Impact of Nrf2 Activation on Macrovascular Function, Microvascular Function, Leg Function, and Walking Capacity in Patients With Peripheral Artery Disease

Purpose: Peripheral artery disease (PAD) is associated with elevated oxidative stress, and oxidative stress has been implicated as the cause of reduced endothelial reactivity in individuals with PAD. Endothelial function is important because the endothelium contributes to the dilation of arteries during exercise, thereby implicating impaired endothelial function as a mechanism contributing to exacerbated exercise-induced ischemia. Therefore, the purpose of this study is to test the hypothesis that acute exogenous diroximel fumarate (Vumerity) intake will improve antioxidant capacity, thereby reducing oxidative stress and improving vascular function and walking capacity in those with PAD. Eligibility: Individuals with PAD will be deemed eligible for this study if they 1) are 50-75 years old and postmenopausal, 2) have a positive history of exercise-limiting claudication (Fontaine II or III), 3) do not have renal impairments, 4) do not have Fontaine stage IV PAD, and 5) are not currently pregnant or nursing. Age-matched controls will be deemed eligible for this study if they 1) are 50-75 years old and postmenopausal, 2) have an ABI greater than 0.9 (no PAD), 3) do not have exercise-limiting diseases or injuries, 4) do not have renal impairments, and 5) are not currently pregnant or nursing. Intervention and Evaluation: During this study, participants will be administered diroximel fumarate or a placebo, and the acute effects of diroximel fumarate on vascular function and walking capacity will be assessed. Vascular function and walking capacity will be assessed with flow-mediated dilation, arterial stiffness, head-up tilt test, blood biomarkers, near-infrared spectroscopy, and a treadmill test. Follow-up: There will be a follow-up visit to assess blood work after diroximel fumarate.

Start Date01 Dec 2024

Sponsor / Collaborator

University of Nebraska

NCT05767736 / Active, not recruitingNot Applicable

An Observational Study Utilising Data From Big MS Data Registries to Evaluate the Long-Term Safety of Vumerity and Tecfidera

The primary objective of the study is to estimate the incidence rate of serious adverse events (SAEs), including but not limited to malignancies and serious and opportunistic infections, among participants with MS treated with Vumerity, Tecfidera, other selected disease modifying therapies (DMTs [teriflunomide, beta interferons, or glatiramer acetate]), or Vumerity after switching from Tecfidera. The secondary objective of the study is to compare the incidence rate of SAEs, including but not limited to malignancies and serious and opportunistic infections, among MS participants treated with Vumerity, Tecfidera, and Vumerity after switching from Tecfidera with the incidence rate of MS participants treated with other selected DMTs (teriflunomide, beta-interferons, or glatiramer acetate), if the sample size allows.

Start Date08 Jun 2024

Sponsor / Collaborator

Biogen, Inc.

NCT05658497 / RecruitingNot Applicable

Vumerity (Diroximel Fumarate) Prospective MS Pregnancy Exposure Registry

The primary objectives of the study are to estimate the risk of major congenital malformations (MCMs) in infants born to women with multiple sclerosis (MS) who were exposed to diroximel fumarate (DRF) at any time from 2 weeks after the first day of their last menstrual period (LMP) up through the first trimester of pregnancy and to comparatively evaluate pregnancy outcomes with MCMs in women with MS who were exposed to DRF at any time from 2 weeks after the first day of their LMP through the first trimester of pregnancy with the following: i) women with MS who were unexposed to disease modifying therapies (DMTs) and, ii) women with MS who were exposed to other DMTs (e.g., Avonex and Tysabri Pregnancy Registries).
The secondary objective of the study is to evaluate pregnancy outcomes in women with DRF exposure at any time from 2 weeks after the first day of their LMP through the end of pregnancy compared with the following: i) women with MS who were unexposed to DMTs, ii) women with dimethyl fumarate (DMF) exposure, iii) women with MS who were exposed to other DMTs (e.g., Avonex and Tysabri Pregnancy Registries), and iv) women without MS (e.g., women from external, general population comparators).

Start Date27 Oct 2023

Sponsor / Collaborator

Biogen, Inc.

100 Clinical Results associated with Diroximel fumarate

100 Translational Medicine associated with Diroximel fumarate

100 Patents (Medical) associated with Diroximel fumarate

Literatures (Medical) associated with Diroximel fumarate

01 Jan 2025·COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY

Time-restricted feeding modulates gene expression related with rhythm and inflammation in Mongolian gerbils

Article

Author: Yang, Lin ; Wang, Chen-Zhu ; Zhang, Xue-Ying ; Wang, Xi-Zhi ; Wang, De-Hua ; Wang, Zhen-Shan

Time-restricted feeding (TRF) has the potential to modulate circadian rhythm and widely studied in humans and laboratory mice. However, less is known about the physiological responses to TRF in wild mammals. Here, we used Mongolian gerbils, Meriones unguiculatus, to explore the effect of 6-week TRF on gene expression related with circadian rhythm and inflammation. The TRF gerbils had higher cumulative food intake than the ad libitum (AL) group, but body mass, feeding frequency/time and metabolic rate did not differ between groups. In the hypothalamus, downregulation of rhythm-related genes Per3, Cry1 and Dbp was detected in the daytime-restricted feeding (DRF) group and Cry1 was downregulated in the nighttime-restricted feeding (NRF) group. In the liver, the expression of Per1/3, Rev-erbα/β and Dbp was lower, and Bmal1 was higher in the DRF than in AL group, while NRF gerbils showed no changes. In the colon, the expression of Bmal1 and Cry1 was higher but Per3, Rev-erbα/β and Dbp were lower in the DRF than in AL group. Further, the expression of inflammation-related genes such as NF-κB, IL-1β, IL-18 and Nlrp3 was lower in the liver of DRF gerbils, and IL-1β was lower both in the hypothalamus and liver of NRF gerbils. Moreover, the genes related with inflammation such as NF-κB, Nlrp3, IL-10/18/1β and Tnf-α were positively or negatively correlated with multiple rhythm-related genes in the central and peripheral organs. In conclusion, TRF, particularly DRF, could modulate rhythm-related genes in the central and peripheral tissues and reduce hepatic expression of inflammation-related genes in gerbils.

01 Jan 2025·BRAIN BEHAVIOR AND IMMUNITY

18 kDa Translocator protein (TSPO) is upregulated in rat brain after peripheral nerve injury and downregulated by diroximel fumarate

Article

Author: Avery, Thomas D. ; Zagrai, Sever M ; Zagrai, Sever M. ; Avery, Thomas D ; Grieco, Anamaria R. ; Loggia, Marco L ; Grace, Peter M ; Grieco, Anamaria R ; Cazuza, Rafael A ; Abell, Andrew D. ; Abell, Andrew D ; Loggia, Marco L. ; Wey, Hsiao-Ying ; Cazuza, Rafael A. ; Grace, Peter M.

Neuroimmune signaling is a key process underlying neuropathic pain. Clinical studies have demonstrated that 18 kDa translocator protein (TSPO), a putative marker of neuroinflammation, is upregulated in discrete brain regions of patients with chronic pain. However, no preclinical studies have investigated TSPO dynamics in the brain in the context of neuropathic pain and in response to analgesic treatments. We used positron emission tomography-computed tomography (PET-CT) and [¹⁸F]-PBR06 radioligand to measure TSPO levels in the brain across time after chronic constriction injury (CCI) of the sciatic nerve in both male and female rats. Up to 10 weeks post-CCI, TSPO expression was increased in discrete brain regions, including medial prefrontal cortex, somatosensory cortex, insular cortex, anterior cingulate cortex, motor cortex, ventral tegmental area, amygdala, midbrain, pons, medulla, and nucleus accumbens. TSPO was broadly upregulated across these regions at 4 weeks post CCI in males, and 10 weeks in females, though there were regional differences between the sexes. Using immunohistochemistry, we confirmed TSPO expression in these regions. We further demonstrated that TSPO was upregulated principally in microglia in the nucleus accumbens core, and astrocytes and endothelial cells in the nucleus accumbens shell. Finally, we tested whether TSPO upregulation was sensitive to diroximel fumarate, a drug that induces endogenous antioxidants via nuclear factor E2-related factor 2 (Nrf2). Diroximel fumarate alleviated neuropathic pain and reduced TSPO upregulation. Our findings indicate that TSPO is upregulated over the course of neuropathic pain development and is resolved by an antinociceptive intervention in animals with peripheral nerve injury.

01 Nov 2024·Multiple Sclerosis and Related Disorders

Safety, tolerability, and efficacy of diroximel fumarate in a cohort of Black patients with multiple sclerosis from the phase 3 EVOLVE-MS-1 study

Article

Author: Antezana, Ariel ; Schreiber, Bethany ; Branco, Filipe ; Hunter, Samuel F ; Levin, Seth ; Scaramozza, Matthew ; Lindsey, John W. ; Osborne, Benjamin ; Tian, Zhe ; Hunter, Samuel F. ; Lindsey, John W ; Lewin, James B ; Lewin, James B.

BACKGROUND:

Multiple sclerosis (MS) has not been well studied in racial and ethnic minorities, as these populations are typically underrepresented in clinical trials. Black or African Americans comprise ∼13 % of the US population, yet are represented by as little as 5 % in clinical trials. Differences in disease course and progression have been reported between races and ethnicities, so there is a need to understand the safety and efficacy of disease-modifying therapies (DMTs) in Black patients, to inform evidence-based approaches to treatment in this population.

METHODS:

EVOLVE-MS-1 (NCT0234307) was an open-label, single-arm, phase 3 study assessing the long-term safety, tolerability, and efficacy of diroximel fumarate (DRF) over 96 weeks in adults with relapsing-remitting multiple sclerosis (RRMS). Patients were either newly initiated to DRF or rolled over from completing EVOLVE-MS-2 (NCT03093324). In this post-hoc analysis of the phase 3 EVOLVE-MS-1 study, we evaluate the safety and exploratory efficacy outcomes for DRF in Black and non-Black patient subgroups.

RESULTS:

Of 1057 patients enrolled, 72 (6.8 %) were Black. In Black vs non-Black patients, mean age was 42 vs 43 years and 75 % vs 72 % were female, respectively. In both groups, median (range) duration of DRF exposure was 1.8 (0.0-2.0) years and mean Expanded Disability Status Scale (EDSS) was 2.7. The most common prior DMTs for both Black vs non-Black patients were interferons (47 % vs 37 %) and glatiramer acetate (36 % vs 24 %). DRF treatment was discontinued in 33 (46 %) Black and 224 (23 %) non-Black patients; most common reasons for discontinuation were withdrawal by patient (n = 11, 15.3 %), adverse events (AEs; n = 7, 9.7 %), and lost to follow-up (n = 7, 9.7 %) in Black patients; AEs (8.2 %) and withdrawal by patient (7.0 %) in non-Black patients. AEs were reported in 90 % Black and 89 % non-Black patients; most AEs were mild or moderate in both groups. Gastrointestinal (GI) AEs were reported in 36 % Black and 32 % non-Black patients; no Black patients discontinued due to GI AEs, vs 7 (0.7 %) non-Black patients. The most commonly reported AE was flushing (18 % Black and 28 % non-Black patients). No AEs of lymphopenia were reported in Black patients compared with 13 % of non-Black patients. Mean absolute lymphocyte count declined from baseline to week 48 by 15 % in Black patients and 29 % in non-Black patients, then plateaued and remained above the lower limit of normal (LLN; 0.91 × 10⁹/L). Adjusted annualized relapse rate (95 % confidence interval) was reduced by 78.2 % (54.6 - 89.5; p < 0.0001) in Black patients, from 12 months before to 96 weeks after DRF treatment; similar to 81.7 % (78.5 - 84.5 %; p < 0.0001) reduction in non-Black patients. Mean number of patients free from confirmed disability progression was 93.4 % by week 48, then 86.2 % vs 90.4 % by week 96 in Black vs non-Black patients, respectively.

CONCLUSION:

This study presents the first analysis of safety and efficacy of DRF in Black patients. Relapse rates remained low in Black patients on DRF, consistent with non-Black patients, and there were no new safety signals identified in the Black patient subgroup in EVOLVE-MS-1. Together, these outcomes support DRF as an effective treatment option in Black patients with RRMS.

News (Medical) associated with Diroximel fumarate

24 Oct 2024

·www.prnewswire.com

Alkermes plc Reports Third Quarter 2024 Financial Results

— Third Quarter Revenues of $378.1 Million — — Net Sales of Proprietary Products Increased Approximately 18% Year-Over-Year — — GAAP Net Income from Continuing Operations of $92.8 Million and Diluted GAAP Earnings per Share from Continuing Operations of $0.56 — — Company Reiterates 2024 Financial Expectations — DUBLIN, Oct. 24, 2024 /PRNewswire/ -- Alkermes plc (Nasdaq: ALKS) today reported financial results for the third quarter of 2024. "Our third quarter financial results reflect strong year-over-year growth of our portfolio of proprietary commercial products and position us well to meet our strategic, operational and financial priorities for the year. Looking ahead, we believe growing our proprietary commercial products and advancing our pipeline, particularly ALKS 2680, our novel, investigational, orexin 2 receptor agonist, and additional orexin development candidates, will serve as the key drivers of shareholder value. We plan to manage the business to deliver significant profitability and cash flow while investing in these strategic initiatives," said Richard Pops, Chief Executive Officer of Alkermes. "2025 has the potential to be a transformational year for Alkermes as we expect to complete the ongoing phase 2 studies in narcolepsy type 1 and narcolepsy type 2, and prepare for potential registrational studies for ALKS 2680. With the potential to transform the treatment of hypersomnolence disorders, and with broad potential applicability across other symptomatic domains, orexin 2 receptor agonists represent one of the most exciting new therapeutic categories in development and we believe a significant opportunity for Alkermes and our shareholders." Key Financial Highlights *As a result of the successful resolution of the arbitration with Janssen Pharmaceutica N.V., the nine months ended September 30, 2023 included approximately $195.4 million of back royalties (and related interest) related to U.S. net sales of long-acting INVEGA® products that would ordinarily have been recognized in prior periods. Revenue Highlights LYBALVI Revenues for the quarter were $74.7 million. Revenues and total prescriptions for the quarter grew 47% and 37%, respectively, compared to the third quarter of 2023. ARISTADAi Revenues for the quarter were $84.7 million. VIVITROL Revenues for the quarter were $113.7 million. Revenues for the quarter grew 14% compared to the third quarter of 2023, driven by the alcohol dependence indication. Manufacturing & Royalty Revenues Royalty revenues from INVEGA SUSTENNA®/XEPLION®, INVEGA TRINZA®/TREVICTA® and INVEGA HAFYERA®/BYANNLI® for the quarter were $58.4 million. VUMERITY® manufacturing and royalty revenues for the quarter were $32.6 million. Key Operating Expenses Please see Note 1 below for details regarding discontinued operations. Balance Sheet At Sept. 30, 2024, the company recorded cash, cash equivalents and total investments of $927.8 million, compared to $962.5 million at June 30, 2024. The company's total debt outstanding as of Sept. 30, 2024 was $288.8 million. Share Repurchase Program During the third quarter of 2024, the company repurchased approximately 4.4 million of the company's ordinary shares under the share repurchase program authorized in February 2024, at a total purchase price of $115.6 million. As of Sept. 30, 2024, the company had $200 million (exclusive of any fees, commissions or other related expenses) remaining under the program. Financial Expectations for 2024 Alkermes reiterates its financial expectations for 2024, as set forth in its press release dated Feb. 15, 2024. Recent Events In October 2024, the company hosted an investor event to review its portfolio of orexin 2 receptor agonists and development strategy. The company presented data from its ALKS 2680 phase 1b study in patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH), and discussed the study design for its ongoing phase 2 studies in NT1 and NT2. The company also announced its plans to initiate a phase 2 study in patients with IH in 2025. In September 2024, the company presented positive clinical data from its phase 1b study of ALKS 2680 in patients with NT2 and IH at the European Sleep Research Society's 27th Congress, Sleep Europe 2024. In August 2024, the company announced the initiation of its Vibrance-2 phase 2 study of ALKS 2680 in patients with NT2. In August 2024, the company published its latest Corporate Responsibility Report, which details how the company integrates environmental, social and governance considerations into its business. A copy of the report is available on the Responsibility section of Alkermes' website. Notes and Explanations 1. The company determined that upon the separation of its oncology business, completed on Nov. 15, 2023, the oncology business met the criteria for discontinued operations in accordance with Financial Accounting Standards Board Accounting Standards Codification 205, Discontinued Operations. Accordingly, the accompanying selected financial information has been updated to present the results of the oncology business as discontinued operations for the three and nine months ended Sept. 30, 2023. Conference Call Alkermes will host a conference call and webcast presentation with accompanying slides at 8:00 a.m. ET (1:00 p.m. BST) on Thursday, Oct. 24, 2024, to discuss these financial results and provide an update on the company. The webcast may be accessed on the Investors section of Alkermes' website at . The conference call may be accessed by dialing +1 877 407 2988 for U.S. callers and +1 201 389 0923 for international callers. In addition, a replay of the conference call may be accessed by visiting Alkermes' website. About Alkermes plc Alkermes plc is a global biopharmaceutical company that seeks to develop innovative medicines in the field of neuroscience. The company has a portfolio of proprietary commercial products for the treatment of alcohol dependence, opioid dependence, schizophrenia and bipolar I disorder, and a pipeline of clinical and preclinical candidates in development for neurological disorders, including narcolepsy and idiopathic hypersomnia. Headquartered in Ireland, Alkermes also has a corporate office and research and development center in Massachusetts and a manufacturing facility in Ohio. For more information, please visit Alkermes' website at . Non-GAAP Financial Measures This press release includes information about certain financial measures that are not prepared in accordance with generally accepted accounting principles in the U.S. (GAAP), including non-GAAP net income and EBITDA. These non-GAAP measures are not based on any standardized methodology prescribed by GAAP and are not necessarily comparable to similar measures presented by other companies. Non-GAAP net income adjusts for certain one-time and non-cash charges by excluding from GAAP results: share-based compensation expense; amortization; depreciation; non-cash net interest expense; change in the fair value of contingent consideration; certain other one-time or non-cash items; and the income tax effect of these reconciling items. EBITDA represents earnings before interest, tax, depreciation and amortization; earnings include share-based compensation expense. The company's management and board of directors utilize these non-GAAP financial measures to evaluate the company's performance. The company provides these non-GAAP financial measures of the company's performance to investors because management believes that these non-GAAP financial measures, when viewed with the company's results under GAAP and the accompanying reconciliations, are useful in identifying underlying trends in ongoing operations. However, non-GAAP net income and EBITDA are not measures of financial performance under GAAP and, accordingly, should not be considered as alternatives to GAAP measures as indicators of operating performance. Further, non-GAAP net income and EBITDA should not be considered measures of the company's liquidity. A reconciliation of GAAP to non-GAAP financial measures has been provided in the tables included in this press release. Note Regarding Forward-Looking Statements Certain statements set forth in this press release constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: the company’s expectations concerning its future financial and operating performance, business plans or prospects, including drivers of shareholder value and profitability; and the company’s expectations regarding development plans, activities and timelines for, and the potential therapeutic and commercial value of, ALKS 2680 and the company’s other orexin portfolio candidates. The company cautions that forward-looking statements are inherently uncertain. The forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those expressed or implied in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: whether the company is able to achieve its financial expectations, including those related to profitability; the unfavorable outcome of arbitration or litigation, including so-called “Paragraph IV” litigation and other patent litigation which may lead to competition from generic drug manufacturers, or other disputes related to the company’s products or products using the company’s proprietary technologies; clinical development activities may not be completed on time or at all; the results of the company’s development activities may not be positive, or predictive of final results from such activities, results of future development activities or real-world results; the U.S. Food and Drug Administration (FDA) or regulatory authorities outside the U.S. may make adverse decisions regarding the company’s products; the company and its licensees may not be able to continue to successfully commercialize their products or support revenue growth from such products; there may be a reduction in payment rate or reimbursement for the company’s products or an increase in the company’s financial obligations to government payers; the company’s products may prove difficult to manufacture, be precluded from commercialization by the proprietary rights of third parties, or have unintended side effects, adverse reactions or incidents of misuse; and those risks and uncertainties described under the heading “Risk Factors” in the company’s Annual Report on Form 10-K for the year ended Dec. 31, 2023 and in subsequent filings made by the company with the U.S. Securities and Exchange Commission (SEC), which are available on the SEC’s website at . Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by law, the company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release. VIVITROL® is a registered trademark of Alkermes, Inc.; ARISTADA®, ARISTADA INITIO® and LYBALVI® are registered trademarks of Alkermes Pharma Ireland Limited, used by Alkermes, Inc. under license; BYANNLI®, INVEGA®, INVEGA HAFYERA®, INVEGA SUSTENNA®, INVEGA TRINZA®, TREVICTA® and XEPLION® are registered trademarks of Johnson & Johnson or its affiliated companies; and VUMERITY® is a registered trademark of Biogen MA Inc., used by Alkermes under license. i The term "ARISTADA" as used in this press release refers to ARISTADA and ARISTADA INITIO®, unless the context indicates otherwise. SOURCE Alkermes plc WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Financial StatementPhase 1Phase 2Clinical Result

25 Sep 2024

·endpts.com

Baltimore sues Biogen, saying the company colluded with PBMs to minimize generic competition

Baltimore’s mayor and city council have sued Biogen, alleging that the Boston-based drug developer worked with pharmacy benefit managers to suppress generic versions of a popular multiple sclerosis drug. The lawsuit, filed in federal court in Illinois on Sept. 20, disputes a core argument that the PBM industry has tried to sell: that the rebates it negotiates with drugmakers eventually cut costs for clients. The city contends that what Biogen described as “rebates” or “fees” to the PBMs were in fact kickbacks for hampering generic versions on formularies. According to the lawsuit’s claims, the rebates Biogen paid were about 19% off Tecfidera’s list price of $90,000 a year, while generic versions were more than 90% discounted. The city alleges that Biogen’s goal was to make lower-cost generics less appealing, and to help boost the company’s newer multiple sclerosis drug, Vumerity, which launched in the fourth quarter of 2019. The lawsuit says that Biogen’s suppression strategy was implemented in part because the Covid-19 pandemic wiped out in-person sales meetings, making it more difficult to convince doctors to switch patients from Tecfidera onto Vumerity. “Biogen denied to purchasers the massive cost savings that would and should have resulted from unimpaired generic competition,” according to the complaint. Biogen declined to comment on the lawsuit. Neither the city of Baltimore nor the lawyers representing it responded to a request for comment. The three largest PBMs — CVS Caremark, Express Scripts and Optum Rx — weren’t included as defendants in the lawsuit, but are listed as co-conspirators. Those companies also didn’t immediately respond to a request for comment on Wednesday. The lawsuit was filed as a class action complaint, and it’s unclear if other municipalities or employers will follow along. While drug developers have worked to paint PBMs as the source of high prescription drug prices in the US, the two industries work closely together to negotiate prices on almost every drug the companies sell. PBMs have likewise argued that pharma companies are the ones that set prices, and that they win discounts for insured consumers. The Federal Trade Commission sued the three largest PBMs this week , arguing that their demand for higher rebates — and by association, manufacturers’ higher list prices — were manipulating the market for insulin. The industry has come under bipartisan scrutiny in Congress, but there has been little progress on legislation to further regulate its business practices.

Patent Infringement

24 Jul 2024

·www.prnewswire.com

Alkermes plc Reports Second Quarter 2024 Financial Results

— Second Quarter Revenues of $399.1 Million — — Net Sales of Proprietary Products Increased Approximately 16% Year-Over-Year — — GAAP Net Income from Continuing Operations of $94.7 Million and Diluted GAAP Earnings per Share from Continuing Operations of $0.55 — — Company Reiterates 2024 Financial Expectations — DUBLIN, July 24, 2024 /PRNewswire/ -- Alkermes plc (Nasdaq: ALKS) today reported financial results for the second quarter of 2024. "Our second quarter results reflect solid execution across our business, delivering double-digit, year-over-year growth for our proprietary commercial product portfolio and robust profitability. We enter the second half of the year in a strong financial position with clear operational priorities to drive the performance of our commercial portfolio and advance our neuroscience development pipeline, including the phase 2 program for ALKS 2680 in narcolepsy type 1 and type 2," said Richard Pops, Chief Executive Officer of Alkermes. "As a profitable, smid-cap biotech growth company with multiple commercial products and a development pipeline with significant value potential, we are executing our plan to become a leader in the field of neuroscience." Key Financial Highlights Revenues Profitability *As a result of the successful resolution of the arbitration with Janssen Pharmaceutica N.V., the three months ended June 30, 2023 included approximately $245.5 million of back royalties (and related interest) related to U.S. net sales of long-acting INVEGA® products (consisting of $195.4 million for 2022 and $50.1 million for the first quarter of 2023) that would ordinarily have been recognized in prior periods. Revenue Highlights LYBALVI Revenues for the quarter were $71.4 million. Revenues and total prescriptions for the quarter grew 52% and 44%, respectively, compared to the second quarter of 2023. ARISTADAi Revenues for the quarter were $86.0 million. New to brand prescriptions for the quarter grew 6% sequentially compared to the first quarter of 2024. VIVITROL Revenues for the quarter were $111.9 million. Revenues for the quarter grew 10% compared to the second quarter of 2023, driven by the alcohol dependence indication. Manufacturing & Royalty Revenues Royalty revenues from INVEGA SUSTENNA®/XEPLION®, INVEGA TRINZA®/TREVICTA® and INVEGA HAFYERA®/BYANNLI® for the quarter were $78.7 million. VUMERITY® manufacturing and royalty revenues for the quarter were $35.2 million. Key Operating Expenses Please see Note 1 below for details regarding discontinued operations. Balance Sheet At June 30, 2024, the company recorded cash, cash equivalents and total investments of $962.5 million, compared to $807.8 million at March 31, 2024. The company's total debt outstanding as of June 30, 2024 was $289.5 million. Share Repurchase Program During the second quarter of 2024, the company repurchased approximately 3.5 million of the company's ordinary shares under the share repurchase program authorized in February 2024, at a total purchase price of $84.7 million. As of June 30, 2024, the company had $315.3 million (exclusive of any fees, commissions or other expenses related to such repurchases) remaining under the program. Financial Expectations for 2024 Alkermes reiterates its financial expectations for 2024, as set forth in its press release dated Feb. 15, 2024. Recent Events In April 2024, the company announced positive topline results from the narcolepsy type 2 and idiopathic hypersomnia cohorts in its phase 1b proof-of-concept study evaluating ALKS 2680, the company's novel, investigational, oral orexin 2 receptor (OX2R) agonist in development as a once-daily treatment for narcolepsy. In April 2024, the company announced initiation of its Vibrance-1 phase 2 study of ALKS 2680 in patients with narcolepsy type 1. In May 2024, the company completed the sale of its development and manufacturing facility in Athlone, Ireland to Novo Nordisk. Alkermes received a cash payment for the facility and certain related assets of approximately $91 million. In May and June 2024, the company presented research related to its psychiatry franchise products—LYBALVI (olanzapine and samidorphan) and ARISTADA (aripiprazole lauroxil)—at several scientific conferences. The conferences included: American Psychiatric Association (APA) Annual Meeting, American Society of Clinical Psychopharmacology (ASCP) Annual Meeting, and Psych Congress Elevate. In June 2024, the company presented new research related to ALKS 2680 and narcolepsy, including new data from the full narcolepsy type 1 cohort in its phase 1b, proof-of-concept study evaluating ALKS 2680, at SLEEP 2024, the 38th annual meeting of the Associated Professional Sleep Societies (APSS). Notes and Explanations 1. The company determined that upon the separation of its oncology business, completed on Nov. 15, 2023, the oncology business met the criteria for discontinued operations in accordance with Financial Accounting Standards Board Accounting Standards Codification 205, Discontinued Operations. Accordingly, the accompanying selected financial information has been updated to present the results of the oncology business as discontinued operations for the three and six months ended June 30, 2023. Conference Call Alkermes will host a conference call and webcast presentation with accompanying slides at 8:00 a.m. ET (1:00 p.m. BST) on Wednesday, July 24, 2024, to discuss these financial results and provide an update on the company. The webcast may be accessed on the Investors section of Alkermes' website at . The conference call may be accessed by dialing +1 877 407 2988 for U.S. callers and +1 201 389 0923 for international callers. In addition, a replay of the conference call may be accessed by visiting Alkermes' website. About Alkermes plc Alkermes plc is a global biopharmaceutical company that seeks to develop innovative medicines in the field of neuroscience. The company has a portfolio of proprietary commercial products for the treatment of alcohol dependence, opioid dependence, schizophrenia and bipolar I disorder, and a pipeline of clinical and preclinical candidates in development for neurological disorders, including narcolepsy. Headquartered in Ireland, Alkermes also has a corporate office and research and development center in Massachusetts and a manufacturing facility in Ohio. For more information, please visit Alkermes' website at . Non-GAAP Financial Measures This press release includes information about certain financial measures that are not prepared in accordance with generally accepted accounting principles in the U.S. (GAAP), including non-GAAP net income and EBITDA. These non-GAAP measures are not based on any standardized methodology prescribed by GAAP and are not necessarily comparable to similar measures presented by other companies. Non-GAAP net income adjusts for certain one-time and non-cash charges by excluding from GAAP results: share-based compensation expense; amortization; depreciation; non-cash net interest expense; change in the fair value of contingent consideration; certain other one-time or non-cash items; and the income tax effect of these reconciling items. EBITDA represents earnings before interest, tax, depreciation and amortization; earnings include share-based compensation expense. The company's management and board of directors utilize these non-GAAP financial measures to evaluate the company's performance. The company provides these non-GAAP financial measures of the company's performance to investors because management believes that these non-GAAP financial measures, when viewed with the company's results under GAAP and the accompanying reconciliations, are useful in identifying underlying trends in ongoing operations. However, non-GAAP net income and EBITDA are not measures of financial performance under GAAP and, accordingly, should not be considered as alternatives to GAAP measures as indicators of operating performance. Further, non-GAAP net income and EBITDA should not be considered measures of the company's liquidity. A reconciliation of GAAP to non-GAAP financial measures has been provided in the tables included in this press release. Note Regarding Forward-Looking Statements Certain statements set forth in this press release constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: the company's expectations concerning its future financial and operating performance, business plans or prospects, including profitability; and the potential therapeutic and commercial value of ALKS 2680 and the company's development pipeline. The company cautions that forward-looking statements are inherently uncertain. The forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those expressed or implied in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: whether the company is able to sustain profitability; the unfavorable outcome of arbitration or litigation, including so-called "Paragraph IV" litigation and other patent litigation which may lead to competition from generic drug manufacturers, or other disputes related to the company's products or products using the company's proprietary technologies; clinical development activities may not be completed on time or at all; the results of the company's development activities may not be positive, or predictive of final results from such activities, results of future development activities or real-world results; the U.S. Food and Drug Administration (FDA) or regulatory authorities outside the U.S. may make adverse decisions regarding the company's products; the company and its licensees may not be able to continue to successfully commercialize their products or support revenue growth from such products; there may be a reduction in payment rate or reimbursement for the company's products or an increase in the company's financial obligations to government payers; the company's products may prove difficult to manufacture, be precluded from commercialization by the proprietary rights of third parties, or have unintended side effects, adverse reactions or incidents of misuse; and those risks and uncertainties described under the heading "Risk Factors" in the company's Annual Report on Form 10-K for the year ended Dec. 31, 2023 and in subsequent filings made by the company with the U.S. Securities and Exchange Commission (SEC), which are available on the SEC's website at . Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by law, the company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release. VIVITROL® is a registered trademark of Alkermes, Inc.; ARISTADA®, ARISTADA INITIO® and LYBALVI® are registered trademarks of Alkermes Pharma Ireland Limited, used by Alkermes, Inc. under license; BYANNLI®, INVEGA®, INVEGA HAFYERA®, INVEGA SUSTENNA®, INVEGA TRINZA®, TREVICTA® and XEPLION® are registered trademarks of Johnson & Johnson or its affiliated companies; and VUMERITY® is a registered trademark of Biogen MA Inc., used by Alkermes under license. i The term "ARISTADA" as used in this press release refers to ARISTADA and ARISTADA INITIO®, unless the context indicates otherwise. SOURCE Alkermes plc

Phase 1Financial StatementPhase 2Clinical ResultASCO

100 Deals associated with Diroximel fumarate

External Link

KEGG	Wiki	ATC	Drug Bank
D11154	Diroximel fumarate	L03	DB14783

R&D Status

Approved

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Indication	Country/Location	Organization	Date
Multiple Sclerosis, Relapsing-Remitting	EU	Biogen Netherlands BV	15 Nov 2021
Multiple Sclerosis, Relapsing-Remitting	IS	Biogen Netherlands BV	15 Nov 2021
Multiple Sclerosis, Relapsing-Remitting	LI	Biogen Netherlands BV	15 Nov 2021
Multiple Sclerosis, Relapsing-Remitting	NO	Biogen Netherlands BV	15 Nov 2021
Multiple Sclerosis	CH	Biogen, Inc.	20 Sep 2021
Multiple sclerosis relapse	US	Biogen, Inc.	29 Oct 2019

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Gangliosidosis, GM1	Phase 3	US	Alkermes, Inc.	10 Dec 2015
Gangliosidosis, GM1	Phase 3	US	Biogen, Inc.	10 Dec 2015
Gangliosidosis, GM1	Phase 3	BE	Alkermes, Inc.	10 Dec 2015
Gangliosidosis, GM1	Phase 3	BE	Biogen, Inc.	10 Dec 2015
Gangliosidosis, GM1	Phase 3	BG	Alkermes, Inc.	10 Dec 2015
Gangliosidosis, GM1	Phase 3	BG	Biogen, Inc.	10 Dec 2015
Gangliosidosis, GM1	Phase 3	CA	Biogen, Inc.	10 Dec 2015
Gangliosidosis, GM1	Phase 3	CA	Alkermes, Inc.	10 Dec 2015
Gangliosidosis, GM1	Phase 3	DE	Biogen, Inc.	10 Dec 2015
Gangliosidosis, GM1	Phase 3	DE	Alkermes, Inc.	10 Dec 2015

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02634307 (EVOLVE-MS-1, Pubmed)	Phase 3	Multiple Sclerosis, Relapsing-Remitting lymphopenia \| ALC decline	-	Diroximel Fumarate	lqmnslvjvf(nitcvbzphl) = takeylcmal iijiknrxis (ruangqyysc )	Positive	27 Jun 2024
NCT02634307 (EVOLVE-MS-1, Pubmed)	Phase 3	Multiple Sclerosis, Relapsing-Remitting	1,057	Diroximel fumarate	gedhfpxlya(glfftmnyrh) = elhtetvyrb knlowhpkqy (jivkahtjtb )	Positive	15 Jun 2024
				Dimethyl fumarate	gedhfpxlya(glfftmnyrh) = dzslexkqyf knlowhpkqy (jivkahtjtb )
ECTRIMS2023	Not Applicable	Multiple Sclerosis	29	Dimethyl Fumarate (DMF)	nnfqseumqf(nkzzxmxnlw) = The incidence of lymphopenia (ALC <910) in this cohort of PwMS who transitioned from DMF to DRF increased from 24% at baseline to 52% 12 months after treatment change. cuskzwwoju (bczsiedscw ) View more	Positive	01 Oct 2023
ECTRIMS2023	Not Applicable	Neuroinflammation	-	Diroximel fumarate (DRF)	xaxpbyfexq(kdengvhugo) = significantly reduced IFNγ secretion in splenocytes isolated from DRF treated mice zgumpmdqcp (vydmzsjdre ) View more	Positive	30 Sep 2023
				Vehicle (methocel)
ECTRIMS2023	Not Applicable	Lymphopenia	72	Dimethyl Fumarate (DMF)	ebpunmshph(vfekocmgtq) = qbmebwqgef btpyofahbm (jpeftalhap )	-	30 Sep 2023
				Diroximel Fumarate (DRF)	ebpunmshph(vfekocmgtq) = bppatgfpex btpyofahbm (jpeftalhap )
ACTRIMS2023	Not Applicable	Multiple Sclerosis	11	Diroximel Fumarate	cyjorucwlh(ukabczpwvh) = subnbkqahc oxodfzrfzm (czfijujpzu ) View more	Positive	30 May 2023
				Dimethyl Fumarate	cyjorucwlh(ukabczpwvh) = vxpoudnqhk oxodfzrfzm (czfijujpzu ) View more
SUNBEAM (RPC01-301), RADIANCE phase 3 (RPC01-201B), EVOLVE-MS-1 (ACTRIMS2023)	Phase 3	Multiple Sclerosis, Relapsing-Remitting	-	Ozanimod 1.0 mg	wvpftypvai(cgrutyxktr): risk ratio = 0.924 (95% CI, 0.646 - 1.324) View more	Positive	30 May 2023
				Diroximel fumarate 462 mg
EVOLVE-MS-1, OPTIMUM (Pubmed)	Phase 3	Multiple sclerosis relapse	-	Diroximel fumarate	zgaeldppac(nrfszhrrnj) = bbamzhhfvf svgcztnmdp (umewaksekj )	-	08 May 2023
NCT02634307 (EVOLVE-MS-1, AAN2023)	Phase 3	Multiple Sclerosis	1,057	Diroximel fumarate	xvidwtvsrz(ohvsrfclvt) = rtpxocavyj shriohzjbk (pzmqfcndlz ) View more	Positive	25 Apr 2023
				Placebo	xvidwtvsrz(ohvsrfclvt) = mmkvejuqfq shriohzjbk (pzmqfcndlz ) View more
NCT02634307 (EVOLVE-MS-1, AAN2023)	Phase 3	Multiple Sclerosis, Relapsing-Remitting	239	Diroximel Fumarate	hximmulnvc(nbtalvhray) = 23 (9.6%) patients discontinued DRF due to adverse events rhtggvxnnc (dzduihoeuh ) View more	Positive	25 Apr 2023

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