APDN, EvviVax Announce Publication of Positive Preclinical Data for Linear DNA™ Platform Approach to Cancer Immunotherapy

On February 17, 2022 Applied DNA Sciences, Inc. (NASDAQ: APDN) (the "Company"), a leader in Polymerase Chain Reaction (PCR)-based DNA manufacturing and nucleic acid-based technologies, and its program development partner, EvviVax, S.R.L. ("Evvivax"), reported the publication of a manuscript detailing a preclinical study (the "study") showing that LinearDNA vaccines used for cancer immunotherapy produced a strong immune and specific antitumoral response in preclinical mouse models (Press release, Applied DNA Sciences, FEB 17, 2022, View Source [SID1234608218]). The study investigated the use of the LinearDNA platform to produce DNA vaccines targeting either tumor-associated antigens (TAA) and tumor-specific antigens (TSA or tumor neoantigens). The manuscript, "Linear DNA Amplicons as a Novel Cancer Vaccine Strategy," is published online on the bioRxiv.org preprint server and has been submitted for peer-reviewed publication. LinearDNA is Applied DNA’s proprietary, large-scale polymerase chain reaction ("PCR")-based manufacturing platform that allows for the large-scale production of specific DNA sequences.

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DNA vaccines that target TAAs hold promise as potential pan-cancer vaccines that, when used in conjunction with existing standards of care, can increase the efficacy of cancer immunotherapies. DNA vaccines targeting TSAs, otherwise known as personalized cancer vaccines, also hold great promise in immunotherapy as they can be customized to induce an immune response only against a patient’s tumor, thereby limiting on-target, off-tumor effects.

TAA: TERT Vaccine
One aspect of the study used a DNA vaccine targeting telomerase reverse transcriptase (TERT), a TAA that holds potential as a target for a pan-cancer vaccine. The TERT DNA vaccine was designed by EvviVax and exclusively licensed by the Company for the LinearDNA platform for veterinary applications. In prior clinical trials conducted by EvviVax, a plasmid form of the TERT DNA vaccine administered along with the standard of care chemotherapy was shown to increase the survival of canines with Stage III/IV B cell lymphoma from 37 weeks to 97 weeks. B-cell lymphoma is the most common type of non-Hodgkin lymphoma in canines, with lymphoma accounting for 15-20% of new cancer diagnoses in canines. For the study, the TERT DNA vaccine was administered to mice in either plasmid DNA or LinearDNA form and the immune response studied and compared. The study’s results demonstrated that both the plasmid DNA and LinearDNA forms of the TERT DNA vaccine induced comparable immune responses in mouse models.

TSA/Neoantigens Vaccine
The second aspect of the study utilized a personalized DNA vaccine specifically targeting several TSAs expressed in a colon cancer mouse model. Personalized cancer vaccines hold great promise in immunotherapy as they can be customized to induce an immune response only against a specific patient’s tumor, thereby limiting off-tumor effects and increasing efficacy and therapeutic index. In the study, LinearDNA and plasmid DNA forms of the personalized cancer vaccine were administered to mice in the colon cancer model. For both forms of the DNA vaccine, several cohorts also received immune checkpoint inhibitors (ICI) based on anti-CTLA-4 and/or anti-PD1. The study demonstrated that the LinearDNA personalized vaccine produces an equal or greater immune and antitumoral response than the plasmid form of the same DNA vaccine, particularly when coupled with ICI.

Dr. James A. Hayward, president and CEO of Applied DNA, stated, "The study demonstrates that LinearDNA and plasmid DNA can elicit a comparable immune response in animal cancer models. We believe this study validates the use of LinearDNA as a more cost- and time-efficient alternative to plasmid DNA for DNA-based cancer vaccines. Cancer immunotherapy is relevant to veterinary and human markets; the latter is expected to reach $169 billion by 2028. As the exclusive licensee of the TERT vaccine for veterinary applications, we believe these data support further investigation of the LinearDNA vaccine as a potential veterinary cancer immunotherapy and, beyond that, for human cancer immunotherapy."

Dr. Luigi Aurisicchio, CEO and chief scientific officer of Evvivax S.R.L., commented, "We believe that DNA vaccines for cancer hold immense promise for both human and veterinary applications. One obstacle to DNA vaccine manufacturing is their current production as plasmid DNA. We believe that the completely cell-free LinearDNA platform avoids the numerous pitfalls of plasmid DNA-based production, making it ideal for DNA vaccine manufacturing broadly, and in cancer immunotherapy, specifically."

Alkermes Presents New Nemvaleukin Alfa Monotherapy Data at the American Society of Clinical Oncology Genitourinary Cancers Symposium

On February 17, 2022 Alkermes plc (Nasdaq: ALKS) reported that new data from the ongoing phase 1/2 ARTISTRY-1 clinical trial for nemvaleukin alfa (nemvaleukin), the company’s novel, investigational, engineered interleukin-2 (IL-2) variant immunotherapy (Press release, Alkermes, FEB 17, 2022, View Source [SID1234608217]). The data were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (GU) Cancers Symposium, taking place Feb. 17-19, 2022.

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The presentation includes updated efficacy and safety data from the monotherapy arm of ARTISTRY-1, in which single-agent, anti-tumor activity of intravenous (IV) nemvaleukin was observed in patients with advanced renal cell carcinoma (RCC), including patients who were checkpoint inhibitor (CPI)-pretreated.

"Nemvaleukin’s single-agent activity is an important differentiating feature in the IL-2 space and suggests that nemvaleukin may contribute clinical benefit when used in combination regimens with other cancer treatments like checkpoint inhibitors," said Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes. "Together with the objective responses previously reported in the melanoma cohort of this study, these data in renal cell carcinoma show nemvaleukin’s monotherapy activity in two tumor types where high-dose IL-2 is approved, thus validating its novel molecular design."

Data highlights from the ASCO (Free ASCO Whitepaper) GU poster presentation include:

ARTISTRY-1, IV Nemvaleukin (6 μg/kg) Monotherapy Arm, RCC Patients
The ARTISTRY-1 monotherapy RCC cohort included 27 patients with advanced RCC, 56% of whom were CPI-pretreated. As of the Oct. 29, 2021 data cutoff:

Nemvaleukin monotherapy induced robust expansion of CD8+ T and natural killer (NK) cells, with minimal effect on regulatory T cells (Tregs).
Among 23 evaluable patients (with at least one post-baseline scan):
Four patients, all of whom were CPI-pretreated, achieved a partial response (one unconfirmed) and three of these patients continued on monotherapy.
Decreases in target lesions of up to 60% were observed.
Stable disease was observed in 10 patients.
Safety among these patients with advanced RCC was consistent with that which was previously reported for the IV nemvaleukin monotherapy-treated population in the ARTISTRY-1 study. Fever, chills, nausea and anemia were the most frequently reported adverse events (AEs), regardless of causality. Chills and anemia were the most commonly reported treatment-related AEs of grade ≥3. There were no deaths due to treatment-related AEs.

Details of the presentation are available on the ASCO (Free ASCO Whitepaper) GU website at View Source

Abstract: 330
Title: Nemvaleukin Alfa in Patients With Advanced Renal Cell Carcinoma: ARTISTRY-1
Presenter: Emiliano Calvo, M.D., Ph.D., Medical Oncologist and Director of Clinical Research at the START Madrid-Centro Integral Oncológico Clara Campal Hospital, Madrid, Spain
Presentation Date: The poster, along with a pre-recorded presentation, will be available on the ASCO (Free ASCO Whitepaper) GU virtual meeting platform beginning Feb. 17, 2022.

About Nemvaleukin Alfa ("nemvaleukin")
Nemvaleukin is an investigational, novel, engineered fusion protein comprised of modified interleukin-2 (IL-2) and the high affinity IL-2 alpha receptor chain, designed to preferentially expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells by selectively binding to the intermediate-affinity IL-2 receptor complex. The selectivity of nemvaleukin is designed to leverage the proven anti-tumor effects of existing IL-2 therapy while mitigating certain limitations.

About the Nemvaleukin Clinical Development Program
ARTISTRY is an Alkermes-sponsored clinical development program evaluating nemvaleukin as a potential immunotherapy for cancer. The ARTISTRY program is comprised of multiple clinical trials evaluating intravenous and subcutaneous dosing of nemvaleukin, both as a monotherapy and in combination with the anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with advanced solid tumors. Ongoing trials in the ARTISTRY program include: ARTISTRY-1, ARTISTRY-2, ARTISTRY-3, ARTISTRY-6 and ARTISTRY-7.

AbbVie Declares Quarterly Dividend

On February 17, 2022 The board of directors of AbbVie Inc. (NYSE: ABBV) reported a quarterly cash dividend of $1.41 per share (Press release, AbbVie, FEB 17, 2022, View Source [SID1234608216]).

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The cash dividend is payable May 16, 2022 to stockholders of record at the close of business on April 15, 2022.

Since the company’s inception in 2013, AbbVie has increased its dividend by more than 250 percent. AbbVie is a member of the S&P Dividend Aristocrats Index, which tracks companies that have annually increased their dividend for at least 25 consecutive years.

Intellia Therapeutics Announces Two Upcoming Investor Events in February 2022

On February 17, 2022 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading clinical-stage genome editing company focused on developing curative therapeutics leveraging CRISPR-based technologies, reported that it will be hosting two virtual investor events in February (Press release, Intellia Therapeutics, FEB 17, 2022, View Source [SID1234608213]).

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Fourth Quarter and Full-Year 2021 Earnings – February 24, at 8:00 a.m. ET
Intellia will present its fourth quarter and full-year 2021 financial results.

To join the call, U.S. callers should dial 1-833-316-0545 and international callers should dial 1-412-317-5726, approximately five minutes before the call. All participants should ask to be connected to the Intellia Therapeutics conference call.
Please visit this link for a simultaneous live webcast of the call.
NTLA-2001 Interim Clinical Data Update – February 28, at 4:30 p.m. ET
Intellia will present additional interim clinical data from the ongoing Phase 1 study of NTLA-2001 in patients with transthyretin (ATTR) amyloidosis with polyneuropathy. The event will include a presentation by Ed Gane, MBChB, MD, FRACP, MNZM, Professor of Medicine at the University of Auckland, New Zealand and Chief Hepatologist, Transplant Physician and Deputy Director of the New Zealand Liver Transplant Unit at Auckland City Hospital and an investigator in the ongoing NTLA-2001 Phase 1 study, along with members of Intellia’s management team.

To join the webcast, please visit this link, or the Events and Presentations page of the Investors & Media section on Intellia’s website at www.intelliatx.com.
A replay of the events will be available through the Events and Presentations page of the Investors & Media section on Intellia’s website at www.intelliatx.com for at least 30 days following the event.

About NTLA-2001
Based on Nobel Prize-winning CRISPR/Cas9 technology, NTLA-2001 could potentially be the first single-dose treatment for ATTR amyloidosis. NTLA-2001 is the first investigational CRISPR therapy candidate to be administered systemically, or through a vein, to edit genes inside the human body. Intellia’s proprietary non-viral platform deploys lipid nanoparticles to deliver to the liver a two-part genome editing system: guide RNA specific to the disease-causing gene and messenger RNA that encodes the Cas9 enzyme, which carries out the precision editing. Robust preclinical data, showing deep and long-lasting transthyretin (TTR) reduction following in vivo inactivation of the target gene, supports NTLA-2001’s potential as a single-administration therapeutic. Intellia leads development and commercialization of NTLA-2001 as part of a multi-target discovery, development and commercialization collaboration with Regeneron.

Insmed Reports Fourth Quarter and Full Year 2021 Financial Results and Provides Business and Pipeline Update

On February 17, 2022 Insmed Incorporated (Nasdaq:INSM), a global biopharmaceutical company on a mission to transform the lives of patients with serious and rare diseases, reported financial results for the fourth quarter and full year ended December 31, 2021 and provided an update on the Company’s business and pipeline (Press release, Insmed, FEB 17, 2022, View Source [SID1234608212]).

"Insmed made tremendous progress across our four pillars throughout 2021, and we begin 2022 from a position of strength, with seven ongoing clinical trials, commercial operations in three major territories, a pathway to ARIKAYCE growth, and a highly innovative research engine to identify what we believe to be the most promising next set of candidates," commented Will Lewis, Chair and Chief Executive Officer of Insmed. "Importantly, our strong cash position will support advancement across our programs as we continue to lay the groundwork for what we believe will be a meaningful inflection point for the Company. I am enormously proud of our world-class team and what we have been able to achieve on behalf of patients with serious and rare diseases."

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Recent Corporate Developments & Program Highlights

ARIKAYCE

•Insmed launched ARIKAYCE in Japan in July of 2021, and early launch progress has been strong, with several positive trends.

•In Europe, ARIKAYCE has now been launched in Germany, the Netherlands, Wales, and Scotland. The Company is pursuing country-by-country reimbursement and launches throughout Europe, with a near-term focus on Italy, France, and England.

•Insmed continues to advance the post-marketing confirmatory frontline clinical trial program of ARIKAYCE in patients with nontuberculous mycobacterial (NTM) lung disease caused by Mycobacterium avium complex (MAC). The ARISE trial, an interventional study designed to validate a patient-reported outcome (PRO) tool in MAC lung disease, is now 50% enrolled. The Company anticipates completing enrollment in the ARISE study in 2022 and having topline data in the first half of 2023. Insmed anticipates completing enrollment in ENCORE, a pivotal study evaluating the clinical benefits and safety of ARIKAYCE in patients with newly diagnosed MAC lung disease using the PRO tool, by the end of 2023.

1Brensocatib

•The Phase 3 ASPEN study, a global, randomized, double-blind, placebo-controlled trial to assess the efficacy, safety, and tolerability of brensocatib in patients with bronchiectasis, is now 50% enrolled. Insmed anticipates completing enrollment in this study in early 2023.

•A Phase 2 pharmacokinetic/pharmacodynamic study of brensocatib in patients with cystic fibrosis is underway and Insmed anticipates sharing data from this study by early 2023.

•Insmed plans to develop brensocatib in two additional neutrophil-mediated diseases – chronic rhinosinusitis without nasal polyps (CRS) and hidradenitis suppurativa (HS) – and to advance one indication into the clinic in 2022. Both CRS and HS are serious diseases in which patients today face significant unmet needs.

TPIP

•Insmed is advancing two Phase 2 studies of treprostinil palmitil inhalation powder (TPIP) in patients with pulmonary arterial hypertension (PAH). The Phase 2a study will measure the impact of TPIP on pulmonary vascular resistance (PVR) over a 24-hour period. The Company anticipates having preliminary data from a small number of patients in this study this year. The Phase 2b study will evaluate the effect of TPIP on PVR and 6-minute walk distance over a 16-week treatment period. As planned, site initiation for this study began in late 2021.

•Site initiation is underway for a Phase 2 study of TPIP in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). This study will assess the safety and tolerability of TPIP over a 16-week treatment period.

Translational Medicine

•Insmed is advancing a translational medicine portfolio consisting of several technology programs running in parallel. The Company anticipates filing an Investigational New Drug Application in a non-pulmonary indication for our first candidate from this portfolio by the end of 2022.

Fourth Quarter and Full-Year 2021 Financial Results

•Total revenue for the fourth quarter ended December 31, 2021 was $56.1 million, compared to total revenue of $41.4 million for the fourth quarter of 2020. Total revenue for the full year 2021 was $188.5 million, compared to total revenue of $164.4 million for the full year 2020.

•Total revenue for the full year 2021 comprised ARIKAYCE net sales of $159.5 million in the U.S., $16.0 million in Japan, and $12.9 million in Europe and rest of world. This compares to net sales of $157.5 million in the U.S. and $6.9 million in Europe for the full year 2020.

•Cost of product revenues (excluding amortization of intangible assets) was $13.3 million for the fourth quarter of 2021, compared to $10.9 million for the fourth quarter of 2020. For the full year 2021, cost of product revenues (excluding amortization of intangible assets) was $44.2 million compared to $39.9 million in 2020.

•Research and development (R&D) expenses were $76.4 million for the fourth quarter of 2021, compared to $67.8 million for the fourth quarter of 2020. For the full year 2021, R&D expenses were $272.7 million compared to $181.2 million in 2020.

•Selling, general and administrative (SG&A) expenses for the fourth quarter of 2021 were $65.3 million, compared to $56.0 million for the fourth quarter of 2020. For the full year 2021, SG&A expenses were $234.3 million, compared to $203.6 million in 2020.

•For the fourth quarter of 2021, Insmed reported a net loss of $113.0 million, or $0.95 per share, compared to a net loss of $102.2 million, or $1.00 per share, for the fourth quarter of 2020. For the full year 2021, Insmed reported a net loss of $434.7 million, or $3.88 per share, compared to a net loss of $294.1 million, or $3.01 per share, in 2020.

2Balance Sheet, Financial Guidance, and Planned Investments

As of December 31, 2021, Insmed had cash and cash equivalents and marketable securities of $766.8 million. The Company’s total operating expenses for the fourth quarter of 2021 were $155.2 million and for the full year 2021 were $563.6 million.

Insmed expects full-year 2022 revenues for ARIKAYCE to increase at least 30% year over year from 2021. The Company anticipates that its cash on hand will support its ongoing programs into 2024.

The Company plans to invest in the following key activities in 2022:

(i)commercialization and expansion of ARIKAYCE globally;

(ii)launch activities for ARIKAYCE in initial European countries and in Japan; and

(iii)clinical trial activities, including (a) advancement of the frontline clinical trial program for ARIKAYCE (ARISE and ENCORE), (b) advancement of brensocatib, including the Phase 3 ASPEN study in patients with bronchiectasis, (c) advancement of the Phase 2 clinical development programs of TPIP, and (d) advancement of our translational medicine efforts.

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 (844) 200-6205 (U.S. toll free), (646) 904-5544 (U.S. local), or +1-929-526-1599 (international) and referencing access code 359415. The call will also be webcast live on the company’s website at www.insmed.com.

A replay of the conference call will be accessible approximately 1 hour after its completion through March 17, 2022, by dialing (866) 813-9403 (U.S. toll free), (929) 458-6194 (U.S. local), or +44-204-525-0658 (international) and referencing access code 838814. A webcast of the call will also be archived for 90 days under the Investor Relations section of the company’s website at www.insmed.com.

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.

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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.


WARNING: RISK OF INCREASED RESPIRATORY ADVERSE REACTIONS

ARIKAYCE has been associated with an increased risk of respiratory adverse reactions, including hypersensitivity pneumonitis, hemoptysis, bronchospasm, and exacerbation of underlying pulmonary disease that have led to hospitalizations in some cases.

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.

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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.

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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 www.fda.gov/medwatch, or call 1‑800‑FDA‑1088. You can also call the Company at 1-844-4-INSMED.