Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study.

OBJECTIVE: This phase 2a randomised, double blind, placebo controlled, parallel group study evaluated the safety and efficacy of a first-in-class drug candidate ABX464 (obefazimod, 50 mg and 100 mg per day), which upregulates the biogenesis of the mRNA inhibitor micro-RNA (miR)-124, in combination with methotrexate (MTX) in 60 patients (1:1:1 ratio) with moderate-to-severe active rheumatoid arthritis (RA) who have inadequate response to MTX or/and to an anti-tumour necrosis factor alpha (TNFα) therapy. METHODS: The primary end point was the safety of ABX464; efficacy endpoints included the proportion of patients achieving American College of Rheumatology (ACR)20/50/70 responses, disease activity scores (DAS) 28, simplified disease activity score, clinical disease activity score), European League Against Rheumatism response, DAS28 low disease activity or remission. RESULTS: ABX464 50 mg was safe and well tolerated. Two serious adverse events were reported (one on placebo group and one on ABX464 100 mg). Eleven patients were withdrawn for AEs (9 patients on 100 mg, 1 on 50 mg and 1 on placebo). Drug discontinuation was mainly due to gastrointestinal disorders. No cases of opportunistic infection, no malignancies and no death were reported. Compared with placebo, ABX464 50 mg showed significantly higher proportions of patients achieving ACR20 and ACR50 responses at week 12. DAS28-C reactive protein (CRP) and DAS28-erythrocyte sedimentation rate decreased significantly and rates of categorical DAS28-CRP response or CDAI remission increased significantly on ABX464 at week 12. A significant upregulation of miR-124 was observed in blood for every patient dosed with ABX464. CONCLUSION: ABX464 50 mg was safe, well tolerated and showed a promising efficacy. Mild-to-moderate gastrointestinal AEs led to a high drop-out rate of patients on ABX464 100 mg, which may not be a relevant dose to use. These findings warrant exploration of ABX464 at 50 mg per day or less for treating patients with RA. TRIAL REGISTRATION NAME: Phase IIa randomised, double blind, placebo controlled, parallel group, multiple dose study on ABX464 in combination with MTX, in patients with moderate to severe active RA who have inadequate response to MTX or/and to an anti- TNFα therapy or intolerance to anti-TNFα therapy.EUDRACT number: 2018-004677-27 TRIAL REGISTRATION NUMBER: NCT03813199.

Low anti-HBc levels are associated with lower risk of virological relapse after nucleos(t)ide analogue cessation in HBe antigen-negative patients.

BACKGROUND AND AIMS: Low anti-HBc serum levels at the time of therapy cessation were linked to a higher relapse risk in predominantly HBeAg-positive cohorts. We investigated the association of anti-HBc levels with relapse in HBeAg-negative patients. METHODS: Serum levels of anti-HBc, HBsAg and HBcrAg were determined in 136 HBeAg-negative patients, participating in a vaccination trial (ABX-203, NCT02249988), before treatment cessation or vaccination. Importantly, vaccination showed no impact on relapse. The correlation between the biomarkers and their predictive value for relapse (HBV DNA >2000 IU/ml ± ALT >2xULN) was investigated. RESULTS: After therapy cessation 50% (N = 68) of patients relapsed. Median anti-HBc prior to treatment stop was significantly higher among relapsers compared to off-treatment responders (520 IU/ml vs. 330 IU/mL, p = .0098). The optimal anti-HBc cut-off to predict relapse was 325 IU/ml according to the Youden-Index. About 35% of patients with anti-HBc level < 325 IU/ml versus 60% of those with values ≥325 IU/mL relapsed (p = .0103; sensitivity 50%, specificity 75%). Combining the optimal cut-offs of HBsAg (>3008 IU/mL) or HBcrAg (≥1790 U/ml) with anti-HBc increased the proportion of patients with relapse to 80% (p < .0001) and 74% (p = .0006), respectively. CONCLUSION: In contrast to predominantly HBeAg-positive cohorts, in our cohort of HBeAg-negative patients lower anti-HBc levels are associated with a significantly lower relapse risk after nucleos(t)ide analogue cessation. The vast majority of included patients were either genotype B or C and the applicability to other genotypes has to be further evaluated. However, anti-HBc level as an indicator of the host response might be prospectively further explored for prediction models.

Contrasting Timing of Virological Relapse After Discontinuation of Tenofovir or Entecavir in Hepatitis B e Antigen-Negative Patients.

Stopping long-term nucleos(t)ide analogue therapy increases hepatitis B virus (HBV) surface antigen (HBsAg) loss rates in HBV e antigen (HBeAg)-negative patients. Viral rebound may induce immune responses facilitating functional cure. We analyzed which factors are associated with timing of virological relapse in 220 Asian HBeAg-negative patients from the prospective ABX203 vaccine study. Unexpectedly, only the type of antiviral therapy was significantly associated with early virological relapse, defined as an HBV DNA load of >2000 IU/mL until week 12, and relapse occurred earlier in patients treated with tenofovir versus those treated with entecavir (median time, 6 vs 24 weeks; P < .0001). This should be considered for future trials and monitoring of patients after treatment discontinuation.

Safety, Pharmacokinetics, and Antiviral Activity of a Novel HIV Antiviral, ABX464, in Treatment-Naive HIV-Infected Subjects in a Phase 2 Randomized, Controlled Study.

We investigated the safety and antiviral effects of an anti-HIV compound (ABX464) with a unique mechanism of viral replication inhibition. This was a randomized, double-blind, placebo-controlled, dose-ranging study in treatment-naive HIV-infected patients. Participants were assigned to eight groups; each group included eight subjects receiving either the study compound, ABX464 (n = 6), or the corresponding placebo (n = 2), according to a randomization code. The first dose administered was 25 mg, given once or 3 times a day over a 2- to 3-week period. Ascending doses of up to 150 mg were delivered after review of the safety data. The primary objective of the study was to assess the safety and tolerability of ABX464 after repeated oral administrations in subjects infected by HIV. Sixty-six subjects were enrolled and were randomized. Sixty-three subjects completed the study according to the study protocol. Twenty-one adverse events (AEs) were reported by 7 subjects out of 16 (44%) who received placebo, and 158 AEs were reported by 39 subjects out of 50 (78%) who received the study drug. In the ABX464 treatment group, all of these adverse events were mild to moderate. No subjects discontinued treatment due to drug-related AEs. Administration of ABX464 at up to 150 mg once a day was safe and well tolerated in HIV-infected subjects. An efficacy signal with respect to a reduction of the viral load by ABX464 was detected, mainly in subjects treated at the highest dose. Further studies will be required to demonstrate antiviral effects in HIV-infected subjects in combination with other antiretroviral therapies. (This study is registered on the ClinicalTrials.gov website under registration no. NCT02452242.).

Randomized Trial of Food Effect on Pharmacokinetic Parameters of ABX464 Administered Orally to Healthy Male Subjects.

ABX464 is an antiviral that provides a novel approach to the reduction and control of HIV infection. Investigation of food influence is important in the optimization of treatment. An open-label, food effect, randomized study which included 2 groups of 24 subjects each was carried out to assess the bioavailability and safety of single (group 1) and repeated (group 2) oral doses of ABX464 (50 mg) under fed or fasted conditions. The maximum concentration (Cmax) and the area under the concentration-time curve from time zero to infinity (AUC0-∞) of ABX464 were demonstrated to increase with food after a single dose of ABX464 (219% and 188%, respectively). The apparent terminal elimination half-lives (t1/2s) under fed and fasted conditions were comparable, at about 0.80 h. The median time to maximum concentration (Tmax) was delayed from 1.5 to 2.8 h, and the ratio of the AUC0-∞ obtained under fed conditions to the AUC0-∞ obtained under fasted conditions (Frel) was 2.69. Comparable results were obtained on day 1 and day 10 in group 2. The increases in Cmax and AUC0-∞ of the metabolite ABX464-N-glucuronide (ABX464-NGlc) were, however, much more limited when ABX464 was given with food. The t1/2s were also comparable under the two conditions (around 100 h). Between day 1 and day 10, the Cmax increased by 5% under the fasted condition and by 25% under the fed condition. The most common related treatment-emergent adverse events were headaches, vomiting, and nausea. It was concluded that food has a significant impact on the levels of ABX464 in plasma with a delay in absorption and increased relative bioavailability, with a lesser impact on its biotransformation into ABX464-NGlc. ABX464 was well tolerated under both fasted and fed conditions. (This study has been registered at ClinicalTrials.gov under registration no. NCT02731885.).

Pharmacokinetics and tolerability of ABX464, a novel first-in-class compound to treat HIV infection, in healthy HIV-uninfected subjects.

Background: An anti-HIV compound (ABX464) has been developed with a novel mechanism of activity in that it blocks viral gene expression in cells that are already infected. Objectives: A first-in-man study was conducted to determine the pharmacokinetic and safety profiles of ABX464. This was carried out as an open label, parallel group, single ascending dose, exploratory study. Methods: Twenty-four male subjects in good health without HIV infection, aged from 18 to 55 years old, with BMIs of 18-27 kg/m 2 were included. A single oral dose of ABX464 (50, 100, 150 or 200 mg) was administered on the morning of day 0 after overnight fasting, with follow-up for 45 days. Safety assessments consisted of vital signs, electrocardiogram, physical examination, laboratory tests and urinalysis. Pharmacokinetic parameters were calculated for ABX464 and its main metabolite ABX-464- N -glucuronide (ABX464-NGlc). The study was registered at https://www.clinicaltrials (trial number NCT02792686). Results: ABX464 was well tolerated; the most frequent related treatment-emergent adverse events were headaches, nausea and vomiting; they were not considered as treatment-limiting effects. ABX464's C max was observed approximately 2 h after administration in all groups. ABX464 was rapidly and substantially metabolized into ABX464-NGlc. The C max of ABX464-NGlc was observed approximately 4 h post-dose and was about 160-fold higher than that of the parent with a much longer t 1/2 (90-110 h). The ratio of metabolite to parent drug was consistent across the complete dose range. Conclusions: These studies confirmed that ABX464 is well tolerated and rapidly and substantially metabolized into ABX464-NGlc in human subjects.

ABX464 (Obefazimod) Upregulates miR-124 to Reduce Proinflammatory Markers in Inflammatory Bowel Diseases.

Advanced therapies have transformed the treatment of inflammatory bowel disease; however, many patients fail to respond, highlighting the need for therapies tailored to the underlying cell and molecular disease drivers. The first-in-class oral molecule ABX464 (obefazimod), which selectively upregulates miR-124, has demonstrated its ability to be a well-tolerated treatment with rapid and sustained efficacy in patients with ulcerative colitis (UC). Here, we provide evidence that ABX464 affects the immune system in vitro , in the murine model of inflammatory bowel disease, and in patients with UC. In vitro , ABX464 treatment upregulated miR-124 and led to decreases in proinflammatory cytokines including interleukin (IL) 17 and IL6, and in the chemokine CCL2. Consistently, miR-124 expression was upregulated in the rectal biopsies and blood samples of patients with UC, and a parallel reduction in Th17 cells and IL17a levels was observed in serum samples. In a mouse model of induced intestinal inflammation with dextran sulfate sodium, ABX464 reversed the increases in multiple proinflammatory cytokines in the colon and the upregulation of IL17a secretion in the mesenteric lymph nodes. By upregulating miR-124, ABX464 acts as "a physiological brake" of inflammation, which may explain the efficacy of ABX464 with a favorable tolerability and safety profile in patients with UC.

ABX464 (obefazimod) for patients with COVID-19 at risk for severe disease: miR-AGE, a randomized, double-blind placebo-controlled trial.

Background: ABX464 (obefazimod) is a small molecule that upregulates a single microRNA (miR-124) in immune cells and reduces the production of various inflammatory cytokines and chemokines. Objective: We assessed the efficacy and safety of the standard of care (SoC) plus oral obefazimod (SoC plus ABX464), 50 mg once daily, versus the SoC plus placebo for prevention of severe acute respiratory syndrome in patients with coronavirus disease 2019 (COVID-19) who are at risk for severe disease. Methods: Eligible patients for this phase 2/3 double-blind, placebo-controlled miR-AGE study were randomized (2:1) into 2 groups: SoC-ABX464 (n = 339) and SoC-placebo (n = 170). The primary end point was the percentage of patients who did not require use of high-flow oxygen or invasive or noninvasive mechanical ventilation within 28 days. The safety analyses included patients who had been randomly assigned and had received at least 1 dose of the study treatment. Results: At the time of the interim analysis, obefazimod showed no benefit over placebo when added to the SoC; the study enrollment was stopped for futility. The evaluation of the safety of obefazimod in 505 patients showed significantly more treatment-emergent adverse events in the SoC-ABX464 group than in the SoC-placebo group (P = .007). Frequently reported AEs in the SoC-ABX464 group included headache (14.6%), abdominal pain (9.6%), diarrhea (9.0%), back pain (6.9%), and nausea (6.0%). No treatment-related changes in laboratory parameters were reported. Conclusion: For patients who have severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and are at risk for severe COVID-19, obefazimod, 50 mg, provided no benefit over placebo when added to the SoC, although it did have a good safety profile (comparable to that reported in many therapeutic areas).

Obefazimod: A First-in-class Drug for the Treatment of Ulcerative Colitis.

Biologic agents and oral small molecules are the mainstays of inflammatory bowel disease [IBD] management. However, an unmet clinical need remains for additional agents with novel mechanism of action which are effective, safe, and disease-modifying; this is due to the substantial proportion of patients who do not respond, lose response, or develop intolerance to currently marketed products. microRNAs [miRNAs] that play a role in the modulation of signal transduction pathways implicated in the development of IBD hold the potential to be used as therapeutic targets. Recently, a novel first-in-class compound, obefazimod, originally conceived as a human immunodeficiency virus [HIV] infection drug, has shown great promise in phase II induction trials for ulcerative colitis [UC] patients. Findings from the maintenance phases of trials showed that long-term obefazimod treatment provides continued improvement in clinical symptoms of disease, with a substantial proportion of patients in clinical remission, and an overall good safety profile. With a novel mechanism of action, obefazimod is an orally available small molecule with anti-inflammatory properties through the specific and selective upregulation of miR-124 expression. The aim of this paper is to critically review the available evidence related to pharmacokinetics and pharmacodynamics, and to discuss the potential clinical implications of this first-in-class oral small molecule.

Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor.

OBJECTIVE: Most patients with systemic mastocytosis bear mutations in the tyrosine kinase receptor gene c-Kit. Limited treatment options exist for mast cell leukemia, a rare form of systemic mastocytosis associated with a dire prognosis. Our aim was to investigate c-Kit mutations associated with mast cell leukemia and find new treatment for this severe form of mastocytosis. PATIENT AND METHODS: We describe here a patient with mast cell leukemia characterized by 42% of circulating mast cells associated with a previously unidentified c-Kit mutation in adult mastocytosis: dup(501-502). MAIN FINDINGS: This patient was treated with masitinib, a novel c-Kit tyrosine kinase inhibitor, with a dramatic response observed following 3 months of treatment, including clinical improvement, disappearance of circulating mast cells, and decrease in both serum histamine and tryptase levels. In vitro and ex vivo research was performed on the patient's cells and revealed constitutive c-Kit phosphorylation in mast cell leukemia. CONCLUSIONS: This case highlights the importance of sequencing all c-Kit exons when the classical D816V c-Kit mutation is not found, even in adults with SM. It also indicates that masitinib may be safe and effective for the treatment for some mast cell leukemia.

ABX464 (obefazimod) for moderate-to-severe, active ulcerative colitis: a phase 2b, double-blind, randomised, placebo-controlled induction trial and 48 week, open-label extension.

BACKGROUND: ABX464 (obefazimod) is a small molecule that selectively upregulates miR-124 in immune cells. We aimed to assess ABX464 as a treatment for patients with moderate-to-severe, active ulcerative colitis. METHODS: In this phase 2b, double-blind, randomised, placebo-controlled induction trial, patients were recruited from 95 centres (hospitals and health-care centres) in 16 countries. Eligible patients were aged 18-75 years, with a diagnosis of moderate-to-severe, active ulcerative colitis and a modified Mayo Score (MMS) of 5 points or higher, and a documented non-response or intolerance to previous treatment. Enrolled patients were randomly assigned (1:1:1:1) via an interactive voice and web response system to receive once daily oral ABX464 100 mg, ABX464 50 mg, ABX464 25 mg, or matched placebo. Randomisation was stratified according to study site (US vs non-US) and to whether the patient had previous exposure to second-line treatment with biologics or JAK inhibitors. The primary endpoint was the change from baseline in MMS at week 8. The primary efficacy analysis was done in the full analysis set (FAS), defined as all randomly assigned patients who received at least one dose of study treatment and had baseline data for at least one efficacy variable, and was analysed according to the principles of intention-to-treat. Safety analyses included patients who had been randomly assigned and who received at least one dose of study treatment. The 96 week open-label extension is ongoing. This study is registered with ClinicalTrials.gov, NCT04023396. FINDINGS: Between Aug 13, 2019, and April 16, 2021, 254 patients were randomly allocated to ABX464 100 mg (n=64), ABX464 50 mg (n=63), ABX464 25 mg (n=63), or placebo (n=64). Two patients, both in the ABX464 25 mg group, were excluded from the FAS. In the FAS at week 8, the least squares mean (LSM) change from baseline in MMS was -2·9 (95% CI -3·4 to -2·5) for the ABX464 100 mg group, -3·2 (-3·7 to -2·7) for the ABX464 50 mg group, -3·1 (-3·6 to -2·6) for the ABX464 25 mg group, and -1·9 (-2·4 to -1·5) for placebo group; the magnitude of the difference in MMS from baseline was significantly greater in all three ABX464 groups compared with placebo (p=0·0039 for ABX464 100 mg vs placebo, p=0·0003 for ABX464 50 mg vs placebo, and p=0·0010 for ABX464 25 mg vs placebo). The most frequently reported adverse event was headache, which was reported for 27 (42%) of 64 patients in the ABX464 100 mg group, 19 (30%) of 63 in the 50 mg group, 13 (21%) of 62 in the 25 mg group, and five (8%) of 64 in the placebo group. Severe (grade 3) headache was reported for three (5%) patients in the ABX464 group 100 mg group, two (3%) in the ABX464 50 mg group, one (2%) in the ABX464 25 mg group, and none in the placebo group. The only serious adverse event reported for two or more patients in any group was ulcerative colitis (one in each of the ABX464 100 mg and 50 mg groups, and three [5%] in the placebo group). INTERPRETATION: All doses of ABX464 significantly improved moderate-to-severe, active ulcerative colitis compared with placebo, as measured by changes in MMS from baseline to week 8. A phase 3 clinical programme is ongoing. FUNDING: Abivax.

Pilot Study Using Machine Learning to Identify Immune Profiles for the Prediction of Early Virological Relapse After Stopping Nucleos(t)ide Analogues in HBeAg-Negative CHB.

Treatment with nucleos(t)ide analogues (NAs) may be stopped after 1-3 years of hepatitis B virus DNA suppression in hepatitis B e antigen (HBeAg)-negative patients according to Asian Pacific Association for the Study of Liver and European Association for the Study of Liver guidelines. However, virological relapse (VR) occurs in most patients. We aimed to analyze soluble immune markers (SIMs) and use machine learning to identify SIM combinations as predictor for early VR after NA discontinuation. A validation cohort was used to verify the predictive power of the SIM combination. In a post hoc analysis of a prospective, multicenter therapeutic vaccination trial (ABX-203, NCT02249988), hepatitis B surface antigen, hepatitis B core antigen, and 47 SIMs were repeatedly determined before NA was stopped. Forty-three HBeAg-negative patients were included. To detect the highest predictive constellation of host and viral markers, a supervised machine learning approach was used. Data were validated in a different cohort of 49 patients treated with entecavir. VR (hepatitis B virus DNA ≥ 2,000 IU/mL) occurred in 27 patients. The predictive value for VR of single SIMs at the time of NA stop was best for interleukin (IL)-2, IL-17, and regulated on activation, normal T cell expressed and secreted (RANTES/CCL5) with a maximum area under the curve of 0.65. Hepatitis B core antigen had a higher predictive power than hepatitis B surface antigen but lower than the SIMs. A supervised machine-learning algorithm allowed a remarkable improvement of early relapse prediction in patients treated with entecavir. The combination of IL-2, monokine induced by interferon γ (MIG)/chemokine (C-C motif) ligand 9 (CCL9), RANTES/CCL5, stem cell factor (SCF), and TNF-related apoptosis-inducing ligand (TRAIL) was reliable in predicting VR (0.89; 95% confidence interval: 0.5-1.0) and showed viable results in the validation cohort (0.63; 0.1-0.99). Host immune markers such as SIMs appear to be underestimated in guiding treatment cessation in HBeAg-negative patients. Machine learning can help find predictive SIM patterns that allow a precise identification of patients particularly suitable for NA cessation.

Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study.

Treatment options for patients suffering from indolent forms of mastocytosis remain inadequate with the hyperactivation of mast cells responsible for many of the disease's systemic manifestations. Masitinib is a potent and highly selective oral tyrosine kinase inhibitor. A combined inhibition of c-Kit and Lyn make it particularly efficient in controlling the activity of mast cells and therefore, of potential therapeutic benefit in mastocytosis. Masitinib was administered to 25 patients diagnosed as having systemic or cutaneous mastocytosis with related handicap (i.e., disabilities associated with flushes, depression, pruritus and quality-of-life) at the initial dose levels of 3 or 6 mg/kg/day over 12 weeks. In accordance with the AFIRMM study, response was based upon change of clinical symptoms associated with patient handicap at week 12 relative to baseline, regardless of disease subtype. Improvement was observed in all primary endpoints at week 12 including a reduction of flushes, Hamilton rating, and pruritus as compared with baseline by 64% (P = 0.0005), 43% (P = 0.0049), and 36% (P = 0.0077), respectively. An overall clinical response was observed in 14/25 patients (56%; [95%CI = 37%-75%]), with sustainable improvement observed throughout an extension phase (>60 weeks). Common adverse events were edema (44%), nausea (44%), muscle spasms (28%), and rash (28%), the majority of which were of mild or moderate severity with a significant decline in frequency observed after 12 weeks of treatment. One patient experienced a serious adverse event of reversible agranulocytosis. Masitinib is a promising treatment for indolent forms of mastocytosis with handicap and indicates acceptable tolerability for long-term treatment regimens.

Safety, tolerability and impact on viral reservoirs of the addition to antiretroviral therapy of ABX464, an investigational antiviral drug, in individuals living with HIV-1: a Phase IIa randomised controlled study.

OBJECTIVES: To assess the safety and tolerability as well as antiretroviral impact of ABX464, an oral investigational drug with a novel mechanism of HIV-1 inhibition (ClinicalTrials.gov NCT02735863). METHODS: Randomised, double-blind, placebo-controlled, Phase IIa study in individuals living with HIV-1 on antiretroviral therapy at six clinical centres in Spain, France and Belgium. ABX464 was administered once a day to 22 fully controlled HIV-1-positive participants at two doses (50 mg, n=6 and 150 mg, n=16) versus placebo, which was given to eight participants for 28 days in combination with a boosted protease inhibitor (darunavir/ritonavir or darunavir/cobicistat). The primary objective of the study was to assess ABX464 safety and tolerability when used in combination with darunavir boosted therapy. The secondary objective was to study antiretroviral efficacy on viral reservoirs using time to viral rebound following treatment interruption. The impact of ABX464 on HIV-1 reservoirs was further assessed by measuring levels of total HIV-1 in peripheral blood mononuclear cells (PBMCs) in the intervention arm versus placebo. A positive response was defined as an absolute reduction in HIV-1 DNA of at least 50 copies/106 PBMCs and a relative decrease >25% of HIV-1 DNA level. RESULTS: Twenty-six of the 30 randomly allocated participants completed the study according to the study protocol. ABX464 was found to be safe and well tolerated with the majority of adverse events (AEs) being mild or moderate. Of the participants, 22 (73.3%) experienced treatment-associated AEs (93.8%, 66.7%, 37.5% in the ABX464 150-mg, 50-mg dose and placebo arms, respectively). Percentages for combined grade 3/4 AEs for the three arms were 6.3%, 0% and 12.5%, respectively. Median time (Kaplan-Meier estimates) to viral rebound for ABX464 150-mg, 50-mg and placebo arms were 12.0 (95% confidence interval [CI]: 10-15), 15.5 (95% CI 14-22) and 15.5 (95% CI 1-22) days, respectively with no significant difference between the 150-mg treatment arm and placebo. Median changes in total HIV-1 DNA copies/106 PBMCs for ABX464 150-mg, 50-mg and placebo arms after 28 days of treatment were -40 (range -434 to +194), -115 (range -116 to -114) and 25 (range -35 to +218), respectively, showing a decrease in the intervention arms. There were 6/14, 2/2, and 0/4 responders for ABX464 150 mg, 50 mg and placebo, respectively. No significant difference was seen between treatment arms and placebo with respect to these virological parameters. CONCLUSIONS: This small controlled study confirmed the good safety and tolerability of ABX464 and provides some evidence of a potential reduction of the HIV-1 reservoir in terms of HIV-1 DNA levels in PBMCs when it was added to an HIV-1 protease inhibitor-based regimen. These results will need to be confirmed in a larger study.

Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy.

Depression in patients with mastocytosis is often reported but its prevalence and characteristics are not precisely described. In addition, the impact of therapies targeting mast cells proliferation, differentiation and degranulation on psychic symptoms of depression have never been investigated. Our objective was to determine the prevalence and to describe features of depression in a large cohort of mastocytosis patients (n = 288) and to investigate the therapeutic impact of the protein kinase inhibitor masitinib in depression symptoms. The description of depression was based on the analysis of a database with Hamilton scores using Principal Component Analysis (PCA). Efficacy of masitinib therapy was evaluated using non parametric Wilcoxon test for paired data within a three months period (n = 35). Our results show that patients with indolent mastocytosis present an elevated prevalence of depression (64%). Depression was moderate in 56% but severe in 8% of cases. Core symptoms (such as psychic anxiety, depressed mood, work and interests) characterized depression in mastocytosis patients. Masitinib therapy was associated with significant improvement (67% of the cases) of overall depression, with 75% of recovery cases. Global Quality of Life slightly improved after masitinib therapy and did not predicted depression improvement. In conclusion, depression is very frequent in mastocytosis patients and masitinib therapy is associated with the reduction its psychic experiences. We conclude that depression in mastocytosis may originate from processes related to mast cells activation. Masitinib could therefore be a useful treatment for mastocytosis patients with depression and anxiety symptoms.

Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study.

INTRODUCTION: Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA. METHODS: This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12. RESULTS: Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends. CONCLUSIONS: Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00831922.