LONDON, UK (GlobalData), 1 June 2012 - Investors reacted swiftly to last week’s unexpected and unwelcome announcement by Vertex Pharmaceuticals of an error in previously reported data from an interim analysis of an ongoing Phase II combination therapy study of Kalydeco (ivacaftor) and the experimental drug VX-809 in people with cystic fibrosis (CF).
The company had accidentally reported lung function data as absolute rather than relative improvements. News that the data was not quite as exciting as originally touted by the company raised concerns that the combination regimen was far less effective than initially reported in early May, prompting a sudden 18% drop in the company’s shares. The decline occurred after shares had risen by 73% following excitement generated by the original release of the data. As if this were not bad enough, on May 29, the same day that Vertex announced the reporting error, the FDA issued an “untitled letter” for the company’s inclusion of misleading content in a promotional video for its Incivek (telaprevir) hepatitis C drug. Vertex attributed the embarrassing gaffe regarding the cystic fibrosis trial to “misinterpretation” of the data it had received from a contract research organization and provided a correction to the interim analysis in the announcement of the reporting error. This analysis, which was based on 37 patients treated with combination therapy and 11 patients who received placebo for 56 days, described the absolute improvement in lung function compared to baseline. In addition, the company provided for the first time data regarding the mean absolute improvement in lung function among the patients who received Kalydeco and VX-809 compared to placebo.
The negative reaction of investors was understandable, particularly in view of the rapid, 3-month approval of Kalydeco last January as the first drug to treat the underlying cause of cystic fibrosis. This success undoubtedly helped fuel high hopes that combination therapy with VX-809 would prove effective in CF patients who cannot take Kalydeco alone because they have a different type of genetic mutation. When viewed with the Incivek marketing troubles, these two events point to a possible underlying problem where Vertex executives became giddy at the success of Kalydeco and Incivek, and simply got ahead of themselves in their excitement. While Vertex’s reputation in the public eye is tarnished, it is not likely to be irreparably damaged. These events nonetheless serve as a critical lesson for the company regarding the need to be more realistic as well as cautious in promoting their products.
More importantly, we must consider the implications of these events for patients who are affected by the diseases that Incivek and Kalydeco are intended to treat. Taking the example of the reporting error concerning combination treatment with Kalydeco and VX-809 in cystic fibrosis, what does this mean from a therapeutic standpoint for patients with this rare genetic disease?
Kalydeco is the first and currently the only approved drug for the treatment of cystic fibrosis and actually addresses the underlying cause of the disease – a faulty gene and its protein product, known as cystic fibrosis transmembrane conductance regulator (CTFR) – rather than just the symptoms. It is specifically indicated for CF patients who have at least one copy of the G551D mutation, which is found in about only 4% of the approximately 1,200 people in the US with the disease. This mutation leads to a CFTR protein that does not function properly once it has reached the cell surface. In contrast, in CF patients with another mutation known as F508del, the mis-functioning CFTR protein does not even reach the cell surface. This mutation is far more common, with nearly 90% of patients having at least one copy of the defective gene, and about 50% having two copies. However, Kalydeco is not indicated for patients with the F508del mutation, which means the majority of CF patients cannot take the drug, forcing them to rely exclusively on symptomatic treatment. However, VX-809, which is still in development, is designed to move the CFTR protein to the cell surface in these patients. The combination with Kalydeco, which helps the protein function properly once at the cell surface, may be the first disease-modifying therapy for a broader class of CF patients.
In combining therapy with Kalydeco and VX-809, Vertex scientists sought to determine if the complementary mechanisms of actions of these two drugs provided enhanced efficacy over either drug alone in patients with the F508del mutation. In other words, would Kalydeco really improve the function of the CFTR protein after VX-809 moves it to the cell surface? The second part of the ongoing Phase II study, which enrolled 108 patients with at least one copy of the F508del mutation, was designed to answer this question. The planned interim analysis provided data from 37 patients with two copies of the F508del mutation who completed 56 days of combination therapy and 11 patients with one or two copies of this mutation who received placebo during this time.
In early May, top-line results from the interim analysis of the Phase II study of combination therapy with Kalydeco and VX-809 were erroneously reported as absolute rather than relative improvements in lung function, which is the single most important marker of disease progression in people with cystic fibrosis and is measured by forced expiratory volume in 1 second (FEV1). Vertex announced that 46% (17/37) of the patients experienced an improvement in lung function of 5 percentage points or more and 30% (11/37) experienced an improvement of 10 percentage points or more from baseline to day 56.
The actual absolute improvements reported in the correction announced by Vertex last week were lower: 35% (13/37) experienced an improvement of 5 percentage points or more and 19% (7/37) experienced an improvement in lung function of 10 percentage points or more from baseline to day 56. As previously announced, none of the patients treated with placebo (0/11) achieved an improvement in lung function of 5 percentage points or more improvement in lung function from baseline to day 56.
Along with the correction, Vertex provided additional data from the interim analysis for patients with two copies of the F508del mutation. A mean absolute improvement in lung function of 8.5 percentage points was observed in the patients treated with Kalydeco and VX-809 compared to patients who received placebo (p=0.002). This result was due to both a 4% increase in lung function in patients treated with combination therapy and a 4.6% decrease in patients who received placebo. This decline is greater than typically seen with placebo in clinical trials, which usually ranges between 1% and 2%. While the improvement in lung function with combination therapy might not be as exciting in a real-world sense as was observed in the Phase II study, this is still a very promising drug candidate.
As of May 29, when the interim analysis data correction was announced, all patients in the study completed dosing. Analyses are ongoing and complete data, including statistical analyses for all patients groups, should be available by mid-year. In addition, Vertex plans to begin a pivotal Phase III study of combination therapy with Kalydeco and VX-809 in patients with two copies of the F508del mutation, pending final study results and discussions with regulatory agencies. In conclusion, GlobalData expects that the Phase III study will provide a clearer idea of the efficacy of combination therapy with Kalydeco and VX-809, but does not anticipate results as outstanding as those that were initially reported in error. However, we do believe that this combination therapy regimen will provide an at least somewhat effective option for the majority of patients with cystic fibrosis who cannot take Kalydeco alone because they have the F508del mutation. Although the corrected results are not as spectacular as those originally reported, they are still very promising. Viewed without reference to the mistaken results, investors would have likely reacted very positively to the most recent release. We also anticipate, or at least hope, that Vertex will proceed more carefully when announcing the results of this trial and in promoting products that are approved in the future.
*Combination Therapy with Kalydeco and VX-809 in Cystic Fibrosis: Too Good to be True?
This expert insight was written by GlobalData’s senior analyst for the genitourinary, genetic and hormonal disorders segment, Denise Lymperis, MS.
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