ARIKACE^® (Inhaled liposomal amikacin) - A Potential New Weapon in the Treatment of Serious Chronic Lung Infections

Amikacin is an FDA approved drug with established efficacy. ARIKACE is a liposomal formulation of amikacin, which is an FDA-approved aminoglycoside antibiotic that is administered intravenously and has proven efficacy in the treatment of gram-negative infections. It is a member of the aminoglycoside class of antibiotics. Amikacin has been long recognized as one of the most potent and effective treatments for gram-negative infections including Pseudomonas, as well as non-tuberculosis mycobacterium (NTM). The value of the systemic use of intravenous (IV) amikacin has been limited by issues of nephrotoxicity (damage to the kidney) and ototoxicity (damage to the ear).

ARIKACE may be desirable because it delivers high, sustained levels of drug to the lung while potentially minimizing systemic exposure well below known toxicity levels, such as nephrotoxicity and ototoxicity.

Pseudomonas Lung Infections in Cystic Fibrosis Patients

Cystic Fibrosis (CF) is an inherited disease that is often diagnosed before the age of two. There are over 70,000 patients living with CF in the U.S. and Europe. Among other issues, CF causes a thick, sticky mucous to form in the lungs, creating an ideal environment for various pathogens, such as Pseudomonas aeruginosa, to form and grow.

Despite extensive treatment with multiple antibiotics, improved nutrition, and other treatments, life expectancy of a CF patient is only 38 years (Cystic Fibrosis Foundation Patient Registry, 2010). Deterioration in lung function is the main cause of death in these patients and despite best efforts, lung function declines by 1% to 3% annually with some patients experiencing declines of 10% or more (Liou et al, Journal of Cystic Fibrosis 9 (2010) 250-256).

According to the Cystic Fibrosis Foundation (Patient Registry, 2010), half of all CF patients have Pseudomonas lung infections. Patients generally receive extensive antibiotic treatments. The antibiotics are delivered via the oral, intravenous and inhaled routes. Antibiotics delivered via inhalation have become part of standard treatments for CF patients with Pseudomonas lung infections and are generally thought to be a way to get more drug directly to the site of infection compared to other routes of administration. In part because of the thick sticky mucous these patients produce in their lungs, CF patients seldom clear their Pseudomonas permanently from their lungs and they become chronically infected in spite of all currently available antibiotic treatments.

CF therapy significantly impacts patient's quality of life. Some patients with CF spend 3-4 hours per day taking medications, including inhaled antibiotics. The current gold-standard inhaled antibiotic is administered twice daily over 30-40 minutes per day for 28 days followed by a 28-day period "off drug". This cycle of "on" and "off" treatment is repeated in a chronic pattern. We anticipate that ARIKACE will be administered once daily for 28 days followed by 28-days off drug. Any Inhaled treatment that may reduce the treatment burden of a CF patient could represent a significant breakthrough in improving the patient's quality of life.

As mentioned above, CF patients produce and have a buildup of mucus in their lungs. In addition, Pseudomonas organisms create a biofilm within the mucus, which acts as an added physical barrier protecting the bacteria from attack by antibiotics. Current belief is that both the patient's mucus and the bacterial biofilm have negative charges and because conventional aminoglycoside antibiotics are positively charged, it is believed that they bind to the surface of the mucus and biofilm and therefore have limited ability to penetrate them, preventing effective dose levels of the drug from reaching the bacteria. In addition, many studies have shown that drugs delivered via inhalation often have a very short residence time in the lung and are cleared rapidly into the blood stream.

We believe that the proprietary liposomal technology upon which ARIKACE is based, which utilizes lipids that occur naturally in the lung, may make it possible for the antibiotic to overcome the protective physical barriers presented by the CF patient's own mucus and by the bacterial biofilm. We believe that the charge-neutral surface of the liposomes used in our patented liposomal formulation allows them to penetrate the negatively charged biofilm and deliver the drug near the bacteria encased within. We have conducted in vitro experiments that demonstrate that ARIKACE liposomes penetrate both human CF sputum and the biofilm of Pseudomonas macro-colonies. We believe getting the FDA-approved antibiotic, amikacin, near to the bacteria enhances the antimicrobial effect of ARIKACE because virulence factors secreted from the targeted bacteria have been shown to facilitate the release of amikacin from the ARIKACE liposomes once they have penetrated the biofilm, a "Trojan Horse" type of effect. In other words, by causing the liposomes to leak once ARIKACE is inside the biofilm, the drug is released where it is needed most, near the bacteria, and, thus, the Pseudomonas bacteria participate in their own potential destruction (Meers et al, Journal of Antimicrobial Chemotherapy (2008) 61, 859-868).

Evidence to date leads us to believe that the sustained effect of the drug reduces dosing frequency, thereby easing a patient's treatment burden and potentially improving patient compliance. Maintenance of the antibiotic above the therapeutic level (minimal level of drug needed to kill Pseudomonas) between doses may also increase efficacy and decrease the potential for the development of resistant strains of bacteria. In preclinical animal studies, the residence time of drug in the lungs from inhalation of ARIKACE was significantly longer than that from inhalation of amikacin solution or tobramycin solution when administered in their conventional delivery vehicles. Additionally, the half-life of antibiotic in the lung was increased by more than 100 times with the use of ARIKACE.

The overall product profile that Insmed is working to develop for ARIKACE may potentially lead to a differentiated inhaled antibiotic treatment that could result in: (1) improved efficacy resulting from sustained deposition of drug in the lung, (2) improved ability to reach the site of infection (for CF Pseudomonas infections that means penetration of Pseudomonas biofilm and facilitated drug release (virulence factors), and for NTM, it means enhanced uptake into macrophages, where NTM often grows); (3) decreased [drug-related] adverse events and improved tolerability; (4) reduced dosing frequency; and (5) decreased administration time.

In clinical studies, ARIKACE has been locally delivered via inhalation using an eFlow^® Nebulizer System (PARI Pharma GmbH), a novel, highly efficient, portable aerosol delivery system.

The data from our completed randomized, placebo-controlled phase 2 clinical study program in CF patients with Pseudomonas lung infections indicated that ARIKACE, delivered at a dose of 560 mg once daily via an eFlow^® Nebulizer System for 28 consecutive days, demonstrated superior clinical benefit compared to placebo as measured by significant and sustained improvement in lung function and reduction in Pseudomonas density. This benefit was sustained for six 28-day-on folowed by 56-day-off treatment cycles (17 months) as observed in a long-term, multi-cycle, open-label study. (Open label means that both the patient and the treating physician know that they are receiving ARIKACE and not placebo.) Typically CF patients with Pseudomonas lung infections are treated with an inhaled antibiotic for 28 days followed by a 28-day-off treatment cycle. In addition, ARIKACE was well-tolerated with overall adverse events reported as consistent with those expected in a population of CF patients receiving inhaled medicines. Please see the press release under News & Events dated Thursday, October 21, 2010 and the posters under NEWS & EVENTS: Publications & Presentations Archive for a summary of the results.

The Company expects to begin enrolling patients in the phase 3 European clinical study of ARIKACE for CF patients with Pseudomonas lung infections in the second quarter of 2012. The European study will be a randomized, phase 3 study comparing ARIKACE 560 mg, delivered once daily via an optimized, investigational eFlow Nebulizer System, to TOBI^®1; (inhaled tobramycin solution), which is a marketed inhaled antibiotic that is delivered twice daily. The Company anticipates that the study will be conducted in approximately 300 patients. The primary endpoint will be change in pulmonary function (FEV-1) measured after three 28 day on-treatment and three 28 day off-treatment cycles (about six months). A key secondary endpoint will be time to pulmonary exacerbation. The study design was previously agreed upon by Insmed and the European Medicines Agency. Eligible patients will have the option to participate in a longer term open-label safety study. See clinicaltrials.gov for more information about this clinical study)

The Company will continue its discussions with the U.S. Food and Drug Administration (FDA) regarding the clinical hold previously placed on the ARIKACE clinical study in CF patients with Pseudomonas lung infections.

ARIKACE has been granted Orphan Drug status in both the U.S. and European Union for lung infections in CF patients that are caused by Pseudomonas aeruginosa.

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Lung Infections due to Nontuberculous Mycobacteria

Nontuberculous mycobacteria (NTM) lung infections can cause severe pulmonary disease for which there are currently limited effective treatments. Consider NTM to be a cousin of tuberculosis (TB). NTM is found in the environment, e.g., soil and water, and can lead to serious infections, the most common of which occur in the lung. Many people have NTM in their bodies, but it does not cause a problem and lead to an infection as it is believed the body's self-regulating immune system successfully combats the threat of NTM infection. It is not completely understood why some individuals are susceptible to NTM infections; however, these patients often are immune-compromised or have structural lung damage at the time they become infected.

Mycobacteria are intracellular organisms that invade and multiply chiefly within macrophages. They are characteristically resistant to most antibiotics. NTM lung infections usually are chronic conditions that can lead to frequent exacerbations and lengthy hospital stays.

According to SDI Healthcare database, more than 30,000 patients visited physician offices suffering with NTM lung disease in the United States during 2008*. There were between 14,000 and 15,000 patients who had a hospital visit for a primary diagnosis of NTM. The average age of these patients was about 66. Approximately two-thirds of the NTM patients received at least one antibiotic and of those receiving an antibiotic, they received between seven and eight courses in 2008.

We believe the unmet need for new therapies is extremely high. Patients are often treated with the same antibiotics that are also used to treat TB. Current treatment for NTM lung infections requires lengthy multi-drug regimens that can be poorly tolerated and poorly effective, especially in patients with severe disease or in those who have failed prior treatment attempts. There have been very few clinical trials to support current treatment recommendations, and no new drugs have been assessed for this disease in many years.

Amikacin, in the currently approved formulation, does not have an FDA approved indication for NTM lung infections but is often part of standard treatment regimens for some NTM patients. It is delivered mostly via intravenous administration, but sometimes via inhalation. As the drug is delivered for months at a time, there can be considerable toxicity associated with treatment due to the high systemic (blood) levels of the drug, which can lead to ototoxicity (hearing loss, ringing in the ears and/or loss of balance) and nephrotoxicity (toxicity to the kidneys).

We believe that ARIKACE^® has an attractive profile to study in patients with NTM because of the ability of the ARIKACE liposomes to be taken up inside lung macrophages that harbor invading organisms such as NTM. Macrophages are immune cells whose primary function includes removing foreign particles and bacteria from the lungs. Ironically, NTM organisms "hide" within the macrophages, making treatment difficult as drugs cannot efficiently gain access to the macrophage interior. Because ARIKACE liposomes are recognized as foreign particles, they are also internalized by the macrophages, consequently delivering very high levels of drug inside the macrophages to reach the NTM bacteria. In addition, we believe that the depot effect of ARIKACE in the lung and lower level of systemic exposure compared to intravenous amikacin may provide additional benefits to these patients and reduce the ototoxicity and nephrotoxicity potential.

The Company expects to begin enrolling patients in phase 2 clinical study in patients with NTM lung infections in mid-2012. The phase 2 clinical study for ARIKACE in NTM patients will consist of a randomized, placebo-controlled study of approximately 100 adult patients with recalcitrant NTM lung disease. Patients who are NTM culture positive will continue with their antibiotic treatment regimen, and receive additionally, either ARIKACE 560 mg, delivered once daily via an optimized, investigational eFlow^® Nebulizer System (PARI Pharma GmbH), or placebo once daily. The primary efficacy endpoint will be change in mycobacterial density from baseline to the end of 84 days of treatment. At the conclusion of the randomized portion of the study, eligible patients will receive ARIKACE 560 mg once daily for an additional 84 days in an open-label design, primarily to measure longer-term safety and efficacy. The clinical trial design was previously agreed upon by Insmed and FDA. (See clinicaltrials.gov for more information about this clinical study)

Insmed intends to file for Orphan Drug status in both the U.S. and Europe for NTM lung infections.

*Source: SDI Healthcare Database, July 2009
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Pseudomonas Lung Infections in Non-CF Bronchiectasis Patients

Non-CF bronchiectasis is a serious pulmonary condition characterized by localized, irreversible enlargement of the bronchial tubes. Accumulation of mucus in the bronchi leads to frequent infections, which causes inflammation and further reduces lung function in these patients. Patients evolve to a chronic inflammation-infection cycle. Disease burden has primarily been linked to productive cough and high levels of sputum (lung mucus) production.

It is estimated about 30% of non-CF bronchiectasis patients are infected with Pseudomonas. When bronchiectasis patients become infected with Pseudomonas, they tend to have more frequent exacerbations and hospitalizations and are more frequent users of antibiotics.

ARIKACE^® randomized, placebo-controlled phase 2 clinical study results in which the drug was administered once daily for 28 days, demonstrated an improvement in time to pulmonary exacerbations/reduced need for anti-Pseudomonas rescue treatment, a decrease in Pseudomonas Log CFU's and a decrease in frequency of cough with expectoration. The study also revealed that Arikace was well-tolerated with adverse events consistent with underlying chronic lung disease in bronchiectasis patients. Patients in the 560 mg cohort had a slightly higher frequency of dry cough than those in the 280 mg cohort, but the cough was of short duration, was self-limiting, and did not result in any physician choosing to discontinue a patient from the study. Please see the press release under News & Events dated Sunday, September 13, 2009 and the poster under NEWS & EVENTS: Publications & Presentations Archive for a summary of the results.

No antibiotics have been approved for this indication.

ARIKACE has been granted Orphan Drug status in the U.S. for the treatment of bronchiectasis in patients with Pseudomonas or other susceptible pathogens.
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Potential Future Pipeline of Products

We believe that Insmed's inhaled liposomal technology has the potential to be applied to a number of different molecules, including small and large molecules, as well as therapeutic proteins and genes. Therefore, Insmed is evaluating a number of liposomal formulations in order to potentially build a robust pipeline of inhaled products.
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• Feb. 10, 2012
  Insmed Incorporated Provides Update on Clinical Program for ARIKACE® Read More
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  Insmed Incorporated Provides Corporate Update Read More

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