Nintedanib Receives Support to Treat Additional Lung Condition Associated with Rare Systemic Sclerosis
Committee: Arthritis Advisory Committee
Indications: The treatment of systemic sclerosis associated interstitial lung disease (SSc-ILD).
Question 1: Overall, do the data provide substantial evidence of the efficacy of nintedanib for the treatment of systemic sclerosis interstitial lung disease?
Vote Results: Yes 10 No 7 abstain 0
Question 2: Is the safety profile of nintedanib adequate to support approval of nintedanib for the treatment of systemic sclerosis interstitial lung disease?
Vote Results: Yes 14 No 2 abstain 0
Question 3: Do you recommend approval of nintedanib at the proposed dose of 150 mg twice daily for the treatment of systemic sclerosis interstitial lung disease?
Vote Results: Yes 10 No 7 abstain 0
Drug/Device: Drug (NINTEDANIB SOFT CAPSULES)
Sponsor: Boehringer Ingelheim Pharmaceuticals, Inc
Background:
Systemic sclerosis (SSc) is a devastating medical condition of unknown etiology. It is a rare, multisystem, connective tissue disease involving the skin, underlying tissues, blood vessels, and major organs. It affects approximately 100,000 people in the United States, and interstitial lung disease (ILD) is one of the most frequent disease manifestations. The progression of ILD tends to be rapid in the first year after diagnosis, and it is the main cause of SSc-related deaths. SSc-associated ILD (SSc-ILD) represents a high and significant unmet medical need as currently no approved treatments exist.
Nintedanib was first approved in the US in 2014 to treat idiopathic pulmonary fibrosis (IPF), and has since been approved for treatment of IPF in more than 70 countries. This new drug application is proposing the use of Nintedanib as a safe and efficacious treatment for patients diagnosed with systemic sclerosis associated interstitial lung disease (SSc-ILD).
Study design:
The clinical development program for Nintedanib as a treatment for SSc-ILD consists of a single double blind, randomized, placebo-controlled, parallel-group study design, Study 1199.214. This trial was designed to evaluate the efficacy and safety of the use of this drug in patients with SSc-ILD. In the study, 576 patients were randomized 1:1 to either the experimental group given two daily oral doses of 150 mg Nintedanib or to the matching placebo group. The primary endpoint was the annual rate of decline in forced vital capacity (FVC) in mL through repeated measures over 52 weeks. Key secondary endpoints included absolute change in modified Rodnan Skin Score (mRSS) at week 52 and absolute change in Saint George’s Respiratory Questionnaire (SGRQ), a patient reported outcome (PRO) at week 52.
The study was conducted as planned. A total of 576 patients, predominantly females (75%), were randomized and treated. Approximately half (53%) of the patients were enrolled at sites in Europe, 25% were enrolled in Canada and the US, and 23% in Asia. Overall, the patient demographic characteristics were balanced and representative of the intended patient population.
Unique Challenges:
Of the 576 patients enrolled, 94% completed visits through week 52. The primary endpoint analysis demonstrated a significant difference between the treatment and placebo arms in the annual rate of decline in FVC in mL over 52 weeks. However, the agency was cautious of the uncertainty in the proposed endpoint to alter natural decline in FVC in a one year study, especially in the absence of preliminary information on the effects of Nintedanib in this patient population. Additionally, the experimental group had a numerically higher study withdrawal rate (8%) compared to the placebo group (5%). Treatment discontinuations occurred in 15% of total patients, with the experimental group again demonstrating a numerically higher discontinuation rate (19%) compared with the placebo group (11%). The most common reason for study withdrawal was adverse event.
Sensitivity analyses:
To assess the robustness of primary analysis, a sensitivity analysis was employed to address missing data resulting from treatment and study discontinuation. While the results for the primary endpoint was statistically significant based on the pre-specified analysis, sensitivity analysis showed mixed results primarily due to the small magnitude of the effect.
Responder analysis:
Given the uncertainty of what delineates clinically significant change in FVC in SSc-ILD patients, responder analysis was conducted by the agency. This analysis evaluated the relative decline in FVC using various thresholds for response, such as “relative 10%” or “relative 5%” decline from baseline at week 52. Patients who discontinud the study or treatment were categorized as non-responders. The FDA-conducted responder analysis demonstrated that “relative 5% decline” favored Nintedanib over the placebo, while “relative 10% decline” showed no favoring for the treatment over the placebo. Using absolute decline in FVC (absolute 10% decline and absolute 5% decline) showed a similar pattern as the analysis using relative decline in FVC. The applicant used the worst observation carried forward approach to imputing missing data and then applied the thresholds to define non-response. In spite of different methods employed, the agency and applicant analyses convey identical information.
Efficacy:
Primary endpoint analysis: The main efficacy analysis was assessed at week 52. The primary endpoint was the annual rate of decline in FVC in mL over 52 weeks, the same primary endpoint from applicant’s the IPF program which was approved on October 2014. The annual rate of decline in FVC in mL over this 52-week treatment period with measurements at pre-defined weeks was compared between the two arms. The adjusted annual rate of decline in FVC was lower in the treatment arm (-52 mL/year) than in the placebo arm (-93 mL/year), with a treatment difference of 41 mL/year.
Subgroup analysis:
The protocol pre-specified group analyses were conducted to evaluate the influence of stable background immunosuppressive therapy and mycophenolate mofetil/sodium use at baseline to study this treatment. A less robust treatment effect was observed in this adjusted annual rate of decline in FVC for all pre-specified subgroups.
Secondary efficacy measures:
The analysis results from the key secondary endpoints did not yield a statistically significant difference between patients receiving the treatment and those receiving the placebo. Neither did these results suggest differences in other secondary endpoints.
Safety and Risk:
Patients were evaluated for safety assessments at pre-defined weeks until week 100. A follow-up visit was scheduled 28 days after the end of treatment visit. Deaths and serious adverse events (AEs) were balanced between treatment arms. There were more AEs leading to a decrease in the use of the drug and discontinuation in the Nintedanib arm. Patients who experienced clinically significant deterioration of SSc-ILD or other SSc symptoms were eligible to receive rescue therapy with permitted medications to manage deterioration.
Benefit / Risk Analysis:
The study showed a statistically significant decreased rate of decline of FVC with the use of Nintedanib compared to the placebo over 52 weeks. However, key secondary endpoints were not supportive of a direct treatment benefit for Nintedanib over the placebo at week 52. Thus, the clinical significance of the treatment effect lowering the rate of decline by 41 mL/year (or approximately 1.2% predicted) remains a question. Though SSc-ILD is a rare and serious disease associated with high morbidity and mortality, it is also a disease with high unmet need for new therapies. Whether or not the use of Nintedanib provides a favorable benefit-risk assessment for the treatment of SSc-ILD remains unclear given the modest treatment effect on FVC and the lack of support from key secondary endpoints.
Many (7 out of 17) of the votes against Nintedanib noted the low magnitude of benefit, more so than safety concerns. The ten panel members (10/17) that voted in favor of Nintedanib were swayed by significant results on FVC changes in a disorder (SSc-ILD) that has no approved indications and for which there is a large unmet need.