-12-week data support initiation of Phase 2b study to evaluate longer treatment duration for VX-509-
The study evaluated four doses of VX-509, and data from the treatment arms of the two highest doses (100 mg and 150 mg) showed statistically significant ACR20, ACR50, ACR70 and DAS28 responses as compared to placebo. The 150 mg treatment arm showed ACR20, ACR50, ACR70 and DAS28 responses of 66 percent, 49 percent, 22 percent and -3.06, respectively, while the placebo arm showed responses of 29 percent, 7 percent, 2 percent and -1.25. Overall, the most frequently reported class of adverse event in the VX-509 and placebo arms was infections. The most common individual adverse events observed, which occurred in approximately five percent or less of people in the study, were nausea, headache and increased alanine transaminase (ALT), regardless of treatment arm. Five percent of people discontinued treatment due to adverse events in the placebo group, compared to 8 percent of all people who received VX-509.
"These early results are encouraging and provide strong support that the
selective targeting of JAK3 by VX-509 may represent a new approach to
the treatment of RA and other autoimmune and inflammatory diseases,"
Data from this study will be submitted for presentation at an upcoming medical meeting. Based on the results announced today, VX-509 will next be evaluated as part of a six-month Phase 2b study in RA. This study is expected to evaluate once-daily (QD) and twice-daily (BID) doses of VX-509 in combination with methotrexate, a commonly prescribed disease-modifying antirheumatic drug (DMARD) for RA that is frequently used in combination with other RA medicines.
About the Study
This double-blind, randomized, placebo-controlled Phase 2a study of
VX-509 enrolled 204 people with active moderate to severe RA. The study
enrolled people who had an inadequate response to at least one currently
available non-biologic (non-injectable) DMARD. The study evaluated four
dose levels of VX-509, which was given twice daily (BID) for 12 weeks.
Patients did not receive methotrexate during this study, but could have
received it prior to the study. Approximately 40 clinical trial sites
participated in the trial in
The study met its two primary endpoints, which were the proportion of people who achieved an ACR20 response at week 12 and the change from baseline in DAS28 at week 12. Additional secondary endpoints were used to evaluate the clinical activity of VX-509, including ACR50 and ACR70 responses at week 12. The ACR responses and DAS scores observed in the two highest dose groups for VX-509 indicated continuous and statistically significant improvements in the signs and symptoms of RA, with these effects being observed in some patients as early as the first week of the study. ACR responses and DAS scores are provided below and are based on an intent-to-treat analysis where patients who discontinued treatment prior to week 12 were counted as non-responders (failures) in the efficacy analyses, regardless of their response to treatment:
|25 mg (n=41)||
|50 mg (n=41)||
|100 mg (n=40)||
|150 mg (n=41)||
An additional analysis of ACR responses was conducted for people in the study who completed 12 weeks of treatment with VX-509. ACR20 response rates of 46 percent, 76 percent, 81 percent and 82 percent were observed for people who received 25 mg, 50 mg, 100 mg and 150 mg of VX-509, respectively, compared to 41 percent in the placebo arm.
Disease Activity Scores at Week 12:
|DAS28 Improvement from Baseline|
The study also evaluated the proportion of patients in each treatment arm who experienced clinical remission, defined as a patient with a DAS28 score of less than 2.6 at week 12. In this study, 35 percent and 37 percent of people achieved DAS28 remission in the 100 mg and 150 mg treatment groups, respectively, compared to 7 percent of people in the placebo arm.
At least 80 percent of all people in each of the VX-509 treatment groups completed the 12-week treatment course, and 68 percent of people who received placebo completed treatment. Eight percent of people who received VX-509 discontinued treatment due to adverse events, compared to 5 percent of people who received placebo. Overall, the most frequently reported class of adverse event in the VX-509 and placebo arms was infections, which occurred in 17 percent of people who received placebo and in 17 percent of people who received VX-509. The most common individual adverse events observed in both the placebo and VX-509 treatment arms were nausea (5 percent), headache (4 percent) and increased alanine transaminase (ALT) (4 percent). Dose-related low-level increases in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were observed in people who received VX-509. Discontinuations due to adverse events occurred more frequently in the 100 mg and 150 mg VX-509 dose groups. Serious adverse events occurred in 2 percent of people in the placebo treatment group, compared to 5 percent in the VX-509 treatment groups. The most common serious adverse events in the VX-509 treatment arms were infections. There were no serious adverse events related to measurements in ALT.
In the 100 mg dose group of the study, one patient died of a hemorrhagic stroke, reported as unrelated to VX-509. Also in this dose group, one patient died of pneumonia. This patient received VX-509 and other medicines also associated with a potential increase in susceptibility to infections. As a result, a contribution of VX-509 to the severity of the pneumonia in this patient cannot be ruled out.
There were no declines observed in measures of hemoglobin or neutrophils among people who received VX-509 compared to those who received placebo. Two percent of all people who received VX-509 discontinued treatment due to lack of efficacy, compared to 14 percent in the placebo group.
VX-509 is an investigational oral medicine being developed by Vertex that is designed to selectively inhibit Janus kinase 3, or JAK3. JAK3 is one of four JAK family kinases, which include JAK1, JAK2, JAK3 and Tyk2. In autoimmune diseases, JAK3 is an essential component of the signaling cascade that contributes to the abnormal immune response that results in chronic inflammation and, in the case of RA, irreversible damage to cartilage and bones. Specific inhibition of JAK3 represents a new approach to the treatment of a range of autoimmune diseases. Based on in vitro data, VX-509 has demonstrated a high degree of potency and selectivity for inhibition of JAK3. VX-509 has been shown to be greater than 1000-fold more selective for JAK3 compared to non-JAK kinases and approximately 25- to 150-fold more selective for JAK3 compared to other JAK isotypes in cell-based assays. This high level of selectivity was confirmed in clinical studies where potent dose-related inhibition of a JAK3 dependent biomarker was observed while little to no effect was shown against a JAK2/JAK1 dependent biomarker. VX-509 was discovered by Vertex scientists.
About Rheumatoid Arthritis
RA is a chronic inflammatory disease that affects 1 percent to 2 percent
of the world's population, including 1.5 million adults in
The treatment of RA focuses on reducing symptoms and inhibiting progression of the disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may reduce the symptoms of pain, swelling and stiffness, but they do not alter the natural course of the disease. Disease-modifying antirheumatic drugs (DMARDs) have shown effects in slowing the progression of joint damage and time to disability and thus altering the natural history of RA. While recently approved medicines are effective in a portion of patients, a significant number of people with RA do not respond adequately or become refractory to these medicines, creating a significant need for new approaches to RA treatment.
About Endpoints in RA: ACR and DAS Responses
The most common endpoints in RA clinical studies are ACR and DAS responses. ACR responses are defined as the proportion of patients in a trial who achieve at least a pre-specified percent improvement in the signs and symptoms of RA, as measured by tender and swollen joint counts and other criteria. For example, an ACR20 response reflects the proportion of people who had at least a 20 percent improvement in both tender and swollen joints in addition to improvements in other criteria such as C-reactive protein (CRP), Health Assessment Questionnaire (HAQ) disability scores and others. DAS responses, including DAS28, are derived from an assessment of multiple measurements of RA, including tender and swollen joints, C-reactive protein (CRP) and a patient's assessment of general health.
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Special Note Regarding Forward-Looking Statements:
This press release contains forward-looking statements as defined in the
Private Securities Litigation Reform Act of 1995, including statements
regarding (i) the results from the completed Phase 2a trial supporting
initiation of a Phase 2b trial to evaluate longer treatment durations
for VX-509 in people with RA; (ii) the possibility that selective
targeting of JAK3 by VX-509 may represent a new approach to treatment of
RA and other autoimmune and inflammatory diseases; (iii) the potential
that a longer-duration trial would show any or additional improvements
in RA activity and further establish the safety profile of VX-509; and
(iv) the potential clinical trial design for the expected Phase 2b
trial. While Vertex believes the forward-looking statements contained in
this press release are accurate, these statements are subject to risks
and uncertainties that could cause actual outcomes to vary materially
from the outcomes referenced in the forward-looking statements. These
risks and uncertainties include, among other things, the risks that
efforts to develop VX-509 may not proceed due to technical, scientific,
commercial, financial or other reasons, that clinical trials may not
proceed as planned, that longer-duration clinical trials of VX-509 may
not show any or any additional improvements in RA activity, that a
safety profile for VX-509 could be established in further nonclinical
studies or clinical trials that could put further development of VX-509
in jeopardy or adversely effect its therapeutic value, and other risks
listed under Risk Factors in Vertex's annual report and quarterly
reports filed with the
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