ALIS In Wonderland: Insmed Reaches Fairy Tale Heights On Lung Disease Results

Insmed will commercialize ALIS, its inhaled amikaycin formerly known as Arikayce, on its own for a rare, bacteria-driven lung disease if the company can win accelerated approval based on new Phase III results.

Insmed Inc.'s stock more than doubled after it reported positive Phase III results for its amikacin liposome inhalation suspension (ALIS) in patients with a rare lung disease, which it hopes could lead to an even wider market.

Bridgewater, NJ-based Insmed said on Sept. 5 that ALIS plus guideline-based therapy (GBT) met its primary endpoint of culture conversion by month six in adult patients with treatment-refractory nontuberculous mycobacterial (NTM) lung disease caused by Mycobacterium avium complex (MAC) – a population of about 26,400 to 34,400 patients in the US, Japan and top five EU markets (EU5). However, the company's estimates of NTM prevalence and its plans for additional indications given the positive Phase III CONVERT clinical trial results suggest a much larger market for ALIS is possible.

Insmed's stock price rose 119.6% to close at $26.99 on Sept. 5 after the company said ALIS plus GBT beat GBT alone by a statistically significant ratio in terms of the percentage of patients with no evidence of bacteria in the sputum in monthly cultures for three months in a row. (Also see "Antibiotic Pipeline Profile: Targeting Delivery To Infection Site" - Scrip, 7 Jul, 2017.)

The company plans to commercialize the drug formerly known as Arikayce on its own if the product wins accelerated approval from the US FDA.

Small Initial Market Could Grow Over Time

The company estimates that the number of patients diagnosed with NTM in 2018 will be between 75,000 and 105,000 in the US, 125,000 to 145,000 in Japan and 14,000 in the EU5. The number of patients treated for NTM caused by MAC is expected to be 40,000 to 50,000 in the US, 60,000 to 70,000 in Japan and 4,400 in the EU5. The estimated number of refractory patients in the MAC-caused NTM population is 10,000 and 15,000 in the US, 15,000 to 18,000 in Japan and 1,400 in the EU5.

That means the treatable population for ALIS in its initial indication – refractory NTM caused by MAC – ranges from 26,400 to 34,400 patients in Insmed's top three markets. President and CEO Will Lewis said during a Sept. 5 conference call that the company intends to market the drug on its own in all of those territories, but will consider partnerships in ex-US markets.

Lewis also noted that based on the strength of the CONVERT data Insmed may seek additional indications, including front-line treatment, maintenance treatment to prevent re-infection and treatment of NTM caused by infections other than MAC. Future indications for earlier and maintenance treatment as well as NTM due to additional bacteria could increase the market for ALIS by several multiples based on the company's estimates of the disease's population.

Leerink analyst Joseph Schwartz projected a 2019 or 2020 launch for ALIS and worldwide peak revenues of $1.6bn in 2031.

Data May Support Accelerated Approval

Insmed said the CONVERT data were consistent with secondary endpoint results seen in a Phase II trial in 2014, which failed on its primary endpoint. (Also see "Insmed flails after Phase II Arikayce fail" - Scrip, 27 Mar, 2014.) The Phase III study enrolled 336 adults with NTM lung disease caused by MAC who were refractory to at least six months of GBT – an anti-mycobacterial multi-drug regimen recommended by the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA), though it is not approved to treat NTM lung disease caused by MAC.

The primary endpoint of culture conversion at six months was achieved by 29% of patients who were treated with ALIS plus GBT versus 9% who received GBT alone (p<0.0001).

"Recall, culture conversion is having achieved culture negative on three consecutive months, which is considered more objective and stringent compared to culture density used in the Phase II TARGET study," Leerink analyst Joseph Schwartz wrote on Sept. 5.

The CONVERT trial was powered to detect a 15% treatment difference, but the difference was 20%. The study will continue for two years to collect long-term efficacy and safety data from patients on and off treatment.

Insmed noted that the six-minute walk test secondary endpoint results were not statistically significant, but the company said patients who achieved culture conversion in both arms of the study did better on the walk test than patients who still showed evidence of MAC infection (p=0.0108). However, the time it took for patients to achieve culture conversion was statistically significant for patients treated with ALIS, who reached the endpoint 30% sooner than those treated with GBT alone. Additional secondary endpoint results will be reported at a medical meeting or in a peer-reviewed journal.

CONVERT principal investigator David Griffith, University of Texas Health Science Center, said in a statement issued by Insmed that "eradication of MAC is the first and most important goal for treatment of patients with MAC lung disease." (Also see "'What Is Microbiologic Success?': Rare Lung Infection Is Microcosm Of Antibiotic Development Challenges" - Pink Sheet, 12 Nov, 2015.)

Therefore, Griffith described the CONVERT results during the company's conference call as "a watershed moment" and said that if ALIS is approved "it would be rapidly incorporated into the treatment strategies of these patients."

Insmed wanted to pursue accelerated approval for the treatment of refractory NTM lung disease caused by MAC based on the secondary endpoint in the Phase II study, and the FDA granted a breakthrough therapy designation based on those results. (Also see "FDA 'breakthrough' status excites Insmed investors; shares rocket" - Scrip, 18 Jun, 2014.) The agency said a Phase III study would be required for approval, but indicated that Insmed could pursue early approval based on the endpoint of culture conversion at six months in the Phase III study with full approval based on longer-term results from the same study. (Also see "FDA: Ph III needed before Arikayce NDA; Insmed plummets" - Scrip, 5 Aug, 2014.)

The FDA also granted fast track status and designated ALIS as a qualified infectious disease product (QIDP) to help speed the inhaled antibacterial therapy to patients with refractory NTM lung disease caused by MAC. Insmed's product candidate also has orphan drug designations from the FDA and the European Medicines Agency (EMA) for NTM caused by MAC.

Lewis declined to give a precise timeline for the Insmed's submission of a new drug application (NDA), but said during the company's Sept. 5 conference call: "We started the process of preparing our NDA prior to seeing these results and are focused on completing this process as soon as possible."

ALIS Fairly Safe In Older, Sick Patients

The symptoms of NTM lung disease include fever, weight loss, cough, lack of appetite, night sweats, blood in the sputum, and fatigue. Lewis said during Insmed's call that NTM is a progressive and destructive disease that causes irreversible lung damage and increases mortality for older patients who generally have other comorbidities. The five-year is estimated to be as high as 33%.

The company cited a decade-long study conducted between 1997 and 2007, which found that NTM prevalence in the US was increasing at about 8% annually and NTM patients on Medicare over the age of 65 were 40% more likely to die than those without the lung disease.

Lewis noted that Insmed expected a 25% dropout rate in CONVERT due to the frailty of the patients enrolled in the study, so the company was pleased with the actual dropout rates of 19.6% in the ALIS arm and 8.9% in the GBT arm (16% overall).

The serious adverse events rates were described as similar across both treatment groups, which were randomized 2:1, but the percentage reporting at least one serious treatment-emergent adverse event was 20.2% (45 patients) in the ALIS-plus-GBT group and 17.9% in the GBT-only group (20 patients).

Serious Treatment-Emergent Adverse Events (STEAEs) In CONVERT
		ALIS + GBT (n=223)	GBT (n=112)
Total STEAEs		20.2% (45 patients)	17.9% (20 patients)
Respiratory, thoracic, mediastinal disorders		11.7% (26)	9.8% (11)
	Hemoptysis	2.7% (6)	4.5% (5)
	COPD exacerbation	3.1% (7)	0.9% (1)
Infections and infestations		9% (20)	5.4% (6)
	Pneumonia	3.6% (8)	1.8% (2)
Cardiac disorders		0.4% (1)	4.5% (5)
Patient deaths		2.7% (6)	4.5% (5)

Lewis noted that "there were no distinctions between treatment arms due to hearing lost or renal impairment, side effects commonly associated with intravenous use of amikacin."

He continued: "Let me emphasize that these are very sick patients with multiple comorbidities and a high mortality rate. As a result, we believe this represents a compelling safety profile for this patient population."

Indeed, Leerink's Schwartz pointed to the lower incidence of cardiac disorders and patient deaths as positives, despite the slightly higher rate of overall serious adverse events.

"Although p-values were not provided for these incidents, the absolute improvements are likely to support ALIS efficacy in conjunction with the primary endpoint of culture conversion," he said.