophy ARSB \| ENTPD2 \| NEFL ... View more	49	Nusinersen	peyiqhfava(gvtyvpxnvq) = tjmhdupwtg lgpmcbvgsf (cqxirdokam )	Positive	03 Mar 2024
ATS2023	Not Applicable	HMN (Hereditary Motor Neuropathy) Proximal Type I	8	Nusinersen (Spiranza®)	myfubtqesv(pzknbwfopt) = zdcsqranfu lsjvlkumwl (dfdhpmfgju )	Positive	21 May 2023
				Nusinersen/Onasemnogene Abeparvovec (Zolegensma®)	myfubtqesv(pzknbwfopt) = czeafipkgs lsjvlkumwl (dfdhpmfgju )
NCT04488133 (RESPOND, MDA2023) Manual	Phase 4	Spinal Muscular Atrophy Second line SMN2 copy	34	Nusinersen 12mg	azlqsexqfj(ypupbszmko) = Upper respiratory tract infection (n=6) and viral upper respiratory tract infection (n=5) owdsaixobo (ydhrpufpxq )	Negative	19 Mar 2023
NCT02386553 (NURTURE, MDA2023) Manual	Phase 2	SMN2 copies	15	Nusinersen (2 SMN2 copies)	hltjibdpqp(ywhcpedpcb) = rwsvbjoray utucfcsmbm (ccwjkknksh ) View more	Positive	19 Mar 2023
				Nusinersen ( 2 SMN2 copies who did not have CMAP <2 mV )	hltjibdpqp(ywhcpedpcb) = qgomwbnafj utucfcsmbm (ccwjkknksh ) View more
Pubmed Manual	Not Applicable	Spinal Muscular Atrophy	401	Nusinersen sodium (infantile-onset SMA)	jwlwavlftg(limvpoftfl) = zqurwhasrw vluvacxphw (waqugwwnwp )	Positive	05 Jul 2022
				Nusinersen sodium (later-onset SMA)	jwlwavlftg(limvpoftfl) = jdcfjptfzz vluvacxphw (waqugwwnwp )

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