Aradigm Announces Detailed Third Party Evaluation Results for Apulmiq (FDA)/Linhaliq (EMA)
Aradigm Corporation (OTCQB: ARDM) ("Aradigm" or the "Company") today announced specific, detailed results of an independent third party evaluation (TPE) of the Phase 3 clinical trial results for Apulmiq.
As previously reported, Aradigm received a Complete Response Letter (CRL) on 26 January 2018, from the US Food and Drug Administration (FDA) regarding its New Drug Application (NDA) for Apulmiq as a treatment for non-cystic fibrosis bronchiectasis (NCFBE) patients with chronic lung infection with Pseudomonas aeruginosa (P. aeruginosa). The CRL identified issues related to a manual re-review of patient-level pulmonary exacerbation (PE) data conducted by Aradigm after errors were discovered in the analyses performed by a contract research organization. The CRL stated that an independent third party would need to verify the results of the ORBIT-3 and ORBIT-4 Phase 3 trials before the FDA could draw any conclusions regarding the safety and efficacy of Apulmiq from these trials.
Aradigm believes the independent TPE results verify the significant treatment effects of Apulmiq in ORBIT-4 for the pre-specified primary endpoint and secondary endpoints as previously reported in the NDA submitted on 26 July 2017. The TPE results also verify the already reported non-significant primary and secondary PE endpoint results of ORBIT-3. A meeting has been scheduled with the FDA to discuss these TPE verified Phase 3 trial results.
Based on the TPE results, in ORBIT-4 the primary endpoint of median time to first PE was 231 days in the Apulmiq group and 158 days in the placebo group, a difference of 73 days. The treatment effect, based on a stratified unweighted log-rank test (stratified by sex and previous number of exacerbations in the past 12 months prior to randomization), was statistically significant (HR: 0.70; 95% CI: 0.52-0.96; p = 0.024). For the first secondary efficacy endpoint, there was a 37% reduction in the frequency of PEs over the 48-week treatment period in the Apulmiq treatment group as compared to the placebo group (negative binomial model; RR: 0.63; 95% CI: 0.48-0.82). This result was statistically significant (p=0.0007). In the analysis of the second secondary endpoint, a statistically significant 61% reduction in the frequency of severe PEs in the Apulmiq group compared with placebo was found (using the negative binomial model; RR: 0.39 (95% CI: 0.21-0.72; p=0.0024).
In ORBIT-3 the median time to first PE was 214 days in the Apulmiq treatment group as compared to 136 days in the placebo group. This increase of 78 days in the median time to first PE was similar to ORBIT-4 but was not statistically significant (HR: 0.97; 95% CI: 0.70-1.34; p = 0.84). For the first secondary efficacy endpoint, there was a 15% reduction in the frequency of all PEs over the 48-week treatment period in the Apulmiq treatment group as compared to the placebo group but it was not statistically significant (RR: 0.85 95% CI: 0.65-1.12; p=0.26). In the analysis of the second secondary endpoint, a statistically non-significant 19% reduction in the frequency of severe PEs in the Apulmiq group compared with placebo was found (p=0.51).
In ORBIT-3 and ORBIT-4, randomization of patients was stratified by the number of PEs treated with antibacterials in the 12 months prior to randomization: 2 to 3, 4 to 7, and more than 7 PEs. As agreed by the FDA and the EMA, due to the low number of subjects enrolled in the “more than 7” prior PE stratum, a combined single stratum of frequent exacerbators (4 or more prior PEs) was used for the purpose of the statistical analyses of the two Phase 3 trials. This trial subpopulation of frequent exacerbators accounts for approximately 22% of the overall trial population in ORBIT-3 and ORBIT-4 and is part of a well-defined and identifiable clinical phenotype (Chalmers, 2018*). This subpopulation has a particularly rare prevalence with more extensive and serious disease, increased risk of future PEs and higher mortality as compared to the overall Phase 3 trial population of NCFBE patients with chronic lung infection with P. aeruginosa.
Although the analyses had low statistical power, due to the relatively small size of the frequent exacerbator group (22% of the overall trial population) the primary and secondary PE results for the frequent exacerbators in both trials were concordant and demonstrated clinically meaningful outcomes in favor of Apulmiq. In ORBIT-4, for the frequent exacerbators the median time to first PE was 211 days in the Apulmiq group and 163 days in the placebo group, a difference of 48 days. In ORBIT-3 the median time to first PE was 163 days in the Apulmiq group and 74 days in the placebo group, a difference of 89 days. The treatment effect, based on the stratified unweighted log-rank test was also very similar in both trials (ORBIT-4 RR: 0.66; 95% CI: 0.35-1.24; p = 0.19 and ORBIT-3: RR: 0.66; 95% CI: 0.37-1.18; p = 0.16).
When analyzing the frequency of PEs in the frequent exacerbators, using the negative binomial model, clinically meaningful and statistically significant results in favor of Apulmiq were observed in ORBIT-4, with an estimated risk reduction of 49% for all PEs (RR = 0.51; 95% CI: 0.31-0.85; p = 0.0094). In ORBIT-3, the risk reduction for all PEs was 34% and of borderline significance (RR = 0.66; 95% CI: 0.43-1.00; p = 0.052). While the frequency analyses of severe PEs had large variability due to small sample size, the analyses for the frequency of moderate and severe PEs showed a consistent risk reduction between 55% in ORBIT-4 and 35% in ORBIT-3. In the frequent exacerbators with 4 or more PEs per year, the observed risk reductions of PEs translates to about 2 fewer PEs per patient per year. Such a reduction is of important clinical relevance because each individual PE may be an irreversible event, and frequent PEs have been shown to increase morbidity in NCFBE patients (Chalmers, 2018*).
There are no approved treatment options for the prevention or reduction of PEs in NCFBE patients with chronic lung infection with P. aeruginosa. We believe that frequency of PEs is a more appropriate endpoint for measuring treatment effectiveness as compared to time to first PE, and based on an FDA Workshop on 26 June 2018 we believe the FDA and clinical NCFBE experts agree with this position.
Aradigm has a meeting with the FDA scheduled for 25 January 2019 to discuss these TPE results and to seek agreement for a resubmission of the Apulmiq NDA. Aradigm is currently also addressing the other issues identified in the CRL, following FDA guidance provided in a Type C meeting. A complete in vitro release method development report has been submitted for FDA review, a new Human Factor study is underway and work to address the product quality deficiencies is nearing completion.
Aradigm remains confident in the efficacy, safety and quality of Apulmiq and is committed to continue working toward the approval of Apulmiq for NCFBE patients with chronic lung infection with P. aeruginosa, who have very severe disease with high morbidity and mortality and no available treatment options.
Aradigm is an emerging specialty pharmaceutical company focused on the development and commercialization of drugs for the prevention and treatment of severe respiratory diseases. Aradigm is currently in Phase 3 development of Apulmiq (an investigational proprietary formulation of ciprofloxacin for inhalation) for the treatment of patients with NCFBE and chronic lung infection with P. aeruginosa. Aradigm's inhaled ciprofloxacin formulations are also product candidates for treatment of patients with cystic fibrosis and non-tuberculous mycobacteria, and for the prevention and treatment of high threat and bioterrorism infections, such as inhaled tularemia, pneumonic plague, melioidosis, Q fever and inhaled anthrax.
About Non-Cystic Fibrosis Bronchiectasis
NCFBE is a severe, chronic and rare disease characterized by abnormal dilatation of the bronchi and bronchioles, frequently associated with chronic lung infections. It is often a consequence of a vicious cycle of inflammation, recurrent lung infections, and bronchial wall damage. NCFBE represents an unmet medical need with high morbidity and mortality that affects more than 150,000 people in the U.S. and over 200,000 people in Europe. There is currently no drug approved for the treatment of this condition.
Except for the historical information contained herein, this news release contains forward-looking statements that involve risk and uncertainties, including the risk that Apulmiq may not receive regulatory approval or be successfully commercialized, as well as the other risks detailed from time to time in the Company’s filings with the Securities Exchange Commission (SEC), including the Company’s Annual Report on Form 10-K for the year ended December 31, 2017 filed with the SEC on March 23, 2018, and the Company’s Quarterly Reports on Form 10-Q.
More information about Aradigm can be found at www.aradigm.com.
* Chalmers JD, Aliberti S, Filonenko A, et al. Characterization of the “frequent exacerbator phenotype” in bronchiectasis. Am J Respir Crit Care Med. 2018;197(11):1410-20.
Aradigm and the Aradigm Logo are registered trademarks of Aradigm Corporation. Apulmiq is a registered trademark of Grifols, S.A.
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