Anaphylaxis

—ARIKAYCE® (amikacin liposome inhalation suspension) Total Revenue of $93.4 Million for the Third Quarter of 2024, Reflecting 18% Growth Over the Third Quarter of 2023— —NDA Submission for Brensocatib in Bronchiectasis Remains on Track for the Fourth Quarter of 2024 with Potential U.S. Launch Still Expected in Mid-2025— —Expanded U.S. Sales Force is Now Fully Deployed; Focusing on Bronchiectasis Disease-State Awareness and Supporting the Growth of ARIKAYCE Prior to the Anticipated Launch of Brensocatib— —Ends the Third Quarter with ~$1.5 Billion in Cash, Cash Equivalents, and Marketable Securities— —Renegotiates Term Loan with Pharmakon Resulting in a Lower Cost of Capital and an Additional $150 Million in Proceeds to be Received in the Fourth Quarter— —Reiterates 2024 Global ARIKAYCE Revenue Guidance in the Range of $340 Million to $360 Million, Reflecting Double-Digit Growth Compared to 2023— BRIDGEWATER, N.J., Oct. 31, 2024 /PRNewswire/ -- Insmed Incorporated (Nasdaq: INSM), a people-first global biopharmaceutical company striving to deliver first- and best-in-class therapies to transform the lives of patients facing serious diseases, today reported financial results for the third quarter ended September 30, 2024, and provided a business update. "I am pleased with the progress the Company is making across multiple ongoing initiatives this quarter." said Will Lewis, Chair and Chief Executive Officer of Insmed. "We remain on track to file our NDA for brensocatib in the fourth quarter of 2024 and continue to expect a potential U.S. launch in the middle of 2025. We have also made great progress on the clinical side, with the ENCORE and PAH studies nearing full enrollment. All of this has been accomplished while delivering yet another quarter of double-digit growth for ARIKAYCE in each of our three commercial regions. With our demonstrated ability to execute both clinically and commercially, and a strengthened balance sheet due to actions we have taken to lower our cost of capital while adding to our cash balance, we believe we are well-positioned to deliver on the tremendous opportunities ahead." Recent Pillar Highlights Pillar 1: ARIKAYCE ARIKAYCE global revenue grew 18% in the third quarter of 2024 compared to the third quarter of 2023, reflecting an all-time revenue high and double-digit year-over-year growth in the U.S., Japan, and Europe and rest of world. Insmed has closed screening of new patients for the ENCORE study and is now expected to exceed its target enrollment of 400 patients with newly diagnosed or recurrent Mycobacterium avium complex (MAC) lung infection who have not started antibiotics. The Company is scheduled to meet with the U.S. Food and Drug Administration (FDA) during the fourth quarter to discuss the possibility of an accelerated approval to expand the label for ARIKAYCE to include all patients with MAC lung infection, based on the positive Phase 3 ARISE trial data. Insmed continues to expect that the full data from the ongoing ENCORE trial will be required for approval. Pillar 2: Brensocatib Insmed remains on track to file a New Drug Application (NDA) with the FDA for brensocatib in patients with bronchiectasis in the fourth quarter of 2024. If priority review is granted and brensocatib is approved, Insmed anticipates a U.S. launch in mid-2025. Launches in Europe and Japan are expected in the first half of 2026, pending approvals. New subpopulation data from 19 pre-specified categories of patients in the ASPEN study were presented in October 2024 at the American College of Chest Physicians Annual Meeting in Boston. The annualized rate of pulmonary exacerbations favored brensocatib at both the 10 mg and 25 mg doses over placebo for almost all subgroups. In a separate analysis, least squares mean difference for brensocatib 25 mg demonstrated a reduced decline in post-bronchodilator forced expiratory volume in 1 second (FEV1) at Week 52 versus placebo for all prespecified subgroups. Insmed is advancing launch readiness activities in the U.S. and has hired, trained, and deployed 120 additional therapeutic sales specialists in advance of launch, focused on bronchiectasis disease-state awareness with an expanded group of pulmonologists while also supporting the growth of ARIKAYCE. The Company continues to enroll patients in the Phase 2b BiRCh trial of brensocatib in patients with chronic rhinosinusitis without nasal polyps (CRSsNP) and anticipates providing top-line data from the study in the second half of 2025. The Company is preparing to activate the first U.S. clinical site for its Phase 2 study of brensocatib in patients with hidradenitis suppurativa (HS) by the end of 2024. Pillar 3: TPIP Enrollment remains ongoing in the Phase 2 study of treprostinil palmitil inhalation powder (TPIP) in patients with pulmonary arterial hypertension (PAH), with more than 90% of the target enrollment currently complete. Insmed remains on track to report topline results from the PAH study in the second half of 2025. The Company continues to anticipate initiating a Phase 3 study of TPIP in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD) in the second half of 2025. Pillar 4: Early-Stage Research Insmed's early-stage research efforts include more than 30 identified pre-clinical programs in development, all of which have the potential to become first-in-class or best-in-class therapies. The Company continues to anticipate the totality of its early-stage research programs will comprise less than 20% of overall spend. Corporate Updates Insmed has taken the following actions intended to further strengthen its balance sheet and financial position: (i) During the third quarter of 2024, the Company completed the redemption of its $225 million convertible notes due in January 2025. Insmed issued approximately 5.7 million shares of common stock in connection with the redemption and earlier conversions of notes. (ii) The Company raised an additional $371 million in net proceeds under its at-the-market equity offering program during the third quarter, at an average sales price of $75.64 per share. (iii) In October 2024, Insmed entered into an agreement to amend its $350 million term loan with investment funds managed by Pharmakon Advisors, LP. Under the terms of the amended agreement, investment funds managed by Pharmakon Advisors, LP will provide an additional $150 million in proceeds, to be received in the fourth quarter of 2024. The maturity date for the full principal amount was extended to 2029, and will carry a reduced fixed-interest rate in the high-single digits. In October 2024, Insmed announced that it has earned the No. 1 ranking in Science's 2024 Top Employers Survey, marking the fourth consecutive year in which Insmed achieved the top ranking. The annual survey polls employees in biotechnology, pharmaceutical, and related industries to determine the 20 best employers, as well as their driving characteristics. Third-Quarter 2024 Financial Results Total revenue for the quarter ended September 30, 2024, was $93.4 million, reflecting 18% year-over-year growth compared to total revenue of $79.1 million for the third quarter of 2023. Total revenue for third-quarter 2024 included ARIKAYCE net sales of $66.9 million in the U.S., $21.0 million in Japan, and $5.6 million in Europe and rest of world. Third-quarter 2024 sales demonstrated year-over-year growth of 13% in the U.S., 31% in Japan, and 45% in Europe and rest of world, reflecting continued growth trends for ARIKAYCE in these regions. Cost of product revenues (excluding amortization of intangibles) was $21.2 million for the third quarter of 2024, compared to $16.7 million for the third quarter of 2023, primarily reflecting increased sales volumes of ARIKAYCE. Research and development (R&D) expenses were $150.8 million for the third quarter of 2024, compared to $109.1 million for the third quarter of 2023. The year-over-year increase in R&D expenses was primarily driven by increases in manufacturing and compensation and benefit-related expenses. Selling, general and administrative (SG&A) expenses for the third quarter of 2024 were $118.9 million, compared to $90.6 million for the third quarter of 2023. The year-over-year increase in SG&A expenses resulted primarily from increases in compensation and benefit-related expenses and stock-based compensation costs due to an increase in headcount associated with launch readiness activities for brensocatib. For the third quarter of 2024, Insmed reported a net loss of $220.5 million, or $1.27 per share, compared to a net loss of $158.9 million, or $1.11 per share, for the third quarter of 2023. Balance Sheet, Financial Guidance, and Planned Investments As of September 30, 2024, Insmed had cash, cash equivalents, and marketable securities totaling $1,467.9 million. Insmed is reiterating its guidance for full-year 2024 global ARIKAYCE revenues in the range of $340 million to $360 million, representing 15% year-over-year growth at the midpoint compared to 2023. Insmed continues to anticipate that over 80% of total expenditures will be on its clinical and commercial programs, and that less than 20% of overall spend will be on its early-stage research programs, reflecting the Company's historical approach to spending. The Company plans to continue to invest in the following key activities in 2024: (i) commercialization and continued growth of ARIKAYCE in its current indication globally, as well as advancement of the clinical trial program intended to potentially support label expansion to include all patients with a MAC lung infection and to satisfy the post-marketing requirement for full approval of its current indication; (ii) advancement of brensocatib, including: a. activities related to regulatory filing and commercial launch readiness for bronchiectasis and b. the ongoing Phase 2 BiRCh trial in patients with CRSsNP and the anticipated Phase 2 program in HS; (iii) advancement of its clinical development programs for TPIP; and (iv) development of its early-stage research programs. Conference Call Insmed will host a conference call beginning today at 8:00 AM Eastern Time. Shareholders and other interested parties may participate in the conference call by dialing (888) 210-2654 (U.S.) and (646) 960-0278 (international) and referencing access code 7862189. The call will also be webcast live on the Company's website at . A replay of the conference call will be accessible approximately 1 hour after its completion through November 7, 2024, by dialing (800) 770-2030 (U.S.) and (609) 800-9909 (international) and referencing access code 7862189. A webcast of the call will also be archived for 90 days under the Investor Relations section of the Company's website at . About ARIKAYCE ARIKAYCE is approved in the United States as ARIKAYCE® (amikacin liposome inhalation suspension), in Europe as ARIKAYCE® Liposomal 590 mg Nebuliser Dispersion, and in Japan as ARIKAYCE® inhalation 590 mg (amikacin sulfate inhalation drug product). Current international treatment guidelines recommend the use of ARIKAYCE for appropriate patients. ARIKAYCE is a novel, inhaled, once-daily formulation of amikacin, an established antibiotic that was historically administered intravenously and associated with severe toxicity to hearing, balance, and kidney function. Insmed's proprietary PULMOVANCE® liposomal technology enables the delivery of amikacin directly to the lungs, where liposomal amikacin is taken up by lung macrophages where the infection resides, while limiting systemic exposure. ARIKAYCE is administered once daily using the Lamira® Nebulizer System manufactured by PARI Pharma GmbH (PARI). About PARI Pharma and the Lamira® Nebulizer System ARIKAYCE is delivered by a novel inhalation device, the Lamira® Nebulizer System, developed by PARI. Lamira® is a quiet, portable nebulizer that enables efficient aerosolization of ARIKAYCE via a vibrating, perforated membrane. Based on PARI's 100-year history working with aerosols, PARI is dedicated to advancing inhalation therapies by developing innovative delivery platforms to improve patient care. About Brensocatib Brensocatib is a small molecule, oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP1) being developed by Insmed for the treatment of patients with bronchiectasis, CRSsNP, and other neutrophil-mediated diseases. DPP1 is an enzyme responsible for activating neutrophil serine proteases (NSPs), such as neutrophil elastase, in neutrophils when they are formed in the bone marrow. Neutrophils are the most common type of white blood cell and play an essential role in pathogen destruction and inflammatory mediation. In chronic inflammatory lung diseases, neutrophils accumulate in the airways and result in excessive active NSPs that cause lung destruction and inflammation. Brensocatib may decrease the damaging effects of inflammatory diseases such as bronchiectasis by inhibiting DPP1 and its activation of NSPs. Brensocatib is an investigational drug product that has not been approved for any indication in any jurisdiction. About TPIP Treprostinil palmitil inhalation powder (TPIP) is a dry powder formulation of treprostinil palmitil, a treprostinil prodrug consisting of treprostinil linked by an ester bond to a 16-carbon chain. Developed entirely in Insmed's laboratories, TPIP is a potentially highly differentiated prostanoid being evaluated for the treatment of patients with PAH, PH-ILD, and other rare and serious pulmonary disorders. TPIP is administered in a capsule-based inhalation device. TPIP is an investigational drug product that has not been approved for any indication in any jurisdiction. IMPORTANT SAFETY INFORMATION AND BOXED WARNING FOR ARIKAYCE IN THE U.S. Hypersensitivity Pneumonitis has been reported with the use of ARIKAYCE in the clinical trials. Hypersensitivity pneumonitis (reported as allergic alveolitis, pneumonitis, interstitial lung disease, allergic reaction to ARIKAYCE) was reported at a higher frequency in patients treated with ARIKAYCE plus background regimen (3.1%) compared to patients treated with a background regimen alone (0%). Most patients with hypersensitivity pneumonitis discontinued treatment with ARIKAYCE and received treatment with corticosteroids. If hypersensitivity pneumonitis occurs, discontinue ARIKAYCE and manage patients as medically appropriate. Hemoptysis has been reported with the use of ARIKAYCE in the clinical trials. Hemoptysis was reported at a higher frequency in patients treated with ARIKAYCE plus background regimen (17.9%) compared to patients treated with a background regimen alone (12.5%). If hemoptysis occurs, manage patients as medically appropriate. Bronchospasm has been reported with the use of ARIKAYCE in the clinical trials. Bronchospasm (reported as asthma, bronchial hyperreactivity, bronchospasm, dyspnea, dyspnea exertional, prolonged expiration, throat tightness, wheezing) was reported at a higher frequency in patients treated with ARIKAYCE plus background regimen (28.7%) compared to patients treated with a background regimen alone (10.7%). If bronchospasm occurs during the use of ARIKAYCE, treat patients as medically appropriate. Exacerbations of underlying pulmonary disease has been reported with the use of ARIKAYCE in the clinical trials. Exacerbations of underlying pulmonary disease (reported as chronic obstructive pulmonary disease (COPD), infective exacerbation of COPD, infective exacerbation of bronchiectasis) have been reported at a higher frequency in patients treated with ARIKAYCE plus background regimen (14.8%) compared to patients treated with background regimen alone (9.8%). If exacerbations of underlying pulmonary disease occur during the use of ARIKAYCE, treat patients as medically appropriate. Anaphylaxis and Hypersensitivity Reactions: Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking ARIKAYCE. Signs and symptoms include acute onset of skin and mucosal tissue hypersensitivity reactions (hives, itching, flushing, swollen lips/tongue/uvula), respiratory difficulty (shortness of breath, wheezing, stridor, cough), gastrointestinal symptoms (nausea, vomiting, diarrhea, crampy abdominal pain), and cardiovascular signs and symptoms of anaphylaxis (tachycardia, low blood pressure, syncope, incontinence, dizziness). Before therapy with ARIKAYCE is instituted, evaluate for previous hypersensitivity reactions to aminoglycosides. If anaphylaxis or a hypersensitivity reaction occurs, discontinue ARIKAYCE and institute appropriate supportive measures. Ototoxicity has been reported with the use of ARIKAYCE in the clinical trials. Ototoxicity (including deafness, dizziness, presyncope, tinnitus, and vertigo) were reported with a higher frequency in patients treated with ARIKAYCE plus background regimen (17%) compared to patients treated with background regimen alone (9.8%). This was primarily driven by tinnitus (7.6% in ARIKAYCE plus background regimen vs 0.9% in the background regimen alone arm) and dizziness (6.3% in ARIKAYCE plus background regimen vs 2.7% in the background regimen alone arm). Closely monitor patients with known or suspected auditory or vestibular dysfunction during treatment with ARIKAYCE. If ototoxicity occurs, manage patients as medically appropriate, including potentially discontinuing ARIKAYCE. Nephrotoxicity was observed during the clinical trials of ARIKAYCE in patients with MAC lung disease but not at a higher frequency than background regimen alone. Nephrotoxicity has been associated with the aminoglycosides. Close monitoring of patients with known or suspected renal dysfunction may be needed when prescribing ARIKAYCE. Neuromuscular Blockade: Patients with neuromuscular disorders were not enrolled in ARIKAYCE clinical trials. Patients with known or suspected neuromuscular disorders, such as myasthenia gravis, should be closely monitored since aminoglycosides may aggravate muscle weakness by blocking the release of acetylcholine at neuromuscular junctions. Embryo-Fetal Toxicity: Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides, including ARIKAYCE, may be associated with total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. Patients who use ARIKAYCE during pregnancy, or become pregnant while taking ARIKAYCE should be apprised of the potential hazard to the fetus. Contraindications: ARIKAYCE is contraindicated in patients with known hypersensitivity to any aminoglycoside. Most Common Adverse Reactions: The most common adverse reactions in Trial 1 at an incidence ≥5% for patients using ARIKAYCE plus background regimen compared to patients treated with background regimen alone were dysphonia (47% vs 1%), cough (39% vs 17%), bronchospasm (29% vs 11%), hemoptysis (18% vs 13%), ototoxicity (17% vs 10%), upper airway irritation (17% vs 2%), musculoskeletal pain (17% vs 8%), fatigue and asthenia (16% vs 10%), exacerbation of underlying pulmonary disease (15% vs 10%), diarrhea (13% vs 5%), nausea (12% vs 4%), pneumonia (10% vs 8%), headache (10% vs 5%), pyrexia (7% vs 5%), vomiting (7% vs 4%), rash (6% vs 2%), decreased weight (6% vs 1%), change in sputum (5% vs 1%), and chest discomfort (5% vs 3%). Drug Interactions: Avoid concomitant use of ARIKAYCE with medications associated with neurotoxicity, nephrotoxicity, and ototoxicity. Some diuretics can enhance aminoglycoside toxicity by altering aminoglycoside concentrations in serum and tissue. Avoid concomitant use of ARIKAYCE with ethacrynic acid, furosemide, urea, or intravenous mannitol. Overdosage: Adverse reactions specifically associated with overdose of ARIKAYCE have not been identified. Acute toxicity should be treated with immediate withdrawal of ARIKAYCE, and baseline tests of renal function should be undertaken. Hemodialysis may be helpful in removing amikacin from the body. In all cases of suspected overdosage, physicians should contact the Regional Poison Control Center for information about effective treatment. U.S. INDICATION LIMITED POPULATION: ARIKAYCE® is indicated in adults, who have limited or no alternative treatment options, for the treatment of Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy. As only limited clinical safety and effectiveness data for ARIKAYCE are currently available, reserve ARIKAYCE for use in adults who have limited or no alternative treatment options. This drug is indicated for use in a limited and specific population of patients. This indication is approved under accelerated approval based on achieving sputum culture conversion (defined as 3 consecutive negative monthly sputum cultures) by Month 6. Clinical benefit has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials . Limitation of Use : ARIKAYCE has only been studied in patients with refractory MAC lung disease defined as patients who did not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy. The use of ARIKAYCE is not recommended for patients with non-refractory MAC lung disease. Patients are encouraged to report negative side effects of prescription drugs to the FDA. Visit , or call 1‑800‑FDA‑1088. You can also call the Company at 1-844-4-INSMED. Please see Full Prescribing Information . About Insmed Insmed Incorporated is a people-first global biopharmaceutical company striving to deliver first- and best-in-class therapies to transform the lives of patients facing serious diseases. The Company is advancing a diverse portfolio of approved and mid- to late-stage investigational medicines as well as cutting-edge drug discovery focused on serving patient communities where the need is greatest. Insmed's most advanced programs are in pulmonary and inflammatory conditions, including a therapy approved in the United States, Europe, and Japan to treat a chronic, debilitating lung disease. The Company's early-stage research programs encompass a wide range of technologies and modalities, including gene therapy, AI-driven protein engineering, protein manufacturing, RNA end-joining, and synthetic rescue. Headquartered in Bridgewater, New Jersey, Insmed has offices and research locations throughout the United States, Europe, and Japan. Insmed is proud to be recognized as one of the best employers in the biopharmaceutical industry, including spending four consecutive years as the No. 1 Science Top Employer. Visit to learn more. Forward-looking Statements This press release contains forward-looking statements that involve substantial risks and uncertainties. "Forward-looking statements," as that term is defined in the Private Securities Litigation Reform Act of 1995, are statements that are not historical facts and involve a number of risks and uncertainties. Words herein such as "may," "will," "should," "could," "would," "expects," "plans," "anticipates," "believes," "estimates," "projects," "predicts," "intends," "potential," "continues," and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) may identify forward-looking statements. The forward-looking statements in this press release are based upon the Company's current expectations and beliefs, and involve known and unknown risks, uncertainties and other factors, which may cause the Company's actual results, performance and achievements and the timing of certain events to differ materially from the results, performance, achievements or timings discussed, projected, anticipated or indicated in any forward-looking statements. Such risks, uncertainties and other factors include, among others, the following: failure to continue to successfully commercialize ARIKAYCE, our only approved product, in the U.S., Europe or Japan (amikacin liposome inhalation suspension, Liposomal 590 mg Nebuliser Dispersion, and amikacin sulfate inhalation drug product, respectively), or to maintain US, European or Japanese approval for ARIKAYCE; our inability to obtain full approval of ARIKAYCE from the FDA, including the risk that we will not successfully or in a timely manner complete the confirmatory post-marketing clinical trial required for full approval of ARIKAYCE, or our failure to obtain regulatory approval to expand ARIKAYCE's indication to a broader patient population; failure to obtain, or delays in obtaining, regulatory approvals for brensocatib, TPIP or our other product candidates in the US, Europe or Japan or for ARIKAYCE outside the US, Europe or Japan, including separate regulatory approval for Lamira® in each market and for each usage; failure to successfully commercialize brensocatib, TPIP or our other product candidates, if approved by applicable regulatory authorities, or to maintain applicable regulatory approvals for brensocatib, TPIP or our other product candidates, if approved; uncertainties or changes in the degree of market acceptance of ARIKAYCE or, if approved, brensocatib or TPIP by physicians, patients, third-party payors and others in the healthcare community; our inability to obtain and maintain adequate reimbursement from government or third-party payors for ARIKAYCE or, if approved, brensocatib or TPIP, or acceptable prices for ARIKAYCE or, if approved, brensocatib or TPIP; inaccuracies in our estimates of the size of the potential markets for ARIKAYCE, brensocatib, TPIP or our other product candidates or in data we have used to identify physicians, expected rates of patient uptake, duration of expected treatment, or expected patient adherence or discontinuation rates; failure of third parties on which the Company is dependent to manufacture sufficient quantities of ARIKAYCE, brensocatib, or TPIP for commercial or clinical needs, to conduct the Company's clinical trials, or to comply with the Company's agreements or laws and regulations that impact the Company's business; the risks and uncertainties associated with, and the perceived benefits of, our secured senior loan with certain funds managed by Pharmakon Advisors L.P. and our royalty financing with OrbiMed Royalty & Credit Opportunities IV, LP, including our ability to maintain compliance with the covenants in the agreements for the senior secured loan and royalty financing and the impact of the restrictions on our operations under these agreements; our inability to create or maintain an effective direct sales and marketing infrastructure or to partner with third parties that offer such an infrastructure for distribution of ARIKAYCE or any of our product candidates that are approved in the future; failure to successfully conduct future clinical trials for ARIKAYCE, brensocatib, TPIP and our other product candidates and our potential inability to enroll or retain sufficient patients to conduct and complete the trials or generate data necessary for regulatory approval of our product candidates or to permit the use of ARIKAYCE in the broader population of patients with MAC lung disease, among other things; development of unexpected safety or efficacy concerns related to ARIKAYCE, brensocatib, TPIP or our other product candidates; risks that our clinical studies will be delayed, that serious side effects will be identified during drug development, or that any protocol amendments submitted will be rejected; the risk that interim, topline or preliminary data from our clinical trials that we announce or publish from time to time may change as more patient data become available or may be interpreted differently if additional data are disclosed, or that blinded data will not be predictive of unblinded data; risk that our competitors may obtain orphan drug exclusivity for a product that is essentially the same as a product we are developing for a particular indication; our inability to attract and retain key personnel or to effectively manage our growth; our inability to successfully integrate our recent acquisitions and appropriately manage the amount of management's time and attention devoted to integration activities; risks that our acquired technologies, products and product candidates are not commercially successful; inability to adapt to our highly competitive and changing environment; inability to access, upgrade or expand our technology systems or difficulties in updating our existing technology or developing or implementing new technology; risk that we are unable to maintain our significant customers; risk that government healthcare reform materially increases our costs and damages our financial condition; business or economic disruptions due to catastrophes or other events, including natural disasters or public health crises; risk that our current and potential future use of AI and machine learning may not be successful; deterioration in general economic conditions in the US, Europe, Japan and globally, including the effect of prolonged periods of inflation, affecting us, our suppliers, third-party service providers and potential partners; the risk that we could become involved in costly intellectual property disputes, be unable to adequately protect our intellectual property rights or prevent disclosure of our trade secrets and other proprietary information, and incur costs associated with litigation or other proceedings related to such matters; restrictions or other obligations imposed on us by agreements related to ARIKAYCE, brensocatib or our other product candidates, including our license agreements with PARI and AstraZeneca AB , and failure to comply with our obligations under such agreements; the cost and potential reputational damage resulting from litigation to which we are or may become a party, including product liability claims; risk that our operations are subject to a material disruption in the event of a cybersecurity attack or issue; our limited experience operating internationally; changes in laws and regulations applicable to our business, including any pricing reform and laws that impact our ability to utilize certain third parties in the research, development or manufacture of our product candidates, and failure to comply with such laws and regulations; our history of operating losses, and the possibility that we never achieve or maintain profitability; goodwill impairment charges affecting our results of operations and financial condition; inability to repay our existing indebtedness and uncertainties with respect to our ability to access future capital; and delays in the execution of plans to build out an additional third-party manufacturing facility approved by the appropriate regulatory authorities and unexpected expenses associated with those plans. The Company may not actually achieve the results, plans, intentions or expectations indicated by the Company's forward-looking statements because, by their nature, forward-looking statements involve risks and uncertainties because they relate to events and depend on circumstances that may or may not occur in the future. For additional information about the risks and uncertainties that may affect the Company's business, please see the factors discussed in Item 1A, "Risk Factors," in the Company's Annual Report on Form 10-K for the year ended December 31, 2023 and any subsequent Company filings with the Securities and Exchange Commission (SEC). The Company cautions readers not to place undue reliance on any such forward-looking statements, which speak only as of the date of this press release. The Company disclaims any obligation, except as specifically required by law and the rules of the SEC, to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. Contact: Investors: Bryan Dunn Executive Director, Investor Relations (646) 812-4030 [email protected] Michael V. Morabito, Ph.D. Director, Investor Relations (917) 936-8430 [email protected] Gianna De Palma Manager, Investor Relations (873) 886-2236 [email protected] Media: Mandy Fahey Vice President, Corporate Communications (732) 718-3621 [email protected] SOURCE Insmed Incorporated WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

文章信息 文章题目 Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch 期刊 Cell 发表时间 2024年10月29日 主要内容 北京大学雷晓光课题组联合北京大学李毓龙课题组，及北京佑安医院陈煜课题组，在Cell杂志上发表了文章Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch，该研究系统地揭示了人体内源“天然产物”分子胆酸诱导胆汁淤积瘙痒的分子机制，并且开发出针对多种肝胆疾病具有良好治疗效果且不存在瘙痒副作用的先导药物分子。 原文链接 https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2024.10.001 使用TransGen产品 TransStart®FastPfu DNA Polymerase (AP221) 研究背景 瘙痒自古以来一直被人们所关注，现代医学已表明，组胺依赖的急性瘙痒，如过敏或蚊虫叮咬等，可通过抗组胺类药物有效缓解。然而，非组胺依赖的全身性慢性瘙痒却无法通过这种药物进行治疗，因此困扰了大量慢性瘙痒患者。 胆酸在人体中具有至关重要的生理功能，主要参与脂肪的消化吸收和胆固醇的代谢调节。胆酸通过肠肝循环不断再利用，维持着机体的代谢平衡。然而，当胆汁流动受阻，发生胆汁淤积时，胆酸无法正常代谢并在体内积累，导致约80%的胆汁淤积患者出现严重的慢性瘙痒，极大地影响他们的生活质量。迄今为止，导致胆汁淤积瘙痒的分子机制仍不明确，且缺乏有效的治疗药物。 文章概述 首先，该研究团队收集到数十例有瘙痒症状或无明显瘙痒症状的胆汁淤积病人血浆样本。通过分析这些样本发现在伴有瘙痒症状的胆汁淤积患者中，一种包含了特殊修饰的3位羟基磺酸化胆酸（BA-3S）含量显著增高，磺酸化修饰的胆酸很可能也与胆汁淤积病人的瘙痒症状有着密切的联系，有望用于预测和监测瘙痒的发生。那么，磺酸化修饰后的胆酸是如何导致胆汁淤积病人产生瘙痒症状的呢？ 接下来，研究者针对这一分子机制展开了详细的研究。研究者怀疑，是不是磺酸化后的胆酸对于hX4具有更强的亲和力，从而产生这种更为严重的瘙痒现象。为了证明这一点，研究者测试了不同修饰类型的胆酸对于hX4的激活活性，结果表明胆酸的3号位羟基（3-OH）对于激活hX4具有非常重要的作用，其被磺酸化修饰后显著提高了亲和力，被氧化后则显著降低了激活活性。接着，研究者发现DCA和DCA-3S这两种胆酸都能够导致人源化大鼠产生瘙痒症状，并且DCA-3S能够产生更为严重的瘙痒。那么磺酸化修饰是如何增强胆酸对于hX4的亲和力的呢？ 研究者推测磺酸化胆酸活性的提高可能与磺酸基团携带了一个负电荷有关。研究者通过人工合成的3位磷酸化修饰胆酸DCA-3P成功解析了胆酸类化合物与hX4的复合物结构，首次揭示了胆酸是如何激活hX4的分子机制。 正如所预测的那样，DCA-3P的磷酸部分（P-Head）被锁定在富含正电氨基酸的结合腔中，这种静电相互作用正是导致磺酸化和磷酸化胆酸激活活性提升的主要原因。此外，研究者也发现，DCA-3P中部的疏水部分（H-Middle）通过疏水相互作用被hX4中间丰富的疏水氨基酸所稳定。这些研究详细阐明了胆酸激活hX4的分子机制，展示了3-OH基团和磺酸化修饰在激活hX4过程中发挥的关键作用，为我们理解胆酸诱发瘙痒提供了全新视角。 随后研究者也同时关注到现有临床药物奥贝胆酸（OCA）在治疗过程中的瘙痒副作用，推测OCA产生瘙痒的副作用可能也是通过激活hX4来实现的。进一步通过分子、动物、人体等多方位的角度证实，OCA确实可以激活hX4并且在人源化大鼠模型，甚至人体上产生剂量依赖性的瘙痒症状。因此，OCA导致瘙痒副作用的靶点确实就是hX4。 为了研究C7的全基因组效应，研究人员对C7和OCA处理后的HepG2细胞进行了RNA测序分析。结果证实了C7在治疗NASH等肝脏疾病方面依然具备显著疗效，且不会引发瘙痒问题。进一步研究发现，C7在胆汁淤积和非酒精性脂肪性肝炎（NASH）模型中展现出强大的肝保护作用和抗纤维化潜力，其有望成为治疗胆汁淤积和NASH等肝病的创新药物。 综上所述，该研究工作围绕胆汁淤积瘙痒和肝病治疗新策略两个方面展开了非常系统的研究。第一个方面，从临床样本出发，结合高分辨质谱发现3位羟基磺酸化修饰胆酸在瘙痒胆汁淤积病人体内显著升高，它们能够通过增强对于hX4的激活活性从而导致更为严重的瘙痒症状。此外，利用冷冻电镜技术，解析了hX4与胆酸类似物的复合物结构，详细地阐明了胆酸的3-OH对于激活hX4的重要作用。第二个方面，研究者针对OCA在临床上导致瘙痒副作用开展了一系列的机制和分子改造研究。首先证实OCA通过激活hX4导致瘙痒副作用，接着根据发现的胆酸激活hX4的分子机制，精准地对OCA进行化学改造，成功地获得了失去瘙痒副作用，并且保留了肝病治疗活性的新一代药物分子C7，为临床肝病治疗提供了全新的可能性，有望彻底解决OCA在临床上应用中遇到的瘙痒难题。 全式金产品支撑 优质的试剂是科学研究的利器。全式金生物的PCR产品 TransStart®FastPfu DNA Polymerase (AP221) 助力本研究。 TransStart®FastPfu DNA Polymerase (AP221)  本产品是用于快速 PCR 的热启动高保真 DNA 聚合酶，其扩增效率高、扩增速度快 (4 kb/min，是普通 Pfu 酶的 8 倍)，克服了普通 Pfu 酶扩增效率低、产量低和扩增速度慢 (0.5 kb/min) 的缺陷，极大地缩短了反应时间，自上市以来多次荣登 Cell、Nature 等知名期刊，助力科学研究。 产品特点 快速：4 kb/min 的延伸速度 高保真性：保真性为普通 Taq 酶的 54 倍，普通 Pfu 酶的 3 倍 长片段扩增：基因组 DNA 片段的扩增可达 15 kb，Plasmid DNA 片段的扩增可达 20 kb 高特异性：采用“TransStart” 双封闭法新型热启动技术，同时封闭引物和模板 扩增能力强：独有的 PCR Stimulant，提升该酶对复杂模板的扩增能力 扩增产物为平端，可直接克隆于 pEASY®-Blunt 系列载体中 数据展示 使用 TransStart®FastPfu DNA Polymerase  (AP221) 产品发表的部分文章： • Yang J, Zhao T J, Fan J P, et al. Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch [J]. Cell, 2024. • Wang Y,  Zhang S, Yang X, et al. Mesoscale DNA feature in antibody-coding sequence facilitates somatic hypermutation[J]. Cell, 2023. • Zhang H, Zhu Y, Liu Z, et al. A volatile from the skin microbiota of flavivirus-infected hosts promotes mosquito attractiveness[J]. Cell,2022. • Lei Z, Meng H, Liu L, et al. Mitochondrial base editor induces substantial nuclear off-target mutations[J]. Nature, 2022. • Chen J, Ou Y, Yang Y, et al. KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing[J]. Nature, 2018 • Fan J, Ran H, Wei P L, et al. Pretrichodermamide A Biosynthesis Reveals the Hidden Diversity of Epidithiodiketopiperazines[J]. Angewandte Chemie, 2023. • Song Z, Zhou S, Zhang H, et al. Fungal secondary metabolism is governed by an RNA-binding protein CsdA/RsdA complex[J]. Nature Communications, 2023. • Lei Y, Fei P, Song B, et al. A loosened gating mechanism of RIG-I leads to autoimmune disorders[J]. Nucleic acids research, 2022. • Zhang H, Li Z, Zhou S, et al. A fungal NRPS-PKS enzyme catalyses the formation of the flavonoid naringenin[J]. Nature Communications, 2022. • Li Y, Zhao L, Zhang Y, et al. Structural basis for product specificities of MLL family methyltransferases[J]. Molecular Cell, 2022. 全式金生物产品再一次登上 Cell 期刊，证明了大家对全式金生物产品品质和实力的认可，也完美诠释了全式金生物一直以来秉承的“品质高于一切，精品服务客户”的理念。全式金生物始终在助力科研的道路上砥砺前行，希望未来能与更多的科研工作者并肩奋斗，用更多更好的产品持续助力科研。

Celltrion USA has expanded access to ZYMFENTRA ® (infliximab-dyyb), the first and only FDA-approved subcutaneous (SC) infliximab, to a significant share of the U.S. market The availability of ZYMFENTRA will support greater patient access and choice while helping to drive greater affordability to patients and health care systems JERSEY CITY, N.J., Oct. 31, 2024 /PRNewswire/ -- Celltrion USA announced today that, through continued partnership with key PBMs and health plans, the company has expanded access to ZYMFENTRA ® (infliximab-dyyb), the first and only U.S. Food and Drug Administration (FDA)-approved subcutaneous infliximab. With these partnerships Celltrion has now secured comprehensive access across the US health care system. ZYMFENTRA has attained access to a significant share of the U.S. market, providing an increase in availability to patients and prescribers. This achievement reflects unmet needs of patients, providers and payers, as well as Celltrion USA's ability to deliver on our strong heritage of supply, manufacturing and commitment to biologics. "Our extensive engagement with PBMs and health plans from the outset have led to the comprehensive expanded access for ZYMFENTRA in a short time frame," said Thomas Nusbickel, Celltrion USA Chief Commercial Officer (CCO). "This achievement underscores ZYMFENTRA's unique and innovative therapeutic advantages, and we look forward to expanding our outreach to deliver its treatment benefits to as many patients in the U.S. as possible." ZYMFENTRA was approved by the FDA in October 2023 through the Biologics License Application (BLA) under the 351 (a) pathway of the Public Health Service Act (a "stand-alone" BLA). ZYMFENTRA is the first FDA-approved subcutaneous infliximab for the treatment of moderately to severely active ulcerative colitis and moderately to severely active Crohn's disease. About Celltrion USA Celltrion USA is Celltrion's U.S. subsidiary established in 2018. Headquartered in New Jersey, Celltrion USA is committed to expanding access to innovative biologics to improve care for U.S. patients. Celltrion currently has five biosimilars approved by the U.S. FDA: INFLECTRA® (infliximab-dyyb), TRUXIMA® (rituximab-abbs), HERZUMA® (trastuzumab-pkrb), VEGZELMA® (bevacizumab-adcd), and YUFLYMA®(adalimumab-aaty) as well as a novel biologic ZYMFENTRA®. Celltrion USA will continue to leverage Celltrion's unique heritage in biotechnology, supply chain excellence, and best-in-class sales capabilities to improve access to high-quality biopharmaceuticals for U.S. patients. For more information, please visit: . About ZYMFENTRA® (infliximab-dyyb) [1] ZYMFENTRA is a prescription medicine used as an injection under the skin (subcutaneous injection) by adults for the maintenance treatment of: moderately to severely active ulcerative colitis following treatment with an infliximab product given by intravenous infusion (IV), moderately to severely active Crohn's disease following treatment with an infliximab product given by intravenous infusion (IV). ZYMFENTRA blocks the action of tumor necrosis factor-alpha (TNF-alpha), a protein that can be overproduced in response to certain diseases and cause the immune system to attack normal, healthy parts of the body. ZYMFENTRA® (infliximab-dyyb) was approved by the FDA through the Biologics License Application (BLA) under the 351 (a) pathway of the Public Health Service Act (a "stand-alone" BLA). ZYMFENTRA is considered a new biologic with a first-approved subcutaneous administration form and thus will be under patent protection for its dosage form by 2037 and for its route of administration by 2040. Indication and Important Safety Information ZYMFENTRA is a prescription medicine indicated in adults for maintenance treatment of: Moderately to severely active Crohn's disease following treatment with an infliximab product administered intravenously. Moderately to severely active ulcerative colitis following treatment with an infliximab product administered intravenously. It is not known if ZYMFENTRA is safe and effective in children under 18 years of age. What is the most important information I should know about ZYMFENTRA? SERIOUS INFECTIONS Patients treated with ZYMFENTRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Discontinue ZYMFENTRA if a patient develops a serious infection or sepsis. Reported infections include: Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with ZYMFENTRA. Treatment for latent infection should be initiated prior to treatment with ZYMFENTRA. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria. The risks and benefits of treatment with ZYMFENTRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with ZYMFENTRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. Risk of infection may be higher in patients greater than 65 years of age, patients with comorbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with infliximab included arthritis bacterial, pneumonia, and urinary tract infection. MALIGNANCIES Malignancies, some fatal, have been reported in children, adolescents, and young adults treated with TNF blockers, including infliximab products. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants. Post-marketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including infliximab products. These cases have had a very aggressive disease course and have been fatal. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis, and most were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. Carefully assess the risks and benefits of treatment with ZYMFENTRA, especially in these patient types. In clinical trials of all TNF blockers, more cases of malignancies were observed compared with controls and the expected rate in the general population. In clinical trials of some TNF blockers, including infliximab products, more cases of other malignancies were observed compared with controls. As the potential role of TNF blocker therapy in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy. Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab products. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. CONTRAINDICATIONS ZYMFENTRA is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab-dyyb, other infliximab products, any of the inactive ingredients of ZYMFENTRA or any murine proteins (severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness). HEPATITIS B VIRUS REACTIVATION TNF blockers, including infliximab products, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating ZYMFENTRA. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing ZYMFENTRA for patients identified as carriers of HBV, and monitor closely for active HBV infection during and following termination of therapy with ZYMFENTRA. Discontinue ZYMFENTRA in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of ZYMFENTRA, and monitor patients closely. HEPATOTOXICITY Hepatobiliary disorders, including acute liver failure, jaundice abnormal hepatic function, hepatic steatosis, hepatitis, hepatotoxicity, hyperbilirubinemia, and non-alcoholic fatty liver, have been reported in patients receiving infliximab products post-marketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, ZYMFENTRA should be discontinued, and a thorough investigation of the abnormality should be undertaken. CONGESTIVE HEART FAILURE Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Some cases had a fatal outcome. In several exploratory trials of other TNF blockers in the treatment of CHF, there were greater proportions of TNF-blocker-treated patients who had CHF exacerbations requiring hospitalization or increased mortality. ZYMFENTRA has not been studied in patients with a history of CHF and ZYMFENTRA should be used with caution in patients with CHF. HEMATOLOGIC REACTION Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to infliximab-product therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of ZYMFENTRA in patients who develop significant hematologic abnormalities. HYPERSENSITIVITY AND OTHER ADMINISTRATION REACTIONS In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylaxis, hypotension, and serum sickness) have been reported following administration of infliximab products. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue ZYMFENTRA. INJECTION SITE REACTIONS In clinical studies, localized injection-site reactions were reported following administration of ZYMFENTRA. If a clinically significant injection-site reaction occurs, institute appropriate therapy and discontinue ZYMFENTRA. NEUROLOGIC REACTIONS Agents that inhibit TNF have been associated with central nervous system (CNS) manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering ZYMFENTRA in patients with these disorders and consider discontinuation if these disorders develop. RISK OF INFECTION WITH CONCURRENT ADMINISTRATION OF OTHER BIOLOGICS PRODUCTS Serious infections and neutropenia have been reported with concurrent use of ZYMFENTRA with other immunosuppressive biological products. The concurrent use of ZYMFENTRA with other immunosuppressive biological products used to treat UC and CD may increase the risk of infection and is not recommended. RISK OF ADDITIVE IMMUNOSUPPRESSIVE EFFECTS FROM PRIOR BIOLOGICAL PRODUCTS Consider the half-life and mode of action of prior biological products to avoid unintended additive immunosuppressive effects when initiating ZYMFENTRA. AUTOIMMUNITY Treatment with TNF blockers may result in the formation of autoantibodies and in the development of a lupus-like syndrome. Discontinue ZYMFENTRA treatment if symptoms of a lupus-like syndrome develop. VACCINATIONS AND USE OF LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS Prior to initiating ZYMFENTRA, update vaccinations in accordance with current vaccination guidelines. Live vaccines or therapeutic infectious agents should not be given with ZYMFENTRA due to the possibility of clinical infections, including disseminated infections. At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to ZYMFENTRA. ADVERSE REACTIONS In clinical trials with ZYMFENTRA, the most common adverse reactions occurring in ≥3% of ZYMFENTRA -treated patients included site reactions, COVID-19, anemia, arthralgia, infection site reaction, increased alanine aminotransferase and abdominal pain for UC, and COVID-19, headache, upper respiratory tract infection, injection site reaction, diarrhea, increased blood creatine phosphokinase, arthralgia, increased alanine aminotransferase, hypertension, urinary tract infection, neutropenia, dizziness and leukopenia for CD. Please click for Full U.S. Prescribing Information. Globally, prescribing information varies; refer to the individual country product label for complete information. For further information please contact: Celltrion Global PR Team [email protected] SOURCE Celltrion USA WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED