{"id":2955,"date":"2016-12-22T15:16:40","date_gmt":"2016-12-22T20:16:40","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=2955"},"modified":"2025-09-20T19:16:18","modified_gmt":"2025-09-21T01:16:18","slug":"aerosolized-antibiotics-part-2-disappointing-news-fronts","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2016\/12\/22\/2955\/aerosolized-antibiotics-part-2-disappointing-news-fronts\/","title":{"rendered":"Aerosolized Antibiotics (Part 2) \u2013 Mixed News on Two Fronts"},"content":{"rendered":"

\"\"<\/a><\/p>\n

INSMED – NTM
\n<\/strong>The company that is developing Arikayce, a preparation of liposomal amikacin inhalation (LAI), for the treatment of NTM had to withdraw its MAA in Europe earlier this year\u00a0[1]<\/a> because data was not convincing enough for regulators to approve the application. Insmed now has to wait until more data become available from a Phase 3 trial which is now underway and called CONVERT.<\/p>\n

A publication of the completed Phase 2 trial was just released giving us a glimpse into the complexity of studying NTM\u00a0[2]<\/a>.\u00a0 In this relatively small study, 89 patients with treatment-refractory NTM and positive sputum cultures for MAI or M. abscessus were randomly assigned to aerosolized LAI or placebo. The primary efficacy variable was based on a semi-quantitative outcome measure (a categorized reduction in bacterial count); the LAI arm\u00a0was numerically better for this endpoint but missed the cut-off for statistical proof of superiority, achieving only a P-value of 0.072. If the team had chosen sputum conversion as their primary outcome variable, the study would have been a resounding success for\u00a0LAI (P=0.006). Too bad!<\/p>\n

Arikayce was not particularly well tolerated. The 12-week treatment course was associated with frequent and occasionally significant AEs (dysphonia, cough, exacerbation of bronchiectasis, oral pain and chest discomfort). These are not minor tolerability issues and would be deemed unacceptable in other more trivial indications. However, when treatment with triple systemic antibiotics is unable to control the pulmonary infection, this should be factored in when assessing therapeutic index and value.

MAI Therapy:\u00a0<\/strong>Start treatment for pulmonary disease with clarithromycin or azithromycin, plus ethambutol and either rifampin or rifabutin. More advanced disease may require the addition of aminoglycosides.\u00a0 From: Mandell \u2013 Ref<\/span> [3]<\/a><\/p>\n<\/div><\/p>\n

LAI treatment really proIvides more than a ray of hope for treatment-refractory MAI patients.\u00a0 Adjuvant LAI was able to improve the microbiology of this chronic infection which had not responded to long-term therapy with a triple antibiotic cocktail. Not a minor feat!<\/p>\n

We should not be too concerned about the fact that mortality or CXR findings or other clinical parameters were not improved, or that walking distance improved but PFT did not; we believe enough in the microbiologic response as the driver of long-term benefit to feel confident that mycobacterial eradication will eventually improve outcomes. With bacterial turn-over in mycobacterial infection occurring only once every 24 hours, nothing very dramatic can be expected within 12-weeks. This duration of therapy is the equivalent of a 30-h antibiotic treatment of an E. coli infection, if we adjust for a cell division time of 20 minutes.<\/p>\n

We wish there were a way to make this much needed medication available to patients before the end of a lengthy Phase 3 study which will take years to complete. It seems Arikayce carries a modest amount of risk but brings a very tangible benefit for many with this hard-to-treat infection.\u00a0 If MAI patients had an advocacy group like the CF Foundation or the HIV activists of the late 80s\/early 90s, Arikayce would have been conditionally approved.<\/p>\n

Alternatively, there is still straight non-liposomal amikacin\u00a0which can be aerosolized and offered to patients as adjunctive therapy. In an observational trial, most patients achieved sputum conversion and benefited clinically with prolonged\u00a0treatment.[5]<\/a><\/p>\n

CARDEAS \u2013 VAP Therapy
\n<\/strong>In a Phase 2 trial Cardeas tested inhaled amikacin+fosfomycin (or AFIS) in VAP patients. In these patients AFIS adjunctive therapy did not improve patient outcomes, not even coming close. While high amounts of drug were deposited in the lungs and bacterial load was reduced in bronchial samples, no clinical benefit was observed over placebo (p=0.7); indeed, mortality was numerically higher in the amikacin+fosfomycin arm. The initial CPIS was 5.6 in the AFIS group with a maximum possible point score of 10.\u00a0 It dropped to 5.0 by the end treatment in the AFIS arm and more so in the placebo group.[4]<\/a><\/p>\n

Although it looks like a well-designed study, we were somewhat surprised that the company chose \u2018Change in CPIS from baseline\u2019 as their primary efficacy measure. The CPIS is such an insensitive scoring system that it is really not very suitable for tracking response to short-term interventions\u00a0[4]<\/a>. This is akin to using a bathroom scale to determine how much salt to add to your soup, just too coarse of a measuring stick, much too crude.<\/p>\n

Only oxygenation status could be considered to be a useful efficacy marker for the purposes of this trial, but temperature, tracheal secretions, WBC or findings on CXR are unlikely to change much during a 10-day treatment course. Remember, in CF trials it is FEV1 that is used as a measure of response. At any rate, it was nice to see that bacterial counts on BAL showed the expected treatment effect with AFIS.<\/p>\n

When FDA set out to determine NI margins: they looked for trials showing HESDE. Investigators are well advised to select their outcome measures carefully to make sure that their primary efficacy variable at least has a chance to meet \u201cESDE\u201d.<\/span><\/p>\n<\/div>\n

The authors provide several valid explanations why the study failed. We agree with them that prior and concomitant use of broad-spectrum antibiotics (meropenem) were major confounders as well.<\/p>\n

(ARADIGM \u2013 some other time)<\/p>\n

Abbreviations
\n<\/strong>VAT, VAP\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 ventilator-associated tracheitis \/ -pneumonia
\nLAI \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0liposomal amikacin inhalation
\nCPIS \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 clinical pulmonary infection score
\nMAA \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0market authorization application
\nMAI \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 Mycobacterium avium-intracellulare
\nNTM \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 non-tuberculous mycobacteria
\nHESDE \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 historical evidence of sensitivity to drug effects
\nFEV1 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0forced expiratory volume, 1st<\/sup> second
\nBAL \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0broncho-alveolar lavage<\/p>\n

Publications
\n<\/strong>[1]<\/a> http:\/\/investor.insmed.com\/releasedetail.cfm?releaseid=974954
\n[2]<\/a> K Olivier.\u00a0 Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung\u00a0Disease. AJRCCM Articles in Press. Published on 17-October-2016 as 10.1164\/rccm.201604-0700OC
\n[3]<\/a> F Gordin. Chapter 253: Mycobacterium avium Complex, \u00a0In: Mandell (ed) Principles and Practice of Infectious Diseases. 8th edition. 2014
\n[4]<\/a> M Zilverberg. Ventilator-Associated Pneumonia: The Clinical Pulmonary Infection Score as a Surrogate for Diagnostics and Outcome. CID 2010; 51:S131
\n[5]<\/a>\u00a0K Davies. Aerosolized amikacin for treatment of pulmonary Mycobacterium avium infections: an observational\u00a0case series. BMC Pulm Med. 2007;7:2<\/p>\n","protected":false},"excerpt":{"rendered":"

INSMED – NTM The company that is developing Arikayce, a preparation of liposomal amikacin inhalation (LAI), for the treatment of NTM had to withdraw its MAA in Europe earlier this year\u00a0[1] because data was not convincing enough for regulators to approve the application. Insmed now has to wait until more Continue reading Aerosolized Antibiotics (Part 2) \u2013 Mixed News on Two Fronts<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":2958,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":true,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[19,227,3,18],"tags":[1866,1859,1271,1860,176,403,594,897,211,596,1863,1856,1864,1858,5,1583,1855,889,598,1862,1865,1861,1847,153,1775,1472,1840,356,79],"class_list":["post-2955","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-recent_literature","category-the_news","category-the_viewpoint","tag-aerosolized-antibiotics","tag-afis","tag-allphase-pharma-consulting","tag-amikacin-fosfomycin-inhaler","tag-aminoglycoside","tag-antibiotic-blog","tag-aradigm","tag-arikayce","tag-azithromycin","tag-cardeas","tag-clarithromycin","tag-combination-antibiotic-therapy","tag-convert","tag-cpis","tag-fda","tag-harald-reinhart","tag-hesde","tag-inhaled-antibiotics","tag-insmed","tag-m-abscessus","tag-mac","tag-mai","tag-nebulized-antibiotics","tag-non-inferiority","tag-non-tuberculous-mycobacteria","tag-ntm","tag-pulmaquin","tag-vabp","tag-vap"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/12\/Inhalational-Abx-sliderPart2.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-LF","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":2942,"url":"https:\/\/allphasepharma.com\/dir\/2016\/12\/15\/2942\/antibiotic-inhalers-galore-part-1-more-combinations-permutations-rubiks-cube\/","url_meta":{"origin":2955,"position":0},"title":"Antibiotic Inhalers Galore (Part 1): \u00a0More Combinations and Permutations than a Rubik\u2019s Cube","author":"Harald","date":"December 15, 2016","format":false,"excerpt":"There is much interest in inhaled antibiotics these days.\u00a0 Prima facie, the logic for this approach is compelling: Getting the antibiotic (and a lot of it) directly to the site of infection, while avoiding systemic toxicity, sounds like optimized efficacy plus optimized safety combined.\u00a0 However, some high-profile failures were published\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/12\/Inhalational-Abx-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/12\/Inhalational-Abx-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/12\/Inhalational-Abx-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1314,"url":"https:\/\/allphasepharma.com\/dir\/2015\/03\/25\/1314\/aerosolized-antibiotics-selling-nebulizers\/","url_meta":{"origin":2955,"position":1},"title":"Aerosolized Antibiotics & Selling Nebulizers","author":"Harald","date":"March 25, 2015","format":false,"excerpt":"\u201cThe medicine comes for free, just pay us for the inhaler\u201d should be the marketing slogan for this group of therapeutics.\u00a0 Nebulizers are good business: hard to copy as a delivery system, they are a great opportunity to \u2018evergreen\u2019 off-patent antibiotics. The inhalational route to administer antibiotics is clearly attractive.\u00a0\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":2205,"url":"https:\/\/allphasepharma.com\/dir\/2015\/12\/23\/2205\/qidp-antibiotics-2015-year-end-update\/","url_meta":{"origin":2955,"position":2},"title":"QIDP Antibiotics – 2015 Year-End Update","author":"Harald","date":"December 23, 2015","format":false,"excerpt":"Here an updated listing of all QIDP drugs we are aware of as of 12\/24\/2015. Today just\u00a0facts and numbers; we will provide an interpretation of the current landscape in upcoming blogs. There are\u00a058 drugs which garnered QIDP status and these are listed in the Main Table below. With the recent\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/12\/QIDP-slider.jpg?fit=640%2C200&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/12\/QIDP-slider.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/12\/QIDP-slider.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":1332,"url":"https:\/\/allphasepharma.com\/dir\/2015\/03\/28\/1332\/drugs-with-qidp-designation-update-3282015\/","url_meta":{"origin":2955,"position":3},"title":"Drugs with QIDP Designation \u2013 Update 4\/8\/2015","author":"Harald","date":"March 28, 2015","format":false,"excerpt":"For the latest QIDP listing, please click HERE Our latest internet search came up with 37 drugs that garnered QIDP status.\u00a0 They are listed in the Table below (if I missed a compound, please leave a comment!!). \u00a0The\u00a0table is searchable so you should be able to massage the data to\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"APPC + QIDP copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/10\/APPC-QIDP-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/10\/APPC-QIDP-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/10\/APPC-QIDP-copy.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2985,"url":"https:\/\/allphasepharma.com\/dir\/2017\/01\/05\/2985\/aerosolized-antibiotics-part-3-avoid-hitting-wall\/","url_meta":{"origin":2955,"position":4},"title":"Aerosolized Antibiotics (Part 3) \u2013 How To Avoid Hitting A Wall","author":"Harald","date":"January 5, 2017","format":false,"excerpt":"As the 2017 Holiday Season\u00a0[1] is upon us, here some concepts to ponder while in the mood. 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Pursuing a new indication is high risk, akin to playing Russian roulette but with\u2026","rel":"","context":"In "The Viewpoint"","block_context":{"text":"The Viewpoint","link":"https:\/\/allphasepharma.com\/dir\/category\/the_viewpoint\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/01\/Inhalational-Abx-sliderPart3.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/01\/Inhalational-Abx-sliderPart3.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/01\/Inhalational-Abx-sliderPart3.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1800,"url":"https:\/\/allphasepharma.com\/dir\/2015\/08\/01\/1800\/qidp-drugs-4th-edition\/","url_meta":{"origin":2955,"position":5},"title":"QIDP Drugs – 4th Edition","author":"Harald","date":"August 1, 2015","format":false,"excerpt":">>> For the latest QIDP list, please click HERE \u00a0<<< Since our\u00a0last QIDP blog from April 8, 2015, several new drugs have made the list which now includes 41 compounds. 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It also indicates whether a drug has been\u00a0the topic of a\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"QIDP 4th edition","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/QIDP-4th-edition.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/QIDP-4th-edition.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/QIDP-4th-edition.jpg?resize=525%2C300 1.5x"},"classes":[]}],"jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/2955","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/comments?post=2955"}],"version-history":[{"count":21,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/2955\/revisions"}],"predecessor-version":[{"id":2977,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/2955\/revisions\/2977"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media\/2958"}],"wp:attachment":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media?parent=2955"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/categories?post=2955"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/tags?post=2955"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}