Mycobacterium Avium-Intracellulare Infection

AN2 Therapeutics still expects to announce top-line data from the phase 2 portion of the trial in the summer. Just five months after launching the phase 3 part of a lung disease trial for its sole clinical asset, AN2 Therapeutics is pressing pause. The California biotech has voluntarily halted a late-stage study of an antibiotic called epetraborole in treatment-refractory mycobacterium avium complex (MAC) lung disease after an analysis of a phase 2 portion of the trial “showed potentially lower than expected efficacy.” The decision was not due to safety concerns, the company pointed out, adding that it still expects to announce top-line data from the phase 2 portion of the trial in the summer. As the biotech’s only clinical-stage asset, epetraborole was at the center of AN2’s pitch to prospective investors when the company went public in a March 2022 IPO that reeled in $69 million. The biotech’s stock has fluctuated in the subsequent two years but looks set for its biggest crash yet on Monday in the wake of the trial’s pause. Shares dropped over 70% in premarket trading to $5.63 from a Friday closing price of $20. “Developing new therapies for patients suffering with treatment-refractory MAC lung disease, a disease with limited treatment options and low response rates to existing therapies, is a complex undertaking,” AN2’s CEO Eric Easom explained in this morning’s release. “In light of recently available blinded aggregate data, we believe our voluntary decision to pause enrollment in the phase 3 part of the study will provide us the opportunity to further evaluate study data, and determine the best path forward,” Easom added. Epetraborole, a small-molecule inhibitor of bacterial leucyl-tRNA synthetase, had been put through clinical trials by Anacor Pharmaceuticals and GSK over a decade earlier, before GSK scrapped the partnership after seeing microbiological resistance in some patients who received the drug in a phase 2 study. Anacor was then bought by Pfizer in 2016, and, three years later, AN2 secured the rights to epetraborole from the Big Pharma. AN2 had big plans for the antibiotic and completed enrollment of 80 patients in the phase 2 portion of the EBO-301 trial by September 2023. The aim was to seamlessly move into a phase 3 segment of the study, which as of this morning had enrolled 100 patients out of a planned 230 across the U.S., Japan, South Korea and Australia. Back in September, Easom pointed out that there remains no approved oral therapies for MAC lung disease. “Given epetraborole’s novel mechanism of action, encouraging clinical and non-clinical data to date, and convenient once daily oral dosing, we believe that if approved, epetraborole has the potential to become the backbone of therapy for patients suffering with often debilitating treatment-refractory MAC lung disease,” the CEO said at the time. AN2 ended September with $150.2 million in cash and investments, which was expected to cover operations through summer 2025.

MENLO PARK, Calif.--( BUSINESS WIRE )--AN2 Therapeutics, Inc. (Nasdaq: ANTX), a clinical-stage biopharmaceutical company focused on developing treatments for rare, chronic, and serious infectious diseases with high unmet needs, today announced the company’s decision to voluntarily pause Phase 3 enrollment in the seamless Phase 2/3 clinical trial (EBO-301) evaluating epetraborole in treatment-refractory MAC lung disease, pending further data review. The double-blind, placebo-controlled trial has two arms comparing epetraborole plus optimized background regimen (OBR) versus placebo plus OBR. The voluntary pause was instituted following a blinded aggregate analysis of the ongoing Phase 2 study, including pooled patients from both treatment arms, which showed potentially lower than expected efficacy. The decision was not due to safety concerns. The Phase 2 part of the trial is intended to inform the Phase 3 part of the trial. The company continues to expect to announce topline data from the Phase 2 part of the trial in summer 2024. The company’s decision to pause enrollment enables time to further evaluate study data and for the independent Data Safety Monitoring Board (DSMB) to conduct an unblinded assessment and recommend next steps, which could include changes to the Phase 3 part of the study protocol. The Phase 2 part of the trial completed enrollment in September 2023 with 80 patients. The Phase 3 part of the trial has enrolled nearly 100 patients to date, a faster enrollment rate than previously anticipated. Patients already enrolled in the Phase 2/3 trial will be allowed to continue on study. “Developing new therapies for patients suffering with treatment-refractory MAC lung disease, a disease with limited treatment options and low response rates to existing therapies, is a complex undertaking. In light of recently available blinded aggregate data, we believe our voluntary decision to pause enrollment in the Phase 3 part of the study will provide us the opportunity to further evaluate study data, and determine the best path forward,” said Eric Easom, Co-Founder, President and Chief Executive Officer of AN2 Therapeutics. “We plan to provide further details regarding the epetraborole Phase 2/3 clinical trial in the second quarter of 2024 following completion of our analysis.” About the Epetraborole Pivotal Phase 2/3 Trial (EBO-301) This double-blind, placebo-controlled superiority trial uses an adaptive design to evaluate the safety and efficacy of epetraborole in patients with treatment-refractory MAC lung disease. The Phase 2 part of the trial (n=80) assesses clinical response using various patient-reported outcome tools as well as the safety, efficacy and pharmacokinetics of epetraborole plus an OBR, when compared to a placebo plus an OBR. The Phase 2 findings will be utilized to inform the clinical response measures evaluated in the Phase 3 part of the trial and confirm the final sample size. The primary objective in Phase 3 (n=at least 234) will be to determine if epetraborole plus an OBR, consisting of two or more standard-of-care drugs, is superior to placebo plus an OBR. For more information, please visit: www.clinicaltrials.gov (NCT05327803). About AN2 Therapeutics, Inc. AN2 Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing treatments for rare, chronic, and serious infectious diseases with high unmet needs. Our initial candidate is epetraborole, which we are studying as a once-daily, oral treatment with a novel mechanism of action for patients with nontuberculous mycobacteria (NTM) lung disease, a rare, chronic, and progressive infectious disease caused by bacteria known as mycobacteria, that leads to irreversible lung damage and can be fatal. For more information, please visit our website at www.an2therapeutics.com . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding: timing of topline data, further evaluation of study data and DSMB review; potential changes to the Phase 3 study protocol; continuation of enrolled patients in the Phase 2/3 trial; timing of completion of AN2’s analysis of study data; and other statements that are not historical fact. These statements are based on AN2’s current estimates, expectations, plans, objectives, and intentions, are not guarantees of future performance and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, but are not limited to, risks and uncertainties related to: the recommendations of the DSMB following its review of blinded data; the number of patients who remain enrolled in the Phase 2/3 trial; the ability of AN2 to resume enrollment in the Phase 2/3 trial, in the event the determination to resume enrollment is made; the ability of AN2 to effectively and timely make amendments to the Phase 2/3 pivotal trial design based on its analysis of the Phase 2 portion of the study and/or pursuant to additional FDA feedback; possible changes to AN2’s plans or priorities as it assesses study data; potential for protocol modifications, redesign or study termination; timely enrollment of patients in AN2’s existing and future clinical trials; AN2’s ability to procure sufficient supply of its product candidate for its existing and future clinical trials; the potential for results from clinical trials to differ from preclinical, early clinical, preliminary, or expected results; significant adverse events, toxicities, or other undesirable side effects associated with AN2’s product candidate; the significant uncertainty associated with AN2’s product candidate ever receiving any regulatory approvals; AN2’s ability to obtain, maintain, or protect intellectual property rights related to its current and future product candidates; implementation of AN2’s strategic plans for its business and current and future product candidates; the sufficiency of AN2’s capital resources and need for additional capital to achieve its goals; global macroeconomic conditions and global conflicts; and other risks, including those described under the heading “Risk Factors” in AN2’s reports filed with the U.S. Securities and Exchange Commission (SEC), including AN2’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2023. These filings, when made, are available on the investor relations section of AN2’s website at investor.an2therapeutics.com and on the SEC’s website at www.sec.gov . Forward-looking statements contained in this press release are made as of this date, and AN2 undertakes no duty to update such information except as required under applicable law.

—ARIKAYCE® (amikacin liposome inhalation suspension) Delivers Full-Year 2023 Revenues Exceeding the Upper End of Guidance Range with Unaudited Global Net Product Sales of Approximately $305.2 Million— —2024 Global ARIKAYCE Revenues Expected to be Between $340 Million and $360 Million, Reflecting Double-Digit Growth Compared to 2023— —Topline Data from the Phase 3 ASPEN Study of Brensocatib in Adult Patients with Bronchiectasis Remains on Track to Read Out in the Latter Part of Second-Quarter 2024— —Enrollment in the Phase 2 Study of TPIP in Patients with PH-ILD Completed in November 2023; Topline Data Expected in Second-Quarter 2024— BRIDGEWATER, N.J., Jan. 5, 2024 /PRNewswire/ -- Insmed Incorporated (Nasdaq: INSM), a global biopharmaceutical company on a mission to transform the lives of patients with serious and rare diseases, today provided an update on the Company's four pillars and outlook for 2024. These updates will be discussed as part of the Company's presentation at the 42nd Annual J.P. Morgan Healthcare Conference in San Francisco on Monday, January 8, 2024, at 3:00 p.m. PT (6:00 p.m. ET). "The year ahead will mark the most transformational period in Insmed's history as we strive to become the next great biotechnology company," said Will Lewis, Chair and Chief Executive Officer of Insmed. "From the readout of our highly anticipated Phase 3 ASPEN study, to our first Phase 2 topline TPIP data, to the advancement of our ARIKAYCE label expansion program, 2024 is the moment we have been waiting for. Each of these three programs, if successful, has the potential to achieve peak sales of more than $1 billion. Over the next 12 months, we have the opportunity to truly break out from the pack, delivering tangible results for our shareholders, while, more importantly, making a meaningful impact in the lives of patients with serious and rare diseases." Preliminary Full Year 2023 Global Net Product Sales (Unaudited) Based on preliminary unaudited financial information, the Company expects total global net product sales of ARIKAYCE to be approximately $305.2 million for the full year 2023, with net sales across the United States, Japan, and Europe as follows. This represents 24% year-over-year growth from the full year 2022, including growth in the U.S. of 21% and in Japan of 16%. These preliminary unaudited results are subject to adjustment. Insmed will report its final and complete fourth-quarter and full-year 2022 financial results in late February 2024, and the actual results could be materially different from these preliminary unaudited financial results. Progress and Anticipated Milestones by Pillar: Pillar 1: ARIKAYCE Insmed anticipates 2024 global ARIKAYCE revenues to be between $340 million and $360 million, representing 15% year-over-year growth at the midpoint compared to 2023. The Company has completed its original target enrollment of 250 patients in the ENCORE trial in patients with newly diagnosed or recurrent nontuberculous mycobacterial lung infection caused by Mycobacterium avium complex (MAC) who had not started antibiotics. Enrollment in the study remains ongoing. Insmed received encouraging written feedback from the U.S. Food and Drug Administration (FDA) on the patient-reported outcome data produced in the Phase 3 ARISE study in December 2023. As expected, the Company will seek a meeting with the Agency in the coming months to gain additional insights and guidance, from which it will finalize its statistical plans for the Phase 3 ENCORE study, including an updated enrollment target for the study. The Company continues to anticipate a topline readout for ENCORE in 2025. Pillar 2: Brensocatib Insmed expects topline data from the Phase 3 ASPEN study of brensocatib in adult patients with non-cystic fibrosis bronchiectasis in the latter part of the second quarter of 2024. If successful, the Company anticipates a launch in the U.S. in mid-2025, followed by launches in Europe and Japan in the first half of 2026. The Data Safety Monitoring Committee for the ASPEN study held its fifth and final meeting in November 2023. No new safety signals were identified, and the Committee unanimously recommended that the trial continue as planned. Insmed anticipates providing topline data from the Phase 2b BiRCh trial of brensocatib in patients with chronic rhinosinusitis without nasal polyps (CRSsNP) in 2025. The Company expects to initiate a Phase 2 study of brensocatib in patients with hidradenitis suppurativa (HS) in the second half of 2024. Pillar 3: TPIP Insmed has completed enrollment in the Phase 2 study of treprostinil palmitil inhalation powder (TPIP) in pulmonary hypertension associated with interstitial lung disease (PH-ILD). The Company exceeded its enrollment target of 32 patients, with 39 patients enrolled. Topline data from the study are anticipated ahead of Phase 3 ASPEN data in the second quarter of 2024. Enrollment in the Phase 2 study of TPIP in pulmonary arterial hypertension (PAH) remains ongoing. The Company anticipates enrolling 99 patients in the study, 45 of whom had been enrolled by year-end 2023, with topline results expected in 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 that the totality of its early-stage research programs will comprise less than 20% of overall spend. Presentation at the 42nd Annual J.P. Morgan Healthcare Conference Will Lewis, Chair and Chief Executive Officer of Insmed, will present at the 42nd Annual J.P. Morgan Healthcare Conference on Monday, January 8, 2024, at 3:00 p.m. PT (6:00 p.m. ET). A live audio webcast of the presentation will be available on the Investor Relations section of the Company's website at . A replay will also be archived for a period of 30 days following the conclusion of the live event. 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 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 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 global biopharmaceutical company on a mission to transform the lives of patients with serious and rare diseases. Insmed's first commercial product is a first-in-disease therapy approved in the United States, Europe, and Japan to treat a chronic, debilitating lung disease. The Company is progressing a robust pipeline of investigational therapies targeting areas of serious unmet need, including neutrophil-mediated inflammatory diseases and rare pulmonary disorders. Insmed is also advancing an early-stage research engine encompassing a wide range of technologies and modalities, including artificial intelligence-driven protein engineering, gene therapy, and protein manufacturing. Insmed is headquartered in Bridgewater, New Jersey, with additional offices and research locations throughout the United States, Europe, and Japan. 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 obtain, or delays in obtaining, regulatory approvals for ARIKAYCE outside the U.S., Europe or Japan, or for the Company's product candidates in the U.S., Europe, Japan or other markets, including separate regulatory approval for the Lamira® Nebulizer System in each market and for each usage; failure to successfully commercialize ARIKAYCE, the Company's 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 U.S., European or Japanese approval for ARIKAYCE, or failure to successfully commercialize any of the Company's product candidates in the future; business or economic disruptions due to catastrophes or other events, including natural disasters or public health crises; impact of the COVID-19 pandemic and efforts to reduce its spread on the Company's business, employees, including key personnel, patients, partners and suppliers; risk that brensocatib or TPIP does not prove to be effective or safe for patients in ongoing and future clinical studies, including, for brensocatib, the ASPEN study; uncertainties in the degree of market acceptance of ARIKAYCE by physicians, patients, third-party payors and others in the healthcare community; the Company's inability to obtain full approval of ARIKAYCE from the FDA, including the risk that the Company will not successfully or in a timely manner validate a PRO tool and complete the confirmatory post-marketing clinical trial required for full approval of ARIKAYCE; inability of the Company, PARI or the Company's other third-party manufacturers to comply with regulatory requirements related to ARIKAYCE or the Lamira® Nebulizer System; the Company's inability to obtain adequate reimbursement from government or third-party payors for ARIKAYCE or acceptable prices for ARIKAYCE or for the Company's other product candidates; development of unexpected safety or efficacy concerns related to ARIKAYCE, brensocatib, TPIP or the Company's other product candidates; inaccuracies in the Company's estimates of the size of the potential markets for ARIKAYCE, brensocatib, TPIP or the Company's other product candidates or in data the Company has used to identify physicians, expected rates of patient uptake, duration of expected treatment, or expected patient adherence or discontinuation rates; the risks and uncertainties associated with, and the perceived benefits of, the Company's secured senior loan with certain funds managed by Pharmakon Advisors, LP and the Company's royalty financing with OrbiMed Royalty & Credit Opportunities IV, LP, including the Company's ability to maintain compliance with the covenants in the agreements for the senior secured loan and royalty financing and the perceived impact of the restrictions on the Company's operations under these agreements; the Company's inability to create 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 the Company's product candidates that are approved in the future; failure to obtain regulatory approval to expand ARIKAYCE's indication to a broader patient population; risk that the Company's competitors may obtain orphan drug exclusivity for a product that is essentially the same as a product the Company is developing for a particular indication; failure to successfully predict the time and cost of development, regulatory approval and commercialization for novel gene therapy products; failure to successfully conduct future clinical trials for ARIKAYCE, brensocatib, TPIP and the Company's other product candidates due to the Company's limited experience in conducting preclinical development activities and clinical trials necessary for regulatory approval and its potential inability to enroll or retain sufficient patients to conduct and complete the trials or generate data necessary for regulatory approval, among other things; risks that the Company's clinical studies will be delayed, that serious side effects will be identified during drug development, or that any protocol amendments submitted will be rejected; risks that interim or partial data sets are not representative of a complete or larger data set or that blinded data will not be predictive of unblinded data; failure of third parties on which the Company is dependent to manufacture sufficient quantities of ARIKAYCE or the Company's product candidates 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 or agreements with the Company; the Company's inability to attract and retain key personnel or to effectively manage the Company's growth; the Company's inability to successfully integrate its recent acquisitions and appropriately manage the amount of management's time and attention devoted to integration activities; risks that the Company's acquired technologies, products and product candidates are not commercially successful; the Company's inability to adapt to its highly competitive and changing environment; risk that the Company is unable to maintain its significant customers; risk that government healthcare reform materially increases the Company's costs and damages its financial condition; deterioration in general economic conditions in the U.S., Europe, Japan and globally, including the effect of prolonged periods of inflation, affecting the Company, its suppliers, third-party service providers and potential partners; the Company's inability to adequately protect its intellectual property rights or prevent disclosure of its trade secrets and other proprietary information and costs associated with litigation or other proceedings related to such matters; restrictions or other obligations imposed on the Company by agreements related to ARIKAYCE or the Company's product candidates, including its license agreements with PARI and AstraZeneca AB, and failure of the Company to comply with its obligations under such agreements; the cost and potential reputational damage resulting from litigation to which the Company is or may become a party, including product liability claims; risk that the Company's operations are subject to a material disruption in the event of a cybersecurity attack or issue; the Company's limited experience operating internationally; changes in laws and regulations applicable to the Company's business, including any pricing reform, and failure to comply with such laws and regulations; the Company's history of operating losses, and the possibility that the Company may never achieve or maintain profitability; goodwill impairment charges affecting the Company's results of operations and financial condition; inability to repay the Company's existing indebtedness and uncertainties with respect to the Company's 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, 2022 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 Insmed (646) 812-4030 [email protected] Eleanor Barisser Associate Director, Investor Relations Insmed (718) 594-5332 [email protected] Media: Mandy Fahey Executive Director, Corporate Communications Insmed (732) 718-3621 [email protected] SOURCE Insmed Incorporated