A Randomized, Placebo-Controlled, Four-Period Crossover, Study to Evaluate the Effect of Volanesorsen on the QTc Interval Using a Therapeutic and Supra-Therapeutic Dose Compared With Placebo in Healthy Volunteers: a Thorough QT Study

The primary objective of this study is to assess the corrected QT interval (QTc) effect of volanesorsen (ISIS 304801) administered as a 300 mg subcutaneous (SC) therapeutic and a 300 mg intravenous (IV; 2-hour infusion) supra-therapeutic dose relative to placebo in healthy adult male and female subjects.

Start Date19 Sep 2016

Sponsor / Collaborator

Ionis Pharmaceuticals, Inc.

[+1]

EUCTR2015-003755-21-FR / Not yet recruitingPhase 3

An Open-Label Extension Study of Volanesorsen Administered Subcutaneously to Patients with Familial Chylomicronemia Syndrome (FCS)

Start Date07 Sep 2016

Sponsor / Collaborator

Ionis Pharmaceuticals, Inc.

100 Clinical Results associated with Volanesorsen

100 Translational Medicine associated with Volanesorsen

100 Patents (Medical) associated with Volanesorsen

Literatures (Medical) associated with Volanesorsen

01 Feb 2024·The New England journal of medicineQ1 · MEDICINE

Volanesorsen to Prevent Acute Pancreatitis in Hypertriglyceridemia

Q1 · MEDICINE

Letter

Author: Geary, Richard S ; Witztum, Joseph L ; Oral, Elif A ; Tsimikas, Sotirios ; Prohaska, Thomas A ; Hegele, Robert A ; Gouni-Berthold, Ioanna ; Li, Lu ; Alexander, Veronica J ; Stroes, Erik S G ; Karwatowska-Prokopczuk, Ewa

01 Jan 2024·Journal of lipid and atherosclerosis

Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors

Review

Author: Li, Yan-Hong ; Tomlinson, Brian ; Zhong, Yi-Ming ; Wu, Qian-Yan

Apolipoprotein C3 (apoC3) and angiopoietin-like protein 3 (ANGPTL3) inhibit lipolysis by lipoprotein lipase and may influence the secretion and uptake of various lipoproteins. Genetic studies show that depletion of these proteins is associated with improved lipid profiles and reduced cardiovascular events so it was anticipated that drugs which mimic the effects of loss-of-function mutations would be useful lipid treatments. ANGPTL3 inhibitors were initially developed as a treatment for severe hypertriglyceridaemia including familial chylomicronaemia syndrome (FCS), which is usually not adequately controlled with currently available drugs. However, it was found ANGPTL3 inhibitors were also effective in reducing low-density lipoprotein cholesterol (LDL-C) and they were studied in patients with homozygous familial hypercholesterolaemia (FH). Evinacumab targets ANGPTL3 and reduced LDL-C by about 50% in patients with homozygous FH and it has been approved for that indication. The antisense oligonucleotide (ASO) vupanorsen targeting ANGPTL3 was less effective in reducing LDL-C in patients with moderate hypertriglyceridaemia and its development has been discontinued but the small interfering RNA (siRNA) ARO-ANG3 is being investigated in Phase 2 studies. ApoC3 can be inhibited by the ASO volanesorsen, which reduced triglycerides by >70% in patients with FCS and it was approved for FCS in Europe but not in the United States because of concerns about thrombocytopaenia. Olezarsen is an N-acetylgalactosamine-conjugated ASO targeting apoC3 which appears as effective as volanesorsen without the risk of thrombocytopaenia and is undergoing Phase 3 trials. ARO-APOC3 is an siRNA targeting apoC3 that is currently being investigated in Phase 3 studies.

01 Nov 2023·Cardiology in review

Drug Therapy for Hypertriglyceridemia and Familial Chylomicronemia Syndrome: Focus on Volnesorsen

Article

Author: Frishman, William H ; Gesner, Matthew

Volanesorsen is a new medication that may soon be used in the treatment of hypertriglyceridemia and familial chylomicronemia syndrome (FCS). Volanesorsen works via binding to Apo C-III mRNA and degrading that mRNA, thus decreasing the synthesis of Apo C-III. This decreased synthesis of Apo C-III will increase the binding of triglycerides to LDL receptors and decrease triglyceride plasma levels. It is important to note that currently there are 3 other medication classes available for the treatment of hypertriglyceridemia, including niacin, fish oil/omega-3-fatty acids, and fibrates. However, there are no Food and Drug Administration-approved medications to treat FCS. Recently, volanesorsen was approved in the European Union for the treatment of FCS, but that indication was denied in the United States by the Food and Drug Administration. This was due to the side effects of the drug. Volanesorsen may cause a decrease in platelet count, renal toxicity, and elevate liver enzymes. The current drug regimen for volanesorsen consists of 285 mg once a week by subcutaneous injection, with a recommendation to immediately stop the medication if any of these side effects are noted, to prevent long-term complications. With these side effects reported, fish oil/omega-3-fatty acids seem likely the best choice when it comes to treating hypertriglyceridemia. If FCS is debilitating or greatly affecting the patient’s life, then one could recommend volanesorsen. Otherwise, at this time, the side effects of volanesorsen may be too severe to justify its use for mild episodes of FCS or hypertriglyceridemia.

News (Medical) associated with Volanesorsen

25 Apr 2024

·www.prnewswire.com

PTC Therapeutics Provides Corporate Update and Reports First Quarter 2024 Financial Results

– Strong revenue performance across product portfolio – – Submitted MAA for sepiapterin and BLA for Upstaza – – On target to achieve remaining 2024 clinical and regulatory milestones, including global submissions for sepiapterin – WARREN, N.J., April 25, 2024 /PRNewswire/ -- PTC Therapeutics, Inc., (NASDAQ: PTCT) today announced a corporate update and financial results for the first quarter ending March 31, 2024. "We are off to a strong start in 2024, with outstanding commercial performance and achievement of all planned clinical and regulatory milestones for the first quarter," said Matthew Klein, M.D., Chief Executive Officer, PTC Therapeutics, Inc. "We remain on track to achieve the many planned 2024 clinical and regulatory milestones, including global regulatory submissions for sepiapterin." Key Corporate Updates: First quarter 2024 total revenue of $210 million First quarter 2024 revenue for the DMD franchise was $161 million Translarna™ (ataluren) net product revenue was $104 million, driven by new patients in existing geographies and continued geographic expansion. Emflaza® (deflazacort) net product revenue was $57 million, resulting from new patient starts and high compliance. Key Clinical and Regulatory Milestones: PTC submitted an MAA to the EMA for sepiapterin for the treatment of PKU in March 2024. The company expects to submit an NDA to the FDA for sepiapterin no later than the third quarter of 2024 and to complete regulatory submissions in Japan and Brazil in 2024. PTC submitted a BLA to the FDA for Upstaza™ for the treatment of AADC deficiency in March 2024. Based on FDA feedback, PTC plans to resubmit the NDA for Translarna for the treatment of nmDMD in mid-2024. Based on FDA feedback, PTC plans to submit an NDA for vatiquinone for the treatment of FA in late 2024. The interim data update for the PIVOT-HD trial of PTC518 for HD patients remains on schedule for the second quarter of 2024. This update will include 12-month data on the initial group of subjects for whom data were reported in June 2023, as well as 12-week data on a larger number of stage 2 and stage 3 HD patients. PTC expects to report topline data for the CardinALS trial of utreloxastat for ALS in the fourth quarter of 2024. First Quarter 2024 Financial Highlights: Total revenues were $210.1 million for the first quarter of 2024, compared to $220.4 million for the first quarter of 2023. Total revenue includes net product revenue across the commercial portfolio of $177.6 million for the first quarter of 2024, compared to $187.6 million for the first quarter of 2023. Total revenue also includes collaboration, royalty, and manufacturing revenue of $32.5 million in the first quarter of 2024, compared to $32.8 million for the first quarter of 2023. Translarna net product revenues were $103.6 million for the first quarter of 2024, compared to $115.1 million for the first quarter of 2023, driven by new patients in existing geographies and continued geographic expansion. The decrease was due to the timing of bulk patient orders. Emflaza net product revenues were $57.5 million for the first quarter of 2024, compared to $54.6 million for the first quarter of 2023. These results were driven by new patient starts and high compliance. Roche reported Evrysdi® 2024 year-to-date sales of approximately $400 million, resulting in royalty revenue of $31.2 million to PTC for the first quarter of 2024, as compared to $30.8 million for the first quarter of 2023. Based on U.S. GAAP (Generally Accepted Accounting Principles), GAAP R&D expenses were $116.1 million for the first quarter of 2024, compared to $195.1 million for the first quarter of 2023. The decrease in research and development expenses reflects strategic portfolio prioritization as the Company continues to focus its resources on its differentiated, high-potential R&D programs. Non-GAAP R&D expenses were $107.2 million for the first quarter of 2024, excluding $9.0 million in non-cash, stock-based compensation expense, compared to $179.8 million for the first quarter of 2023, excluding $15.3 million in non-cash, stock-based compensation expense. GAAP SG&A expenses were $73.3 million for the first quarter of 2024, compared to $86.9 million for the first quarter of 2023. The decrease in selling, general and administrative expenses reflects lower employee costs as a result of the reduction in workforce in 2023. Non-GAAP SG&A expenses were $63.9 million for the first quarter of 2024, excluding $9.4 million in non-cash, stock-based compensation expense, compared to $73.4 million for the first quarter of 2023, excluding $13.5 million in non-cash, stock-based compensation expense. Change in the fair value of deferred and contingent consideration was a gain of $0.1 million for the first quarter of 2024, compared to a loss of $2.4 million for the first quarter of 2023. The net loss was $91.6 million for the first quarter of 2024, compared to a net loss of $139.0 million for the first quarter of 2023. Cash, cash equivalents, and marketable securities was $884.8 million on March 31, 2024, compared to $876.7 million on December 31, 2023. Shares issued and outstanding as of March 31, 2024, were 76,653,960. PTC Reaffirms Full Year 2024 Financial Guidance: PTC anticipates total revenues for full year 2024 to be between $600 million and $680 million. PTC anticipates GAAP R&D and SG&A expense for full year 2024 to be between $740 and $835 million. PTC anticipates Non-GAAP R&D and SG&A expense for full year 2024 to be between $660 and $755 million, including expected R&D expense milestone payments of up to $65 million and excluding estimated non-cash, stock-based compensation expense of $80 million. PTC anticipates up to $90 million of payments for full year 2024 upon achievement of potential regulatory success-based milestones from previous acquisitions, of which up to $65 million will be recorded as R&D operating expense. Non-GAAP Financial Measures: In this press release, the financial results of PTC are provided in accordance with GAAP and using certain non-GAAP financial measures. In particular, the non-GAAP R&D and SG&A expense financial measures exclude non-cash, stock-based compensation expense. These non-GAAP financial measures are provided as a complement to financial measures reported in GAAP because management uses these non-GAAP financial measures when assessing and identifying operational trends. In management's opinion, these non-GAAP financial measures are useful to investors and other users of PTC's financial statements by providing greater transparency into the historical and projected operating performance of PTC and the company's future outlook. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. Quantitative reconciliations of the non-GAAP financial measures to their respective closest equivalent GAAP financial measures are included in the table below. Acronyms: AADC: Aromatic l-Amino Acid Decarboxylase ALS: Amyotrophic Lateral Sclerosis BLA: Biologics License Application CHF: Confoederatio Helvetica Francs (Swiss francs) DMD: Duchenne Muscular Dystrophy EMA: European Medicines Agency FA: Friedreich Ataxia FDA: U.S. Food and Drug Administration GAAP: Generally Accepted Accounting Principles HD: Huntington's Disease MAA: Marketing Authorization Application NDA: New Drug Application nmDMD: Nonsense Mutation Duchenne Muscular Dystrophy PKU: Phenylketonuria R&D: Research and Development SG&A: Selling, General, and Administrative Today's Conference Call and Webcast Reminder: To access the call by phone, please click here to register and you will be provided with dial-in details. To avoid delays, we recommend participants dial in to the conference call 15 minutes prior to the start of the call. The webcast conference call can be accessed on the Investor section of the PTC website at . A replay of the call will be available approximately two hours after completion of the call and will be archived on the company's website for 30 days following the call. About PTC Therapeutics, Inc. PTC is a global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders. PTC's ability to globally commercialize products is the foundation that drives investment in a robust and diversified pipeline of transformative medicines and our mission to provide access to best-in-class treatments for patients who have an unmet medical need. The company's strategy is to leverage its strong scientific expertise and global commercial infrastructure to maximize value for its patients and other stakeholders. To learn more about PTC, please visit us at and follow us on Facebook, on Twitter at @PTCBio, and on LinkedIn. For More Information: Investors: Kylie O'Keefe +1 (908) 300-0691 [email protected] Media: Jeanine Clemente +1 (908) 912-9406 [email protected] Forward-Looking Statements: This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this release, other than statements of historic fact, are forward-looking statements, including the information provided under the heading "PTC Reaffirms Full Year 2024 Revenue Guidance", including with respect to (i) 2024 total revenue guidance, (ii) 2024 GAAP and non-GAAP R&D and SG&A expense guidance and (iii) 2024 acquisition related milestone payment guidance, and statements regarding: the future expectations, plans and prospects for PTC, including with respect to the expected timing of clinical trials and studies, availability of data, regulatory submissions and responses, commercialization and other matters with respect to its products and product candidates; PTC's strategy, future operations, future financial position, future revenues, projected costs; the extent, timing and financial aspects of our strategic pipeline prioritization and reductions in workforce; and the objectives of management. Other forward-looking statements may be identified by the words, "guidance", "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions. PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of pricing, coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC commercializes or may commercialize in the future; PTC's ability to maintain its marketing authorization of Translarna for the treatment of nmDMD in Brazil, Russia, the European Economic Area (EEA) and other regions, including whether the European Commission adopts the negative opinion from the Committee for Medicinal Products for Human Use (CHMP) for the conditional marketing authorization for Translarna in the EEA; PTC's ability to use the results of Study 041, a randomized, 18-month, placebo-controlled clinical trial of Translarna for the treatment of nmDMD followed by an 18-month open-label extension, and from its international drug registry study to support a marketing approval for Translarna for the treatment of nmDMD in the United States; whether investigators agree with PTC's interpretation of the results of clinical trials and the totality of clinical data from our trials in Translarna; expectations with respect to Upstaza, including any regulatory submissions and potential approvals, commercialization, manufacturing capabilities, the potential achievement of development, regulatory and sales milestones and contingent payments that PTC may be obligated to make; expectations with respect to the commercialization of Evrysdi under our SMA collaboration; expectations with respect to the commercialization of Tegsedi and Waylivra; the timing of and actual expenses incurred in connection with the discontinuation of PTC's preclinical and early research programs in gene therapy and reductions in workforce, which may be in different periods and may be materially higher than estimated; the savings that may result from the discontinuation of PTC's strategic pipeline prioritization and reductions in workforce, which may be materially less than expected; significant business effects, including the effects of industry, market, economic, political or regulatory conditions; changes in tax and other laws, regulations, rates and policies; the eligible patient base and commercial potential of PTC's products and product candidates; PTC's scientific approach and general development progress; the potential financial impact and benefits of PTC's leased biologics manufacturing facility; PTC's ability to satisfy its obligations under the terms of its lease agreements, including for its leased biologics manufacturing facility; the sufficiency of PTC's cash resources and its ability to obtain adequate financing in the future for its foreseeable and unforeseeable operating expenses and capital expenditures; and the factors discussed in the "Risk Factors" section of PTC's most recent Quarterly Report on Form 10-Q and Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in any territory, or prove to be commercially successful, including Translarna, Emflaza, Upstaza, Evrysdi, Tegsedi or Waylivra. The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law. SOURCE PTC Therapeutics, Inc.

Financial StatementNDA

21 Feb 2024

·www.biospace.com

Ionis reports fourth quarter and full year 2023 financial results

WAINUA™ approved with launch underway; on track for EU and Canada approval decisions this year Positive Phase 3 olezarsen and donidalorsen data, preparing regulatory submissions for FCS and HAE, respectively Olezarsen granted Breakthough Therapy designation by the FDA for FCS Ionis provides full year 2024 financial guidance CARLSBAD, Calif., Feb. 21, 2024 /PRNewswire/ --Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company"), today reported financial results for the fourth quarter and full year ended December 31, 2023. "This past year included many remarkable achievements as we continued to advance our vision to bring better futures to people with serious diseases. Ionis achieved two FDA approvals, delivered three positive Phase 3 data readouts, expanded our rich Phase 3 pipeline to nine medicines and advanced our next wave of wholly owned medicines as well as our technology," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "In 2024, we anticipate building on our success with important catalysts and continued value creation. The WAINUA U.S. launch is underway for patients with hereditary ATTR polyneuropathy, and we expect additional approvals in other countries this year. We plan to present positive Phase 3 data for olezarsen in familial chylomicronemia syndrome and donidalorsen in hereditary angioedema, positioning Ionis to independently launch these two medicines. We also anticipate additional readouts from multiple mid-stage programs that, if positive, would advance into Phase 3 development, further strengthening our ability to deliver a steady cadence of potentially transformational medicines for years to come." Fourth Quarter and Full Year 2023 Summary Financial Results(1): Financial Highlights Revenue more than doubled for the fourth quarter of 2023 compared to the same period in the prior year and increased 34% for the full year, driven by the successful progression of Ionis' pipeline and technology platform Operating expenses increased compared to the prior year, primarily due to strategic investments to bring eplontersen, olezarsen and donidalorsen to patients 2023 operating loss significantly improved over prior year due to substantial revenue earned during the year Cash and short-term investments of $2.3 billion as of December 31, 2023 enables continued investments to drive increasing value, including supporting our potential upcoming launches Recent Marketed Medicines Highlights WAINUA approved in the U.S., resulting in a $50 million milestone payment from AstraZeneca; launch underway for treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) SPINRAZA continued to be the global market leader for the treatment of spinal muscular atrophy (SMA) with global sales of $1.7 billion in 2023 Recent Late-Stage Pipeline Highlights Eplontersen granted Fast Track designation by the FDA for the treatment of patients with ATTR cardiomyopathy (ATTR-CM) Olezarsen granted Breakthrough Therapy designation by the FDA for the treatment of patients with familial chylomicronemia syndrome (FCS) Olezarsen granted orphan drug designation by the FDA for the treatment of patients with FCS Achieved multiple milestones with donidalorsen for the treatment of patients with hereditary angioedema (HAE): Reported positive topline data from the Phase 3 OASIS-HAE study in patients treated every four weeks or every eight weeks; preparing to submit NDA Licensed European donidalorsen commercialization rights to Otsuka; Otsuka preparing to submit MAA Donidalorsen granted orphan drug designation by EMA Reported positive Phase 2 data from the open label extension study in patients with HAE treated for two years Bepirovirsen granted fast track designation by the FDA for the treatment of patients with chronic hepatitis B (CHB) Recent Other Pipeline Highlights Achieved multiple milestones with ION582 (BIIB121) for the treatment of patients with Angelman syndrome: Completed enrollment in the Phase 1/2 HALOS study in patients with Angelman syndrome; on track for data readout in mid-2024 Presented positive clinical update from ongoing HALOS study at the FAST (Foundation for Angelman Syndrome Therapeutics) Summit Extended the long-term extension portion of HALOS study Sapablursen and ION356 granted fast track designation by the FDA for the treatment of patients with polycythemia vera (PV) and Pelizaeus-Merzbacher disease (PMD), respectively Initiated the Phase 1/2 PrPro of ION717 in patients with Prion disease AstraZeneca licensed ION826 for the treatment of heart failure, resulting in a $36 million payment from AstraZeneca Recent Technology Advancement Highlights Licensed Vect-Horus' blood-brain barrier crossing technology for the development of RNA-targeted neurological disease medicines Fourth Quarter, Full Year 2023 Financial Results and 2024 Financial Guidance "In 2023, we earned substantial revenues due to continued success with our pipeline and technology. As a result, we exceeded our 2023 revenue guidance, which drove a smaller than anticipated operating loss," said Elizabeth L. Hougen, chief financial officer of Ionis. "In 2024, with WAINUA's launch for ATTRv-PN underway, we are adding a new stream of royalty revenue to our substantial and sustained revenues. We will continue to deploy our capital resources toward growth opportunities that can enable Ionis to unlock next-level value. This includes continuing to make significant investments in near-term commercial opportunities, the expansion of our wholly owned pipeline, and advancing our technology, all of which should empower future growth." Revenue Ionis' revenue was comprised of the following: Commercial revenues in 2023 were comparable to 2022. Commercial revenue for 2023 included $240 million from SPINRAZA royalties, which was comparable to 2022. Ionis' commercial revenue in 2023 also included royalties from QALSODY U.S. product sales. R&D revenue significantly increased in 2023 compared to 2022 primarily due to continued success with Ionis' pipeline and technology. As a result, Ionis earned significant partner payments, including $50 million from AstraZeneca for the FDA approval of WAINUA for ATTRv-PN in the U.S., $36 million from AstraZeneca for licensing ION826 and payments from Ionis' new collaborations with Otsuka, Roche and Novartis. Operating Expenses Ionis' operating expenses increased for the year ended December 31, 2023 compared to 2022 primarily due to certain one-time costs, including a non-cash charge associated with a lease exit and the license fee Ionis paid to Vect-Horus. As Ionis advanced its robust pipeline, study costs increased compared to the same periods in 2022 as many of the Company's Phase 3 studies are either fully enrolled or approaching full enrollment, resulting in higher R&D expenses year over year. R&D expenses for the fourth quarter of 2023 were lower compared to the fourth quarter of 2022, primarily due to the $80 million upfront payment Ionis paid to Metagenomi in 2022. Ionis' SG&A expenses increased year over year primarily due to launch preparation activities for WAINUA, olezarsen and donidalorsen. Balance Sheet As of December 31, 2023, Ionis' cash, cash equivalents and short-term investments increased to $2.3 billion compared to $2.0 billion at December 31, 2022 primarily due to the $500 million Ionis received from Royalty Pharma in January 2023 and significant partner payments throughout 2023. Ionis' working capital also increased over the same period primarily due to the Company's higher cash and short-term investments balance. In 2023, the Company recorded a long-term liability for future royalties due to Royalty Pharma. In June 2023, Ionis issued $575 million of senior convertible notes due in June 2028 with an interest rate of 1.75%. The Company used the majority of the proceeds to repurchase $504 million of its 0.125% convertible notes. 2024 Financial Guidance The Company's 2024 guidance reflects its plan to deploy its capital resources toward growth opportunities, including continued investments in its near-term commercial opportunities, expanding its wholly owned pipeline and advancing its technology platform. Additionally, the Company expects to continue earning substantial revenue from its commercial portfolio and partnered programs. Webcast Management will host a conference call and webcast to discuss Ionis' fourth quarter and full year 2023 results at 11:30 a.m. Eastern time on Wednesday, February 21, 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 fourth quarter and full year 2023 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 Ionispharma.com and follow us on X (Twitter) and LinkedIn. 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, 2022, and most recent Form 10-Q, which are on 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. QALSODYTM is a trademark of Biogen. SPINRAZA® is a registered trademark of Biogen. WAINUATM is a registered trademark of the AstraZeneca group of companies. *In October 2022, Ionis entered into a sale and leaseback transaction for several of its real estate assets. As a result, the Company recognized a $150 million gain on sale of real estate assets in the fourth quarter of 2022. The Company excluded the gain on sale of real estate assets and the related tax effect from its non-GAAP amounts for the applicable periods. Reconciliation of GAAP to Non-GAAP Basis As illustrated in the Selected Financial Information in this press release, non-GAAP operating expenses, non-GAAP income (loss) from operations, and non-GAAP net income (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. In 2022, Ionis' non-GAAP net loss excluded the gain on real estate assets related to the sale and leaseback transaction and the related tax effects. 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) Company Codes: NASDAQ-NMS:IONS

Clinical ResultBreakthrough TherapyPhase 3Drug ApprovalOrphan Drug

08 Jan 2024

·www.biospace.com

PTC Therapeutics Provides an Update on Commercial Progress and R&D Pipeline at 42nd Annual J.P. Morgan Healthcare Conference

– Unaudited 2023 total revenue of $946 million, representing 35% year-over-year growth – – Regulatory filings in the EU and US for sepiapterin in PKU, a potential $1 billion global commercial opportunity, remain on track for 2024 – – Multiple study readouts planned for 2024, including 12-month interim data from the PIVOT-HD study of PTC518 in HD patients – SOUTH PLAINFIELD, N.J., Jan. 8, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) will present an update on its commercial progress and R&D pipeline at the 42nd Annual J.P. Morgan Healthcare Conference today, Monday, January 8, at 10:30am EST/7:30am PST. Matthew B. Klein, M.D., Chief Executive Officer of PTC Therapeutics, will provide an update on 2023 accomplishments and highlight potential 2024 value-creating milestones. Preliminary 2023 unaudited financial results and 2024 financial guidance will also be provided. The presentation is being webcast live on the Events and Presentations page of the Investors section of PTC Therapeutics website at . "2023 was a transformational year for PTC as we made necessary and important changes to become a leaner, more focused and financially stronger company positioned for future success," said Matthew B. Klein, M.D., Chief Executive Officer of PTC Therapeutics. "We look forward to a successful 2024, with anticipated key global regulatory submissions for our PKU program and multiple data readouts, including from our PTC518 HD program." Key 2023 Corporate Highlights: Unaudited net product revenue of $661 million in 2023 representing 23% year-over-year growth. Strong year-over-year growth for the Duchenne muscular dystrophy (DMD) franchise, with unaudited net product revenue of $355 million for Translarna™ (ataluren) and $255 million for Emflaza® (deflazacort) in 2023. Translarna growth was driven by new patients in existing geographies and continued geographic expansion. Emflaza growth was due to continued new prescriptions, high compliance, and more favorable access. PTC announced positive readouts from key programs in its clinical pipeline in 2023: Highly statistically significant and clinically meaningful results in the Phase 3 registration-directed APHENITY clinical trial of sepiapterin in adult and pediatric patients with PKU. Achievement of all key objectives of the readout of 12-week interim data in the PIVOT-HD study of PTC518 in HD. PTC announced strategic portfolio prioritizations, which resulted in reductions in both operating expenses and headcount of approximately 25% and 30%, respectively. In October, PTC finalized a royalty agreement, in which Royalty Pharma acquired additional royalties of Evrysdi for $1.0 billion upfront. The agreement included options for PTC to sell the remainder of its royalties of Evrysdi for up to $500 million or for Royalty Pharma to acquire half of such retained royalties for up to $250 million at a later date, less royalties received by PTC. PTC maintains all economics associated with up to $250 million in the remaining commercial sales milestones associated with Evrysdi global net sales. The proceeds from the financing were used to retire all outstanding debt obligations with Blackstone Life Sciences. 2024 Potential Key Clinical and Regulatory Events: Submission of a MAA to the EMA for sepiapterin for the treatment of PKU is expected in the first quarter. Submission of an NDA to the FDA for sepiapterin for the treatment of PKU is expected no later than the third quarter. Results from 12-month interim data from the PIVOT-HD trial of PTC518 in HD patients are expected in the second quarter. Submission of a BLA to the FDA for Upstaza for the treatment of AADC deficiency is expected in the first quarter. Topline results from the CardinALS trial of utreloxastat in ALS are expected in the fourth quarter. PTC expects the CHMP opinion from the re-examination procedure of the negative opinion on the Translarna conditional marketing authorization renewal in late January 2024, with ratification of that opinion by the European Commission 67 days later. FDA meeting for Translarna to align on the specific contents of a potential NDA resubmission is scheduled for the first quarter. FDA meeting for vatiquinone to discuss how the MOVE-FA data along with additional clinical and preclinical data could support an NDA submission in FA is scheduled for the first quarter. Scientific advice feedback from the EMA on a potential submission of vatiquinone for conditional marketing authorization for Friedreich ataxia is expected in the first quarter. Unaudited 2023 Financial Results: Total unaudited net revenue for full-year 2023 was approximately $946 million. Total unaudited net product revenue for full-year 2023 was approximately $661 million. DMD franchise unaudited revenue for full-year 2023 was approximately $610 million, including unaudited net product revenue for Translarna of approximately $355 million and for Emflaza of approximately $255 million. PTC expects to report approximately $278 million for full-year 2023 collaboration and royalty revenue associated with Evrysdi. PTC is currently in the process of finalizing its financial results for the 2023 fiscal year. The above information is based on preliminary unaudited information and management estimates for the full year 2023, subject to the completion of PTC's financial closing procedures. Evrysdi royalty revenue estimates are based on internal estimates. 2024 Financial Guidance: PTC anticipates total revenues for the full-year 2024 to be between $600 million and $850 million. PTC anticipates GAAP R&D and SG&A expense for the full-year 2024 to be between $740 and $835 million. PTC anticipates Non-GAAP R&D and SG&A expense for the full year 2024 to be between $660 and $755 million, including expected R&D expense milestone payments of up to $65 million and excluding estimated non-cash, stock-based compensation expense of $80 million. PTC anticipates up to $90 million of payments for the full year 2024 upon achievement of potential regulatory success-based milestones from previous acquisitions, of which up to $65 million will be recorded as R&D operating expense. Non-GAAP Financial Measures: In this press release, the financial results and financial guidance of PTC are provided in accordance with GAAP and using certain non-GAAP financial measures. In particular, the non-GAAP financial measures exclude non-cash, stock-based compensation expense. These non-GAAP financial measures are provided as a complement to financial measures reported in GAAP because management uses these non-GAAP financial measures when assessing and identifying operational trends. In management's opinion, these non-GAAP financial measures are useful to investors and other users of PTC's financial statements by providing greater transparency into the historical and projected operating performance of PTC and the company's future outlook. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. Quantitative reconciliations of the non-GAAP financial measures to their respective closest equivalent GAAP financial measures are included in the table below. Acronyms: AADC: Aromatic I-Amino Acid Decarboxylase ALS: Amyotrophic Lateral Sclerosis BLA: Biologics License Application CHMP: Committee for Medicinal Products for Human Use DMD: Duchenne Muscular Dystrophy EMA: European Medicines Agency FDA: Food and Drug Administration MAA: Marketing Authorization Application NDA: New Drug Application PKU: Phenylketonuria R&D: Research and Development SG&A: Selling, General and Administrative SMA: Spinal Muscular Atrophy About PTC Therapeutics, Inc. PTC is a science-driven, global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders. PTC's ability to innovate to identify new therapies and to globally commercialize products is the foundation that drives investment in a robust and diversified pipeline of transformative medicines. PTC's mission is to provide access to best-in-class treatments for patients who have little to no treatment options. PTC's strategy is to leverage its strong scientific and clinical expertise and global commercial infrastructure to bring therapies to patients. PTC believes this allows it to maximize value for all its stakeholders. To learn more about PTC, please visit us at and follow us on Instagram, Facebook, Twitter, and LinkedIn. For More Information: Investors Kylie O'Keefe +1 (908) 300-0691 kokeefe@ptcbio.com Media Jeanine Clemente +1 (908) 912-9406 jclemente@ptcbio.com Forward-Looking Statements: This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this release, other than statements of historic fact, are forward-looking statements, including the information provided under the heading "2024 Financial Guidance", including with respect to (i) 2024 total revenue guidance, (ii) 2024 GAAP and non-GAAP R&D and SG&A expense guidance and (iii) 2024 acquisition related milestone payment guidance, and statements regarding: the future expectations, plans and prospects for PTC, including with respect to the expected timing of clinical trials and studies, availability of data, regulatory submissions and responses, commercialization and other matters with respect to its products and product candidates; PTC's strategy, future operations, future financial position, future revenues, projected costs; the extent, timing and financial aspects of our strategic pipeline prioritization and reductions in workforce; and the objectives of management. Other forward-looking statements may be identified by the words, "guidance," "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions. PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of pricing, coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC commercializes or may commercialize in the future; PTC's ability to maintain its marketing authorization of Translarna for the treatment of nmDMD in Brazil, Russia, the European Economic Area (EEA) and other regions, including whether the European Medicines Agency (EMA) determines in the re-examination process that the benefit-risk balance of Translarna authorization supports renewal of such authorization; PTC's ability to use the results of Study 041, a randomized, 18-month, placebo-controlled clinical trial of Translarna for the treatment of nmDMD followed by an 18-month open-label extension, which was a specific obligation to continued marketing authorization in the EEA, to support a renewal of the conditional marketing authorization for Translarna for the treatment of nmDMD in the EEA; PTC's ability to utilize results from Study 041 to support a marketing approval for Translarna for the treatment of nmDMD in the United States; whether investigators agree with PTC's interpretation of the results of clinical trials and the totality of clinical data from our trials in Translarna; expectations with respect to Upstaza, including any regulatory submissions and potential approvals, commercialization, manufacturing capabilities, the potential achievement of development, regulatory and sales milestones and contingent payments that PTC may be obligated to make; expectations with respect to the commercialization of Evrysdi under our SMA collaboration; expectations with respect to the commercialization of Tegsedi and Waylivra; the timing of and actual expenses incurred in connection with the discontinuation of PTC's preclinical and early research programs in gene therapy and reductions in workforce, which may be in different periods and may be materially higher than estimated; the savings that may result from the discontinuation of PTC's strategic pipeline prioritization and reductions in workforce, which may be materially less than expected; significant business effects, including the effects of industry, market, economic, political or regulatory conditions; changes in tax and other laws, regulations, rates and policies; the eligible patient base and commercial potential of PTC's products and product candidates; PTC's scientific approach and general development progress; the potential financial impact and benefits of PTC's leased biologics manufacturing facility; PTC's ability to satisfy its obligations under the terms of its lease agreements, including for its leased biologics manufacturing facility; the sufficiency of PTC's cash resources and its ability to obtain adequate financing in the future for its foreseeable and unforeseeable operating expenses and capital expenditures; and the factors discussed in the "Risk Factors" section of PTC's most recent Quarterly Report on Form 10-Q and Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in any territory, or prove to be commercially successful, including Translarna, Emflaza, Upstaza, Evrysdi, Tegsedi or Waylivra. The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law. Company Codes: NASDAQ-NMS:PTCT

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KEGG	Wiki	ATC	Drug Bank
D11648	Volanesorsen	J05AB	DB15067

R&D Status

Approved

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Indication	Country/Location	Organization	Date
Familial chylomicronaemia syndrome	EU	Akcea Therapeutics Ireland Ltd.	03 May 2019
Familial chylomicronaemia syndrome	IS	Akcea Therapeutics Ireland Ltd.	03 May 2019
Familial chylomicronaemia syndrome	LI	Akcea Therapeutics Ireland Ltd.	03 May 2019
Familial chylomicronaemia syndrome	NO	Akcea Therapeutics Ireland Ltd.	03 May 2019

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Lipodystrophy, Familial Partial	Phase 3	US	Akcea Therapeutics, Inc.	28 Dec 2015
Lipodystrophy, Familial Partial	Phase 3	BE	Akcea Therapeutics, Inc.	28 Dec 2015
Lipodystrophy, Familial Partial	Phase 3	BR	Akcea Therapeutics, Inc.	28 Dec 2015
Lipodystrophy, Familial Partial	Phase 3	CA	Akcea Therapeutics, Inc.	28 Dec 2015
Lipodystrophy, Familial Partial	Phase 3	DE	Akcea Therapeutics, Inc.	28 Dec 2015
Lipodystrophy, Familial Partial	Phase 3	NL	Akcea Therapeutics, Inc.	28 Dec 2015
Lipodystrophy, Familial Partial	Phase 3	RU	Akcea Therapeutics, Inc.	28 Dec 2015
Familial Hyperchylomicronemia Syndrome	Phase 3	US	Akcea Therapeutics, Inc.	23 Dec 2015
Familial Hyperchylomicronemia Syndrome	Phase 3	BR	Akcea Therapeutics, Inc.	23 Dec 2015
Familial Hyperchylomicronemia Syndrome	Phase 3	CA	Akcea Therapeutics, Inc.	23 Dec 2015

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


SSIEM2023	Not Applicable	Familial chylomicronaemia syndrome homozygous lipoprotein lipase (LPL) mutation C.337 TC (p.Trp113Arg)	-	Volanesorsen	ybolfgpkgh(ehlqpwzuil) = szsehpprom lkhmhmqlvy (sikxgprrva ) View more	-	30 Aug 2023
Pubmed	Not Applicable	Lipodystrophy	5	Volanesorsen 300 mg	fiwzogwvoj(wafzvnvqay) = aeeakzswcz hkaqxaisdd (ddhlkwjmwn ) View more	-	22 Sep 2022
				Placebo	fiwzogwvoj(wafzvnvqay) = fdsxjyzevh hkaqxaisdd (ddhlkwjmwn ) View more
NCT02211209 (CTgov)	Phase 3	Familial chylomicronaemia syndrome	67	Placebo (Placebo)	iuqxtphjeu(xyziqxbsyz) = wyaiftfylo urtrexusyx (gqxdcsxzvl, gowspdtkbw - iwqnydpmkq) View more	-	13 Apr 2022
				Volanesorsen (Volanesorsen)	iuqxtphjeu(xyziqxbsyz) = omdwbsksut urtrexusyx (gqxdcsxzvl, knjezlbiym - xxtzorifyc) View more
NCT02300233 (CTgov)	Phase 3	Hypertriglyceridemia	114	Placebo (Placebo)	yliwbgjmdy(rzizmnodqb) = estxrlzoox sxwxlhmztq (wedylrcmkj, wsmlncvdgq - gffmvlbwpi) View more	-	13 Apr 2022
				Volanesorsen (Volanesorsen 300 mg Weekly)	cbciuvnnxu(aecodvufmx) = xdrigljhve ibsbonqbkj (mufcvoajwy, vuqpkgybeq - iigddpwtpp) View more
NCT02527343 (CTgov)	Phase 2/3	Lipodystrophy, Familial Partial	40	placebo+volanesorsen (Randomized Treatment Period: Placebo)	ebsxftkfoa(ykpqditsnr) = btuispcdqh dmsynzaicz (gdvzypvjxi, vapjkqyqxq - qqvgoyigcs) View more	-	18 Oct 2021
				volanesorsen (Randomized Treatment Period: Volanesorsen)	ebsxftkfoa(ykpqditsnr) = abkuxpkhlc dmsynzaicz (gdvzypvjxi, gytnvpmipv - roogupgzto) View more
NCT02658175 (ISIS 304801-CS7, CTgov)	Phase 3	Familial chylomicronaemia syndrome \| Familial Hyperchylomicronemia Syndrome	68	Volanesorsen (Treatment-naïve Group)	mtevsxspya(bxhhrkwwty) = hrjklnpgub hkcuafjlki (viiajsvcmt, fbcntidzbp - kygdrovleh) View more	-	26 Aug 2021
				Volanesorsen (CS6-Volanesorsen)	mtevsxspya(bxhhrkwwty) = oplaprtzhk hkcuafjlki (viiajsvcmt, dnepayjvvu - wnhnpacjpx) View more
NCT02300233 (COMPASS, Pubmed \| Lancet Diabetes Endocrinol) Manual	Phase 3	Familial chylomicronaemia syndrome	114	volanesorsen	gchdyjygwa(kjjoirwwkh) = jujbbfgqbc vyhinhmfnb (yhajsjncpe, -79.3 ~ -63.2) View more	Positive	01 May 2021
				Placebo	gchdyjygwa(kjjoirwwkh) = gtoytpxojw vyhinhmfnb (yhajsjncpe, -13.9 ~ 12.2) View more
NCT02639286 (CTgov)	Phase 2	Lipodystrophy, Partial, Acquired	5	Placebo (Placebo)	ftphavqkks(uasoqgzgky) = suqyyrvacl kfkyemybgs (kbeqqsapck, bqqmkfacfe - zevotojvbq) View more	-	20 Oct 2020
				ISIS 304801 (ISIS 304801)	ftphavqkks(uasoqgzgky) = dawbmbqygq kfkyemybgs (kbeqqsapck, vvqkkbskzg - kgcrszukar) View more
NCT02211209 (Pubmed \| Br Dent J) Manual	Phase 3	Familial chylomicronaemia syndrome	66	volanesorsen	waeflpyslt(acayrcgipl) = taupklprpo ppjkczqtui (qcztafrflg ) View more	Positive	08 Aug 2019
				Placebo	waeflpyslt(acayrcgipl) = qlmebhmujk ppjkczqtui (qcztafrflg ) View more
NCT02527343 (BROADEN, GlobeNewswire) Manual	Phase 2/3	Lipodystrophy, Familial Partial	40	Volanesorsen	pqwlizelsd(aohnndgrns) = nqffgspviv omjnrcpalf (aowdpkoais ) View more	Positive	06 Aug 2019
				Placebo	pqwlizelsd(aohnndgrns) = avkjiykqxf omjnrcpalf (aowdpkoais ) View more

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