Insmed’s Amikacin Faces US FDA Questions On Surrogate Endpoint, Target Population
Executive Summary
Amikacin liposome inhalation suspension seeking accelerated approval to treat nontubercuolous mycobacterial lung disease caused by Mycobacterium avium complex in adults but has only studied patients with refractory disease; agency also wants its advisory committee to opine on confirmatory trial design.
The adequacy of the surrogate endpoint, the breadth of the target population, and the design of a confirmatory trial will be up for discussion when the US FDA’s Antimicrobial Drugs Advisory Committee meets Aug. 7 to consider the efficacy and safety of Insmed Inc.'s amikacin.
Insmed is seeking accelerated approval of amikacin liposome inhalation suspension (ALIS) for treatment of nontubercuolous mycobacterial (NTM) lung disease caused by Mycobacterium avium complex (MAC) in adults as part of a combination antibacterial drug regimen.
The application relies on a surrogate endpoint of sputum culture conversion, defined as three consecutive monthly sputum cultures within six months of treatment. Although the pivotal trial demonstrated a statistically significant effect on this endpoint, there was no benefit on a secondary clinical outcome based upon the six-minute walk test (6MWT).
The pivotal trial enrolled patients with refractory disease and “no data are available for the treatment of a broader patient population with MAC lung disease,” FDA said.
On the safety side, there was a higher frequency of treatment discontinuations, adverse events and hospitalizations with ALIS relative to the comparator group.
In draft questions, FDA asks the committee to vote on whether the surrogate endpoint of sputum culture conversion based on three consecutive negative sputum cultures is reasonably likely to predict clinical benefit.
The agency's briefing document notes that the data supporting ALIS’ efficacy and safety in MAC lung diseases are primarily from the pivotal trial, which studied patients with refractory disease. “No data are available for the treatment of a broader patient population with MAC lung disease,” FDA notes.
In light of this fact, and perhaps given questions about the surrogate endpoint’s reliability and concerns about the drug’s safety profile, FDA asks the panel vote on whether substantial evidence of effectiveness and sufficient evidence of safety has been provided for two NTM patient populations: “adult patients” (the requested indication) and “adult patients with limited or no treatment options.”
In the event of a “yes” vote for either population, the agency seeks labeling recommendations and input “on the design of the trial that will need to be conducted to confirm clinical benefit.” For those panelists voting “no,” the agency requests recommendations on additional studies and analyses that are needed.
The advisory committee’s review of ALIS could be informed by discussion at a June workshop that served as a post mortem for the failure of two recent new drug applications (NDAs) to pass regulatory muster for bronchiectasis indications. (Also see "Breathing Life Into Inhaled Antibiotics: US FDA Tries To Move Class Ahead After Two Rejections" - Pink Sheet, 23 Jul, 2018.)
Progressive, Irreversible Lung Disease
NTM lung disease is characterized by progressive, irreversible lung damage and increased mortality, FDA’s briefing document states. Prevalence is estimated at 26.7 per 100,000 persons after age 60 years. About 80% of pulmonary NTM disease is caused by MAC.
NTM lung infections were the focus of an FDA patient-focused drug development meeting in 2015. (Also see "'What Is Microbiologic Success?': Rare Lung Infection Is Microcosm Of Antibiotic Development Challenges" - Pink Sheet, 12 Nov, 2015.)
Treatment typically includes the combination of a macrolide, a rifamycin and ethambutol, and continues for 12 months after sputum cultures test negative. Reported rates of treatment success range from 20%-90%.
Failure to convert sputum to culture negative after at least six months of treatment has been used to define refractory disease.
“Treatment options for patients who do not respond to first-line therapy are limited and may include switching from intermittent to daily therapy, parenteral administration of amikacin or streptomycin, use of clofazimine, or lung resection,” FDA said. “The addition of inhaled amikacin to an optimized background regimen (OBR) may represent another treatment option.”
A Drug With Many Regulatory Designations
ALIS is a liposomal suspension of amikacin sulfate, a broad spectrum aminoglycoside antibiotic. It is administered via the Lamira Nebulizer System at a dose equivalent to 590 mg of amikacin once daily.
Insmed’s drug holds designations under FDA’s orphan product, fast track, qualified infectious disease product and breakthrough therapy programs. The NDA, which seeks accelerated approval, is under priority review with a Sept. 28 goal date.
The pivotal trial (Study 212) was an open-label, randomized trial comparing ALIS with OBR versus OBR alone in subjects with refractory MAC lung infection. The primary endpoint was sputum culture conversion, which was defined as three consecutive negative monthly sputum cultures within six months of treatment. (Also see "Insmed Phase III Date Support Accelerated Approval For ALIS In Rare Lung Disease" - Pink Sheet, 5 Sep, 2017.)
“The degree of uncertainty in the surrogate endpoint of sputum culture conversion was considered acceptable in Study 212, given the unmet need in patients with refractory MAC lung disease and the seriousness of the disease.” – FDA
“There are limited data that suggest a higher mortality in patients with NTM lung infections who remain culture positive despite treatment compared to those who are culture negative,” the agency said. “Although there are uncertainties with sputum culture conversion predicting clinical benefit in this patient population, the degree of uncertainty in the surrogate endpoint of sputum culture conversion was considered acceptable in Study 212, given the unmet need in patients with refractory MAC lung disease and the seriousness of the disease.”
“In addition, there was an expectation of a finding supportive of efficacy in a clinical outcome,” such as the 6MWT, FDA said.
“Data on the durability of sputum culture conversion three months after completion of MAC therapy and clinical outcomes are being collected in patients who are continuing in Study 212,” FDA said, adding however, that a comparative assessment of later clinical outcomes may be limited due to the study’s design.
Surrogate Endpoint Success …
Study 212 randomized 336 subjects in a 2:1 ratio to ALIS or OBR. If a subject demonstrated culture conversion within the first six months, the total duration of treatment was to be 12 months from the first of three consecutive, negative cultures. If culture conversion was not achieved with six months of treatment, the subject was discontinued at the eight-month visit.
“Additionally, subjects who experienced a relapse or recurrence within six months of treatment were to be discontinued from the study at Month 8,” FDA said. “This makes follow-up data difficult to interpret.”
Interpretation of the long-term data is further complicated by the protocol allowing nonconverters or those who experienced a relapse or recurrence within the first six months in either study arm to enroll in an extension study (Study 312) and either initiate or continue ALIS, FDA said.
In Study 212, almost four times as many subjects discontinued in the active treatment group compared to the control (33.5% versus 8.0%), with the most common reason for discontinuation being adverse events.
On the primary endpoint, significantly more subjects achieved culture conversion by six months in the ALIS plus OBR arm compared to OBR alone (29.0% versus 8.9%). This finding remained intact even under a sensitivity analysis that considered subjects who achieved the culture conversion criteria, but met the protocol definition of recurrence by month six, as treatment failures.
… But Clinical Benefit In Question
Change from baseline to month six in the 6MWT distance was a key secondary endpoint. However, subjects in the ALIS plus OBR arm experienced a mean decrease of 1.9 meters in their 6MWT distance compared to an increase of 1.3 meters for subjects in the OBR arm, although this difference was not statistically significant.
In Insmed's briefing document, the company said it was anticipated that patients who achieved culture conversion may derive a functional benefit, as assessed by the 6MWT distance. The company presents results from a prespecified exploratory analysis of change from baseline in the 6MWT distance based upon conversion status.
Overall, converters showed an improvement in the 6MWT distance at month six, with a mean difference of 24.7 meters between treatment arms, the company said.
“Results were consistent when analyzed by treatment arm. In the ALIS + Multidrug Regimen arm, converters showed an improvement in the 6MWT distance at Month 6, with a [least squares] mean difference of 31.2 (P=0.005),” Insmed’s briefing document states. Similarly, in the Multidrug Regimen Alone arm, converters showed an improvement in the 6MWT distance at Month 6 with a LS mean difference of 25.2; however, this difference did not reach statistical significance (P=0.33) due to the small number of converters in this arm (N=10).”
The application also includes supportive information from two additional trials.
Study 112 was a Phase II trial of subjects with refractory MAC or M. abscessus lung infections and included patients with cystic fibrosis (CF). In the 89-patient study, treatment with ALIS plus OBR failed to demonstrate a statistically significant benefit on the primary endpoint, change from baseline on the semi-quantitative scale for mycobacterial culture at Day 84, compared to the comparator group that received placebo vehicle in addition to OBR.
However, a greater proportion of subjects in the ALIS group (31.8%) achieve a negative culture than subjects in the placebo group (8.9%). In addition, subjects in the ALIS group had a mean increase from baseline of 20.6 meters on the 6MWT compared to a mean decrease of 25.0 meters in the placebo group.
Study 312 is an ongoing, open-label, single-arm extension study of patients from either arm of Study 212 who did not achieve culture conversion or had a relapse or recurrence by month six.
The agency said efficacy data from Study 312 “are difficult to interpret at this time as the study is ongoing and not all subjects have completed the Month 6 visit by the time of the data cutoff date. Additionally, it will be very difficult to compare outcomes between the two non-randomized groups.”
Higher Rate of AEs, Hospitalizations
The safety database includes 820 subjects who received at least one dose of ALIS and 802 subjects who received multiple doses. Of this number, 352 were non-CF patients with refractory pulmonary MAC infection.
While there was no mortality imbalance between the ALIS plus OBR arm and the control arms in clinical studies, there were more study discontinuations in the ALIS-treated subjects due to treatment emergent adverse events (TEAEs) and “withdrawal by subject,” FDA said.
“The majority of the TEAEs were in the ‘Respiratory, thoracic and mediastinal disorders’ and ‘Infections and infestations’ system organ classes," FDA said. "Notable TEAEs in the Phase III trial (Study 212) that were more common in the ALIS plus OBR arm as compared with the OBR alone arm included: dysphonia, cough, dyspnea, upper airway inflammation, fatigue and asthenia, diarrhea, nausea, tinnitus, wheezing, and rash.”
In addition, there were slightly more Study 212 patients in the ALIS plus OBR arm who experienced serious adverse events, including pneumonia and chronic obstructive pulmonary disease exacerbations, FDA said.
Data from the three NTM studies suggests the highest, at-risk period for experiencing TEAEs was the first six weeks after starting ALIS therapy, the agency said.
There also was an imbalance in hospitalizations among subjects in Study 212.
“There were 92 hospitalizations in 47 (21.1%) subjects in the ALIS plus OBR arm compared to 24 hospitalizations in 15 (13.4%) subjects in the OBR alone arm,” FDA said.
“While the administration of ALIS has been associated with primarily respiratory-related AEs, they were mostly local and were mild to moderate in severity.” – Insmed
“The most common reasons for hospitalization in the ALIS plus OBR arm included pneumonia, exacerbation of underlying lung disease (COPD, bronchiectasis), hemoptysis, respiratory failure, and dyspnea,” FDA said. “The most common reasons for hospitalization for the OBR alone arm included hemoptysis, exacerbation of underlying lung disease, MAC infection and acute myocardial infarction.”
The agency said its review of the hospitalizations is ongoing.
Insmed’s briefing document asserts the safety of ALIS has been well characterized. “While the administration of ALIS has been associated with primarily respiratory-related AEs, they were mostly local and were mild to moderate in severity,” the company said.
“The rate of AEs leading to discontinuation of ALIS was relatively low compared to the overall incidence. Dose interruptions are often sufficient to manage local respiratory AEs,” Insmed said. “The safety profile is acceptable given the significant risk of the disease, the inadequacy of current treatment approaches, and early indications of positive clinical outcomes from the use of ALIS, including a potential mortality benefit.”