Eplontersen

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

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