A Phase 3 Randomized, Placebo-Controlled Trial With a Longitudinal Natural History Run-In and Open-Label Extension to Evaluate BIIB067 Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation

The primary objective of this study is to evaluate the efficacy of tofersen in presymptomatic adult carriers of a superoxide dismutase 1 (SOD1) mutation with elevated neurofilament (NF). The secondary objectives of this study are to evaluate the safety and tolerability tofersen and to evaluate the effect of tofersen on pharmacodynamics (PD)/treatment response biomarkers when initiated prior to versus at the time of emergence of clinically manifest amyotrophic lateral sclerosis (ALS).

Start Date17 May 2021

Sponsor / Collaborator

Biogen, Inc.

NCT03764488 / CompletedPhase 1

A Phase 1, Safety, Tolerability, and Distribution Study of a Microdose of Radiolabeled BIIB067 Co-administered With BIIB067 to Healthy Adults

The primary objective of the study is to evaluate the distribution in the central nervous system (CNS) of a microdose 99mTc-MAG3-BIIB067 co-administered with unlabeled BIIB067 (Tofersen). The secondary objective of the study is to assess the safety and tolerability of unlabeled BIIB067 co-administered with a microdose of 99mTc-MAG3-BIIB067 to healthy participants.

Start Date20 Dec 2018

Sponsor / Collaborator

Biogen, Inc.

NCT03070119 / CompletedPhase 3

An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB067 Administered to Previously Treated Adults With Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation

The primary objective of the study is to evaluate the long-term safety and tolerability of BIIB067 (tofersen) in participants with amyotrophic lateral sclerosis (ALS) and confirmed superoxide dismutase 1 (SOD1) mutation. The secondary objectives are to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), biomarker effects, and efficacy of BIIB067 administered to participants with ALS and a confirmed SOD1 mutation.

Start Date08 Mar 2017

Sponsor / Collaborator

Biogen, Inc.

[+1]

100 Clinical Results associated with Tofersen

100 Translational Medicine associated with Tofersen

100 Patents (Medical) associated with Tofersen

Literatures (Medical) associated with Tofersen

01 Nov 2024·NEUROBIOLOGY OF DISEASE

Specific analysis of SOD1 enzymatic activity in CSF from ALS patients with and without SOD1 mutations

Article

Author: Zetterström, Per ; Öberg, Agneta ; Nordström, Ulrika ; Jonsson, Eva ; Marklund, Stefan L. ; Hjertkvist, Karin ; Andersen, Peter M. ; Forsberg, Karin M.E. ; Marklund, Stefan L ; Leykam, Laura ; Andersen, Peter M ; Forsberg, Karin M E

Mutations in superoxide dismutase-1 (SOD1) are a cause of hereditary amyotrophic lateral sclerosis (ALS) through a gain-of-function mechanism involving unfolded mutant SOD1. Intrathecal gene therapy using the antisense-oligo-nucleotide drug tofersen to reduce SOD1 expression delays disease progression and has recently been approved in the United States and the European Union. However, the discovery of children homozygous for inactivating SOD1 mutations developing the SOD1 Deficiency Syndrome (ISODDES) with injury to the motor system suggests that a too low SOD1 antioxidant activity may be deleterious in humans. Measuring SOD1 activity in cerebrospinal fluid (CSF) in tofersen-treated patients is recommended but difficult due to low concentration and the presence of the isoenzyme SOD3. We here present a sensitive method to assess SOD1 activity by removing SOD3 from CSF samples using highly specific immobilized antibodies and subsequent measurement of the SOD activity. We validated the method on 171 CSF samples from ALS patients with and without mutations and controls and used paired erythrocyte samples for comparison. We found that in ALS patients with wildtype SOD1, the SOD1 activity in CSF was equal to controls, but patients with mutant SOD1 show lower activity in CSF, even for patients with mutants previously reported to have full activity in erythrocytes. Activity variation in CSF was large among patients carrying the same SOD1 mutation and larger than in erythrocytes and in post-mortem nervous tissue. Additionally, we identified a discrepancy between the SOD1 activity and protein level measured with ELISA in both CSF and erythrocytes. Since antibodies used for SOD1 ELISA-quantification are raised against the natively folded wildtype SOD1, the concentration of mutant SOD1s may be underestimated. Analysis of SOD1 enzymatic activity in CSF is therefore a more reliable way to monitor the effect of SOD1-lowering drugs.

01 Nov 2024·Brain and nerve = Shinkei kenkyu no shinpo

[Gold Coast Criteria: A New Diagnostic Paradigm in the Era of Disease-Modifying Therapy for Amyotrophic Lateral Sclerosis].

Review

Author: Urushitani, Makoto ; Yamakawa, Isamu

Significant progress has been made in the development of disease-modifying drugs for amyotrophic lateral sclerosis (ALS), with the introduction of tofersen, an antisense oligonucleotide drug for familial ALS, marking a turning point in the treatment. These drugs are most effective when administered early in the disease course, highlighting the need for improved diagnostic sensitivity. The 2020 Gold Coast Diagnostic Criteria allow ALS diagnosis in cases without upper motor neuron symptoms, potentially increasing early detection rates. However, careful differential diagnoses are necessary when applying these criteria to maintain diagnostic specificity. This review outlines the key points to consider when using the Gold Coast Criteria, balancing the need for an early diagnosis with caution to avoid overdiagnosis.

01 Nov 2024·Brain and nerve = Shinkei kenkyu no shinpo

[Current Landscape of Tofersen in SOD-1-associated Amyotrophic Lateral Sclerosis].

Article

Author: Nagata, Tetsuya ; Ishiguro, Taro ; Yokota, Takanori

Since the identification, in 1993, of the causative gene for familial amyotrophic lateral sclerosis (ALS), which is associated with SOD1 mutations, research has focused on the pathogenesis and therapeutics of ALS for more than 30 years. Tofersen, a highly anticipated gene-specific therapy that has been aligned with the disease-specific pathology, has been approved for marketing by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) However, as significant data on tofersen's safety and efficacy are required, the evaluation of this treatment is ongoing. This paper introduces the current clinical and commercial status of Tofersen, along with expectations for its approval in Japan.

162

News (Medical) associated with Tofersen

15 Nov 2024

·www.biopharmadive.com

How a Biogen drug set the stage for a new biotech targeting ALS

Trace Neuroscience, a freshly launched startup, is developing a type of genetic medicine it believes could help most, if not all, people with ALS.Its a bold idea, considering nearly every attempt to combat the nerve-destroying disease has ended in failure. Researchers still arent sure what causes 90% of cases. And in the U.S., the short list of drugs approved to treat ALS, or amyotrophic lateral sclerosis, got shorter still this year, as a once-promising medication hit a major setback that ultimately got it pulled from the market.Yet Trace was still able to fundraise $101 million from a group of prominent biotechnology investment firms that includes Third Rock Ventures, Atlas Venture, RA Capital Management and Alphabets venture capital arm, GV. Jeffrey Tong, a Third Rock partner whos now on Traces board of directors, says there are a few reasons why the startup earned his firm's support.One was the companys underlying science. It was built on recent discoveries from the labs of Aaron Gitler, a Stanford University professor; Pietro Fratta, a professor of cellular and molecular neuroscience at University College London; and Michael Ward, a senior investigator in the National Institutes of Healths neurological disorders division. Almost at the same time, these labs identified connections between an important RNA-processing molecule and a protein thats often impaired in people with ALS and other neurodegenerative disorders.Another selling point, according to Tong, was the precedent set by Biogens Qalsody.Like Traces medicine, Qalsody is whats known as an antisense oligonucleotide, meaning it regulates protein production by binding to RNA. Qalsody flunked the main trial designed to show it can slow the functional decline associated with ALS. The drug was still approved last year, though, due to its apparent effects on neurofilament light chain, a protein tied to nerve cell damage.Traces CEO, Eric Green, plans to incorporate those learnings into the development plans for his companys drug, which is on track to enter human testing in early 2026.Green has helped set up multiple Third Rock portfolio companies. He co-founded the precision medicine developer Maze Therapeutics and served as head of translational research at heart drug startup MyoKardia. In an interview with BioPharma Dive, Green explained why his new, big-swing endeavor resonated with investors.The following conversation has been edited and condensed for clarity.BIOPHARMA DIVE: Was there a concerted effort to go to these different parties and ask them to come together and build a single company, rather than three separate ones?ERIC GREEN: Absolutely. This, to me, was just a central part of how I thought about this. I wanted us to join forces and not dilute our efforts across three companies, because everybody here brings different expertise. It's a really nice complementary team.This is my third go around doing this with Third Rock. One of the things I have learned over the years is that the more you can bring together a group of diverse experts who understand an area of biology, the greater chance you're going to have to be successful in translating that into a medicine.We have an academic world that I think is very much oriented toward independent discoveries and independent credit. That makes perfect sense from an academic standpoint, but as we think about trying to make this into a medicine, we need to join forces.There really is that shared goal and shared mission here, recognizing that we're stronger together.Atlas, RA, GV what about those firms made you want them to be part of your investor syndicate?GREEN: The first thing I had in mind was to allow us to raise a sum of money that would allow us to get through what we see as the key clinical data points where we're going to be able to learn about how this medicine is working in people with ALS.But [another piece was] to bring together a diverse set of voices. Atlas, for example, built a number of different RNA therapy and oligonucleotide companies. That was something really important to me, thinking about how we can build companies. [We wanted] a syndicate that has different perspectives, both really early company creation in the case of Third Rock and Atlas but then also people who think about company growth and some of the longer-term horizons. This was where having a group like RA has been really helpful to us. And similarly, with Google Ventures, a group that really sees companies across the life cycle, from very early discovery all the way through to clinical development and commercialization.One of the things that, to me, is a little unusual, maybe particularly exciting, about this opportunity is that we're very early. We're not far from the original discovery. But there's a potential here to move really quickly, and to go from being a discovery company to a company that's generating really meaningful clinical data. And in this indication, meaningful clinical data can have a very direct path towards getting a drug on the market.You raised $101 million. Why stop there, or set that as the goal, in terms of fundraising?GREEN: We want to build an R&D plan that we think is the right one, and then finance that. Not, Lets test the waters and see how much money we could raise. Yes, we could have certainly gotten $1 more than [our goal] and so, by definition, we were oversubscribed. But I have a pet peeve about that myself. Our goal was to set out to raise the amount of money we needed to support the R&D plan, and that's what we did. In general, we're really happy with the round we put together. And we'll have a lot of options with this syndicate to take the next steps.Your company is at the intersection of genetic medicine and neuroscience, two research areas that could be seen as high-risk. What were the biggest concerns among these investors? Do you think youve alleviated them?GREEN: ALS, and neurodegenerative diseases more broadly, are an area where there's been a lot of disappointment.It was really important for me to be able to convey what we thought was different about this opportunity. I can summarize it with three components. Here is this focus on robust human genetics as our guide to give us confidence we're going after a mechanism relevant in people with ALS, rather than in some cell or animal model of the disease. The quality of the human genetics evidence here is exceptionally high, both because it's been reproduced across so many different cohorts, but also because of this relationship with disease progression and survival. And that's unusual, as opposed to having a relationship with just the risk of disease. It really gives us confidence there's a window to intervene on this mechanism after people are diagnosed.But genetics is not enough. You need to understand what the mechanism is by which the gene is working. And this is where that set of discoveries I described from Aaron and Pietro and Michael was so critical of saying we really understand how this gene is working. This has been, even with some of the previous genetic targets, one of the limitations. We don't exactly know what it is that's going on, and therefore we don't exactly know what we want to do therapeutically.Then the third piece was, this is a mechanism that really is amenable to a particular modality, in this case, antisense oligonucleotides.Where we are today, we have a lot more confidence we actually have a particular molecule that has all those properties we're looking for that can potently correct splicing, both in cells and animal models of disease, and that can do that in a way that is sufficiently well tolerated so we'll be able to have some flexibility in how we dose in the clinic.Trace remains a single-asset company. Is that a harder sell right now, given that biotech investors appear at least somewhat more risk averse?GREEN: This was something I spent a lot of time thinking about, because my prior experience at MyoKardia, Maze, other companies, has been in broader, platform-oriented companies. So this was a big part of the thought process I had as we went from this discovery to: What's the right company?A big part of what made the single asset make sense is it allows us to really get to those important clinical inflection points on a Series A raise, as opposed to saying we're going to explore a bunch of different things, but not be able to get any of them to the point where we get the meaningful clinical data. That was also something that really resonated with investors, because I think there is a real focus on being able to get that meaningful clinical data. That was, in some ways, a tailwind for us.There are some aspects of increased risk when you think about a single asset company. So for us, it was being able to have things far enough along by the time that we launched, that we felt like we had mitigated a lot of those risks. We felt strongly about the genetics, we felt strongly about the mechanism, and we felt strongly enough about being able to find a molecule that could meet our criteria. The risk of not getting to the point where we can test this in patients is relatively mitigated. This wouldn't have made sense when we were talking in 2020 and said, Oh, here's an interesting idea, and here's an interesting mechanism, but we don't know whether it's going to be possible to find a molecule.In some ways, it became an advantage. Now we can really focus the organization on being able to get that critical data. And then after that think about how we might broaden the company, whether it be to other indications or other ways of attacking this target.Whats the current development timeline investors envision for your asset? What data represent a go-no go decision for Trace and its investors?GREEN: We're on track with our lead molecule to be in the clinic by early 2026. We'll be able to, very quickly, do these trials in patients, so that the first studies have the opportunity to show us meaningful clinical data.This is one of the places were able to benefit from some of the work that was done with [Qalsody], even though the focus there is on a very rare population of people with ALS. A lot of the things they learned with respect to biomarkers, in particular, are very relevant for how we think about our clinical development. [In particular] they were able to take advantage of neurofilament as a biomarker of disease progression that really correlated well with the ultimate changes we all hope to see, which is improvements in how people feel, function and survive with ALS.I think that gives us a much stronger toolkit for evaluating our molecules than we had before. So we're obviously going to be looking for those clinical signs, but having some strong biomarkers will help accelerate and give us more tools to see proof-of-concept in the clinic earlier. '

Oligonucleotide

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 Tofersen

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KEGG	Wiki	ATC	Drug Bank
D11811	-	-	DB14782

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Indication	Country/Location	Organization	Date
Amyotrophic Lateral Sclerosis	EU	Biogen, Inc.	30 May 2024
Amyotrophic Lateral Sclerosis	IS	Biogen, Inc.	30 May 2024
Amyotrophic Lateral Sclerosis	LI	Biogen, Inc.	30 May 2024
Amyotrophic Lateral Sclerosis	NO	Biogen, Inc.	30 May 2024
Amyotrophic Lateral Sclerosis 1	US	Biogen MA, Inc.	25 Apr 2023

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02623699 (FDA) Manual	Phase 3	Amyotrophic Lateral Sclerosis 1 SOD1 Mutation	108	QALSODY 100 mg (ITT population)	zukrodgeec(mxdayynlgr) = daadwolicm eeknpbncup (qxblpiwcuy ) View more	Positive	25 Apr 2023
				Placebo (ITT population)	zukrodgeec(mxdayynlgr) = pgbaypbmxc eeknpbncup (qxblpiwcuy ) View more
NCT02623699 (VALOR, Pubmed \| Br Dent J) Manual	Phase 3	Amyotrophic Lateral Sclerosis 1 SOD1 Mutation	108	Tofersen	sjawiahaea(easwsjyqme) = zgiwkobldc ojphozkgoh (lnjsqxoxuj )	Negative	22 Sep 2022
				placebo	sjawiahaea(easwsjyqme) = dnirtiximg ojphozkgoh (lnjsqxoxuj )
NCT02623699 (VALOR, Corporate Publications) Manual	Phase 3	Amyotrophic Lateral Sclerosis 1 SOD1	108	Tofersen	aeervygkdw(uhawkzfojf) = ygcdnyenqo casqmftbdx (kanrojvwny )	Positive	03 Jun 2022
				Placebo	aeervygkdw(uhawkzfojf) = ocdyszfdau casqmftbdx (kanrojvwny )
NCT02623699 (VALOR, Corporate Publications) Manual	Phase 3	Amyotrophic Lateral Sclerosis 1 SOD1 mutation	108	tofersen	gyhbrdrckv(coxlrorhmy) = vmanasiefc xekhbzosew (zbbntpgkoo ) View more	Positive	17 Oct 2021
				Placebo	gyhbrdrckv(coxlrorhmy) = wgpnhgzntq xekhbzosew (zbbntpgkoo ) View more
NCT02623699 (VALOR, Pubmed \| Br Dent J \| N Engl J Med) Manual	Phase 1/2	Amyotrophic Lateral Sclerosis 1 SOD1 Mutation	50	Tofersen	fpzynchnyg(rllbmebimc) = dnctyqarqz bnutotmodv (pdsdstqogv ) View more	Positive	09 Jul 2020
				Placebo	dvtmksnilu(rifrflpndf) = pxkndwuvep apdzmtaomx (uocvhuvdhv )
NCT01041222 (Pubmed) Manual	Phase 1	Amyotrophic Lateral Sclerosis 1 SOD1 Mutation	32	ISIS 333611	bpwqfuykqo(ncgkukgzax) = fjxtoqbhnf iieblixlcj (dgfvgazspb ) View more	Positive	01 May 2013
				Placebo	-

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