Secukinumab, an anti-interleukin-17A monoclonal antibody, improved the signs and symptoms of ankylosing spondylitis (AS) in two phase 3 studies (MEASURE 1 and MEASURE 2). Here, we present 52-week ...results from the MEASURE 3 study assessing the efficacy and safety of secukinumab 300 and 150 mg subcutaneous maintenance dosing, following an intravenous loading regimen.
A total of 226 patients were randomized to intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous secukinumab 300 mg (IV-300 mg) or 150 mg (IV-150 mg) every 4 weeks, or matched placebo. Patients in the placebo group were re-randomized to subcutaneous secukinumab at a dose of 300 or 150 mg at week 16. The primary endpoint was the Assessment of SpondyloArthritis international Society criteria for 20% improvement (ASAS20) response rate at week 16 in the IV-300 mg or IV-150 mg versus placebo. Other endpoints assessed through week 52 included improvements in ASAS40, ASAS 5/6, Bath Ankylosing Spondylitis Disease Activity Index, and ASAS partial remission responses, as well as the change from baseline in high-sensitivity C-reactive protein levels. Statistical analyses followed a predefined hierarchical hypothesis testing strategy to adjust for multiplicity of testing, with non-responder imputation used for binary variables and mixed-model repeated measures for continuous variables.
The primary efficacy endpoint was met; the ASAS20 response rate was significantly greater at week 16 in the IV-300 mg (60.5%; P < 0.01) and IV-150 mg (58.1%; P < 0.05) groups versus placebo (36.8%). All secondary endpoints were met at week 16, except ASAS partial remission in the IV-150 mg group. Improvements achieved with secukinumab in all clinical endpoints at week 16 were also sustained at week 52. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period. During the entire treatment period, pooled incidence rates of Candida infections and grade 3-4 neutropenia were 1.8% for both of these adverse events in secukinumab-treated patients.
Secukinumab (300 mg and 150 mg dose groups) provided rapid, significant and sustained improvement through 52 weeks in the signs and symptoms of patients with AS. The safety profile was consistent with previous reports, with no new or unexpected findings.
ClinicalTrials.gov, NCT02008916 . Registered on 8 December 2013. EUDRACT 2013-001090-24. Registered on 24 October 2013). The study was not retrospectively registered.
ObjectiveTo evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA).MethodsIn this double-blind, ...phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16.ResultsACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%, p=0.0134) and 12 mg once a day (62.7%, p=0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs and no occurrence of herpes zoster, opportunistic infections and major adverse cardiovascular events, or differences versus placebo in mean changes in laboratory parameters with deucravacitinib treatment.ConclusionsTreatment with the selective TYK2 inhibitor deucravacitinib was well tolerated and resulted in greater improvements than placebo in ACR-20, multiplicity-controlled secondary endpoints and other exploratory efficacy measures in patients with PsA. Larger trials over longer periods of time with deucravacitinib are warranted to confirm its safety profile and benefits in PsA.Trial registration number NCT03881059.
Objective
To report the primary (1‐year) results from PREVENT, the first phase III study evaluating secukinumab in patients with active nonradiographic axial spondyloarthritis (SpA).
Methods
A total ...of 555 patients were randomized (1:1:1) to receive subcutaneous secukinumab 150 mg with a loading dose (loading dose LD group), secukinumab 150 mg without a loading dose (non–loading dose NL group), or placebo weekly and then every 4 weeks starting at week 4. The NL group received placebo at weeks 1, 2, and 3 to maintain blinding. Switch to open‐label secukinumab or standard of care was permitted after week 20. The study had 2 independent analysis plans, per European Union and non‐US (plan A; week 16) and US (plan B; week 52) regulatory requirements. The primary end point was 40% improvement in disease activity according to the Assessment of SpondyloArthritis international Society (ASAS40) criteria at week 16 (in the LD group) and at week 52 (in the NL group) in tumor necrosis factor inhibitor (TNFi)–naive patients. Safety analyses included all patients who received ≥1 dose of study treatment.
Results
Overall, 481 patients completed 52 weeks of treatment, including 84.3% (156 of 185) in the LD group, 89.7% (165 of 184) in the NL group, and 86.0% (160 of 186) in the placebo group. The proportion of patients who switched to open‐label or standard of care between weeks 20 and 48 was 50.8% in the LD group, 47.3% in the NL group, and 64.0% in the placebo group. Both primary and all secondary end points were met at week 16. The proportion of TNFi‐naive patients who met ASAS40 was significantly higher for LD at week 16 (41.5%) and NL at week 52 (39.8%) versus placebo (29.2% at week 16 and 19.9% at week 52; both P < 0.05). No new safety findings were reported.
Conclusion
Our findings indicate that secukinumab 150 mg provides significant and sustained improvement in signs and symptoms of nonradiographic axial SpA through 52 weeks. Safety was consistent with previous reports.
Fasinumab, a fully human monoclonal antibody against nerve growth factor, was generally well-tolerated and associated with a significant reduction in walking knee pain in patients with ...osteoarthritis.
The safety, tolerability, and efficacy of fasinumab (REGN475), a fully human monoclonal antibody against nerve growth factor, was evaluated for the treatment of pain in patients with osteoarthritis (OA) of the knee. This was a 24-week, double-blind, placebo-controlled, parallel-group, repeat-dose, exploratory study. Eligible patients 40 to 75 years of age with a diagnosis of OA of the knee and moderate to severe pain were randomized 1:1:1:1 to intravenous fasinumab 0.03, 0.1, or 0.3mg/kg or placebo and received study drug on day 1 and day 57. Pain intensity was recorded daily using the numeric rating scale. Safety and tolerability, assessed by the incidence of treatment-emergent adverse events (TEAEs), was the primary study endpoint. Secondary study endpoints included the change from baseline in daily walking knee pain and the assessment of pain, function, and stiffness using the Western Ontario and McMaster Osteoarthritis (WOMAC) index. Baseline characteristics were similar among treatment groups (N=217). After 24 weeks, the incidence of TEAEs ranged from 66.1% to 75.0% in the fasinumab groups vs 63.6% for placebo. The most common TEAEs included arthralgia, hyperesthesia, myalgia, peripheral edema, and joint swelling. Discontinuation for TEAEs occurred in 5.6% of fasinumab patients and 3.7% of placebo patients. All 3 doses of fasinumab were associated with significant (P<.05) improvements compared with placebo in walking knee pain and WOMAC total and subscale scores. Fasinumab was generally well tolerated, and was associated with a significant reduction in walking knee pain and an improvement in function for up to 8 weeks.
Objective
To prospectively assess the efficacy, general safety, and joint safety of fasinumab, an anti–nerve growth factor monoclonal antibody, in osteoarthritis (OA) hip and/or knee pain.
Methods
...Patients with moderate‐to‐severe OA pain (knee or hip) and history of inadequate response or intolerance to analgesics were randomized to receive fasinumab (at 1 mg, 3 mg, 6 mg, or 9 mg) or placebo every 4 weeks over 16 weeks and were followed up to week 36. Efficacy end points were the change from baseline to week 16 in the pain and physical function subscale scores of the Western Ontario and McMaster Universities OA Index (WOMAC), and patient global assessment (PGA) of OA. Joints were monitored at scheduled assessments (by plain film radiography and magnetic resonance imaging) during treatment and follow‐up, and if prompted, at the time of active joint symptoms.
Results
Of the 421 patients randomized, 342 completed the 36‐week study. All doses of fasinumab yielded statistically significant and clinically important reductions in pain compared to placebo (least squares mean difference in WOMAC pain subscale scores at week 16 ranging −0.78 to −1.40), without any clear dose dependence. Physical function and PGA scores improved in parallel. Treatment‐emergent adverse event rates were 17% with fasinumab and 10% with placebo, and 4% and 1% of patients, respectively, discontinued treatment. Arthropathies (25 in total, 7% of fasinumab‐treated patients and 1% of placebo‐treated patients) occurred in a dose‐dependent manner, with 2 occurring in patients receiving the lowest dose of fasinumab and 10 in patients receiving the highest dose. Most of the arthropathies (16 of 25) were discovered with scheduled radiographs and not based on symptoms. Destructive arthropathy (in 1 of 337 treated patients) occurred in 1 patient who was receiving 6 mg fasimumab.
Conclusion
Fasinumab provided improvements in OA pain and function, even in those benefitting little from previous analgesics. The observed benefit‐to‐risk relationship favors further clinical development to explore the lowest doses of fasinumab in patients with knee or hip OA.
To determine the effect of prior tumor necrosis factor inhibitor (TNFi) therapy on secukinumab efficacy in psoriatic arthritis (PsA).
Patients were randomized to secukinumab 300 mg, 150 mg, 75 mg, or ...placebo.
American College of Rheumatology 20 responses at Week 24 with secukinumab 300 mg, 150 mg, 75 mg, and placebo were 58.2%, 63.5%, 36.9%, and 15.9% in TNFi-naive (n = 258), and 45.5%, 29.7%, 14.7%, and 14.3% in TNFi-exposed patients (n = 139), respectively. Week 52 responses with secukinumab 300 mg, 150 mg, and 75 mg were 68.7%, 79.4%, and 58.5% in TNFi-naive, and 54.5%, 37.8%, and 35.3% in TNFi-exposed patients, respectively.
Secukinumab was efficacious in TNFi-naive and TNFi-exposed patients with PsA, with greatest improvements in TNFi-naive patients.
Romosozumab (formerly AMG 785/CDP7851) is a monoclonal antibody that blocks sclerostin from inhibiting osteoblast maturation and function. This double-blind, placebo-controlled, randomized, ascending ...multiple-dose study enrolled 32 postmenopausal women and 16 healthy men with low bone mass. Women received six doses of 1 or 2 mg/kg once every 2 weeks (Q2W) or three doses of 2 or 3 mg/kg once every 4 weeks (Q4W) or placebo; and men received 1 mg/kg Q2W or 3 mg/kg Q4W or placebo. Mean serum romosozumab exposures increased approximately dose-proportionally. Romosozumab increased serum type 1 aminoterminal propeptide (PINP) by 66-147%, decreased serum C-telopeptide (sCTX) by 15-50%, and increased lumbar spine bone mineral density by 4-7%. Two subjects developed neutralizing antibodies without discernable effects on pharmacokinetics, pharmacodynamics, or safety. Adverse event rates were balanced between groups without any significant safety findings. These data support continued investigation of sclerostin inhibition in disorders that could benefit from increased bone formation.
AMG 108 is a fully human, immunoglobulin subclass G2 (IgG2) monoclonal antibody that binds the human interleukin-1 (IL-1) receptor type 1, inhibiting the activity of IL-1a and IL-1b. In preclinical ...studies, IL-1 inhibition was shown to be beneficial in models of osteoarthritis (OA). The purpose of this two-part study was to evaluate the safety and pharmacokinetics (PK; Part A) and clinical effect (Part B) of AMG 108 in a double-blind, placebo-controlled, multiple-dose study in patients with OA of the knee.
In Part A, patients received placebo or AMG 108 subcutaneously (SC; 75 mg or 300 mg) or intravenously (IV; 100 mg or 300 mg) once every 4 weeks for 12 weeks; in Part B, patients received placebo or 300 mg AMG 108 SC, once every 4 weeks for 12 weeks. The clinical effect of AMG 108 was measured in Part B by using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score.
In Part A, 68 patients were randomized, and 64 received investigational product. In Part B, 160 patients were randomized, and 159 received investigational product. AMG 108 was well tolerated. Most adverse events (AEs), infectious AEs, serious AEs and infections, as well as withdrawals from the study due to AEs occurred at similar rates in both active and placebo groups. One death was reported in an 80-year-old patient (Part A, 300 mg IV AMG 108; due to complications of lobar pneumonia). AMG 108 serum concentration-time profiles exhibited nonlinear PK. The AMG 108 group in Part B had statistically insignificant but numerically greater improvement in pain compared with the placebo group, as shown by the WOMAC pain scores (median change, -63.0 versus -37.0, respectively).
The safety profile of AMG 108 SC and IV was comparable with placebo in patients with OA of the knee. Patients who received AMG 108 showed statistically insignificant but numerically greater improvements in pain; however, minimal, if any, clinical benefit was observed.
This study is registered with ClinicalTrials.gov with the identifier NCT00110942.
Abstract
Objectives
The PALACE 4 trial evaluated apremilast monotherapy in patients with active PsA who were DMARD-naive.
Methods
Eligible patients were randomized (1:1:1) to placebo, apremilast 20 ...mg twice a day or apremilast 30 mg twice a day. At week 16 or 24, placebo patients were rerandomized to apremilast. Double-blind apremilast treatment continued to week 52, with extension up to 4 years. The primary endpoint was the proportion of patients achieving ⩾20% improvement in ACR response criteria (ACR20) at week 16; secondary endpoints included the mean change in the HAQ Disability Index (HAQ-DI) score at week 16.
Results
A total of 527 patients with mean disease duration of 3.4 years and high disease activity were randomized and received treatment. More apremilast patients achieved ACR20 response at week 16 placebo, 15.9%; 20 mg, 28.0% (P = 0.0062); 30 mg, 30.7% (P = 0.0010). The mean HAQ-DI improvements were −0.17 (20 mg; P = 0.0008) and −0.21 (30 mg; P < 0.0001) vs 0.03 (placebo). Both apremilast doses showed significant ACR50 responses vs placebo at week 16 and improvements in secondary efficacy measures (swollen/tender joint counts) and psoriasis assessments, with sustained improvements through week 52. Common adverse events (AEs) over 52 weeks were diarrhoea, nausea, headache and upper respiratory tract infection; most events were mild or moderate. Serious AEs and AEs leading to discontinuation were comparable between groups. Laboratory abnormalities were infrequent and transient.
Conclusions
In DMARD-naive patients, apremilast monotherapy improved PsA signs/symptoms over 52 weeks and was generally well tolerated.
Trial registration
ClinicalTrials.gov (http://clinicaltrials.gov), NCT01307423.
Biologic drugs have transformed the standard of care for many diseases. However, many biologics induce the formation of anti-drug antibodies (ADAs), which can compromise their safety and efficacy. ...Preclinical studies demonstrate that biodegradable nanoparticles-encapsulating rapamycin (ImmTOR), but not free rapamycin, mitigate the immunogenicity of co-administered biologic drugs. Here we report the outcomes from two clinical trials for ImmTOR. In the first ascending dose, open-label study (NCT02464605), pegadricase, an immunogenic, pegylated uricase enzyme derived from Candida utilis, is assessed for safety and tolerability (primary endpoint) as well as activity and immunogenicity (secondary endpoint); in the second single ascending dose Phase 1b trial (NCT02648269) composed of both a double-blind and open-label parts, we evaluate the safety of ImmTOR (primary endpoint) and its ability to prevent the formation of anti-drug antibodies against pegadricase and enhance its pharmacodynamic activity (secondary endpoint) in patients with hyperuricemia. The combination of ImmTOR and pegadricase is well tolerated. ImmTOR inhibits the development of uricase-specific ADAs in a dose-dependent manner, thus enabling sustained enzyme activity and reduction in serum uric acid levels. ImmTOR may thus represent a feasible approach for preventing the formation of ADAs to a broad range of immunogenic biologic therapies.
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