Summary Background In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly ...and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy. Methods RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged ≥18 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratified by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by an interactive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea at the maximum tolerated dose, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov ( NCT02038036 ) and is ongoing but not recruiting patients. Findings Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 49% of 75 in the best available therapy group), interferon or pegylated interferon (ten 13% of 75), pipobroman (five 7% of 75), lenalidomide (one 1% of 75), no treatment (21 28% of 75), and other (one 1% of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7·28 95% CI 3·43–15·45; p<0·0001). The most frequent haematological adverse events of any grade were anaemia (ten 14% of 74 in the ruxolitinib group vs two 3% of 75 in the best available therapy group) and thrombocytopenia (two 3% vs six 8%). No cases of grade 3–4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3–4 anaemia and three patients (4%) reported grade 3–4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3–4 non-haematological adverse events were hypertension (five 7% of 74 vs three 4% of 75) and pruritus (0 of 74 vs two 3% of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two 3% of 75 in the best available therapy group) and angina pectoris (two 3% of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group. Interpretation RESPONSE-2 met its primary endpoint. The findings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population. Funding Novartis.
RESPONSE-2 is a phase 3 study comparing the efficacy and safety of ruxolitinib with the best available therapy (BAT) in hydroxyurea-resistant/hydroxyurea-intolerant polycythemia vera (PV) patients ...without palpable splenomegaly. This analysis evaluated the durability of the efficacy and safety of ruxolitinib after patients completed the visit at week 80 or discontinued the study. Endpoints included proportion of patients achieving hematocrit control (< 45%), proportion of patients achieving complete hematologic remission (CHR) at week 28, and the durability of hematocrit control and CHR. At the time of analysis, 93% (69/74) of patients randomized to ruxolitinib were receiving ruxolitinib; while in the BAT arm, 77% (58/75) of patients crossed over to ruxolitinib after week 28. No patient remained on BAT by week 80. Among patients who achieved a hematocrit response at week 28, the probability of maintaining response up to week 80 was 78% in the ruxolitinib arm. At week 80, durable CHR was achieved in 18 patients (24%) in the ruxolitinib arm versus 2 patients (3%) in the BAT arm. The safety profile of ruxolitinib was consistent with previous reports. These data support that ruxolitinib treatment should be considered also as a standard of care for hydroxyurea-resistant/hydroxyurea-intolerant PV patients without palpable splenomegaly.
BACKGROUND: Polycythemia vera (PV) is characterized by increased red cell mass often associated with elevated leukocyte and platelet counts, splenomegaly and significant symptom burden. In the ...RESPONSE study, which only enrolled PV patients with splenomegaly, ruxolitinib (Rux) demonstrated superior improvements in hematocrit (HCT) control and reductions in spleen volume compared with best available therapy (BAT) in pts who were resistant to or intolerant of HU. Supportive data included clinically meaningful improvements in PV-related symptom burden and quality of life (QOL) measures. Here, we describe the baseline (BL) characteristics and symptom burden of PV pts resistant to or intolerant of HU enrolled in the RESPONSE-2 study, which unlike RESPONSE, enrolled PV patients with a nonpalpable spleen.
METHODS: RESPONSE-2 is an open-label, randomized (1:1), multicenter, phase 3 study evaluating the efficacy and safety of Rux vs BAT in PV pts who are HU-resistant/-intolerant, require phlebotomy (PBT), and have no palpable spleen. Pts' BL symptom burden, BL QOL and BL pt-reported outcomes (PRO) were assessed by using 10-items modified Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), the Pruritus Symptom Impact Scale (PSIS), European QOL Questionnaire (EQ-5D-5L), and Work Productivity and Activity Impairment: Polycythemia Vera V2.0 (WPAI: PV).
RESULTS: A total of 149 pts were enrolled. BL demographic data from both arms combined are summarized in the Table. Forty percent of the patients were resistant whereas 60% were intolerant of HU treatment. Other than HU, prior treatments included interferons (15.4%), alkylating agents (8.1%), alkyl sulfonates (2.7%), pyrimidine analogs (0.7%), and other antineoplastic agents (1.0%). Ninety-seven percent of pts had at least 1 PBT within 16 weeks (wks) prior to screening and 72% had ≥ 2 PBT within 24 wks prior to screening. Past medical histories included hypertension (49%), pruritus (23%) and fatigue (9%). BL demographics of pts in RESPONSE-2 were generally comparable with previous PV studies (Table). Despite using frequent phlebotomy and cytoreductive agents during the screening period prior to randomization, 55% and 52% of pts had WBC counts greater than 10 × 109/L and platelet counts greater than 400 × 109/L, respectively, suggesting inadequately controlled disease even while receiving therapy. Additionally, pts had significant symptom burden at BL as measured by the MPN-SAF with fatigue (3.6) and pruritus (3.4) (Table). As measured by EQ-5D-5L scale, 26% and 19% of pts reported moderate to extreme pain/discomfort and depression, respectively. In WPAI outcomes, 40 of 149 pts reported missing work due to PV accounting for 14.3% of their working time.
SUMMARY/CONCLUSION: Demographic and BL data from the RESPONSE-2 study highlight the significant unmet medical need in this inadequately controlled HU-resistant/-intolerant PV population. As expected, pts in RESPONSE-2 reported lower scores for symptoms associated with splenomegaly (early satiety, 1.8 vs 2.0; abdominal discomfort, 1.7 vs 2.0) as compared with RESPONSE population. In comparison to PV pts with splenomegaly in the RESPONSE trial, pts without splenomegaly in the RESPONSE-2 trial have a distinct but comparable disease burden with marked fatigue and pruritus.
Table 1Baseline demographics and symptoms (n = 149)Age, median (range), years66.0 (26.0, 87.0)Time since diagnosis of PV, median, months80.7Male, %57.7Female, %42.3ECOG performance status, % 0 172.5 26.8Hematocrit (%), median,(n=149)43.0n (%) < 40 ≥ 40 to ≤ 45 > 452 (1.3) 146 (98.0) 1 (0.7)WBC count (x 109/L), median (n=149)10.6n (%) ≤ 10 > 10 and ≤ 15 > 1567 (45.0) 43 (28.9) 39 (26.2)PLT count (x 109/L), median (n=148)420.0n (%) < 100 ≥ 100 and < 400 ≥ 400 to < 600 ≥ 6002 (1.3) 68 (45.6) 38 (25.5) 40 (26.8)JAK2 mutation, n (%) (n=149) Positive Negative Unknown143 (96.0) 4 (2.7) 2 (1.3)MPN-SAF Symptom (n)Mean (SD)Total score (n=145)2.0 (1.67)Fatigue (n=146)3.6 (2.72)Early satiety (n=145)1.8 (2.47)Abdominal discomfort (n=143)1.7 (2.44)Inactivity (n=142)2.1 (2.77)Concentration problem (n=146)2.3 (2.75)Night sweats (n=145)2.2 (3.07)Pruritus (n=145)3.4 (3.37)Bone pain (n=144)2.1 (2.89)Fever (n=144)0.2 (0.92)Weight loss (n=142)0.7 (1.72)
Passamonti:Novartis: Consultancy. Cavo:JANSSEN, CELGENE, AMGEN: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Bensasson:Novartis: Employment. Khan:Novartis: Employment. Mounedji:Novartis: Employment.
Introduction: Deferasirox (Exjade®, ICL670) is an oral iron chelator approved for the treatment of iron overload due to chronic transfusions in more than 80 countries. Deferasirox is mainly ...eliminated via biliary excretion following glucuronidation. Oxidative metabolism, presumably by CYP1A and CYP2D6 enzymes, accounts for approximately 6% and 2%, respectively. Deferasirox has been shown to be a weak inhibitor of CYP3A4/5 in vitro. It is possible that deferasirox could potentially alter the metabolism of other drugs eliminated via this pathway. Midazolam, a rapid-onset benzodiazepine, is almost exclusively metabolized via CYP3A4/5 making it an ideal probe to investigate the effect of an inhibitor/inducer of CYP3A4/5 in vivo. This drug-drug interaction study was undertaken to investigate the effect of deferasirox on midazolam pharmacokinetics (PK).
Methods: This was a single-center, open-label, one-sequence, cross-over study conducted in healthy volunteers. There were two treatment periods. During Period 1, volunteers received a midazolam 5 mg oral solution and midazolam PK were performed at 0–12 hours. During Period 2, volunteers received doses of deferasirox 30 mg/kg daily for 5 days and on Day 4, a midazolam 5 mg oral solution was given. Midazolam PK were performed at 0–48 hours.
Results: Twenty-two healthy volunteers were enrolled, and 21 completed the study. Mean age was 32 years, 59% of volunteers were male and all were Caucasian. Descriptive statistics for mean plasma concentration of midazolam and its metabolite, 1-hydroxymidazolam, are summarized below:
AUCinf (h.ng/mL)AUClast (h.ng/mL)Cmax (ng/mL)Tmax (h)T½ (h)Midazolam PKMidazolam alone, n=22Mean (SD)68.3 (28.4)63.8 (26.4)34.4 (17.4)0.44 (0.17)3.7 (0.9)Deferasirox + midazolam, n=22Mean (SD)61.7 (37.4)60.3 (37.2)27.1 (13.6)0.47 (0.26)4.4 (1.4)1-hydroxymidazolam PKMidazolam alone, n=22Mean (SD)22.3 (8.8)20.8 (7.9)12.8 (6.7)0.48 (0.15)3.3 (1.5)Deferasirox + midazolam, n=22Mean (SD)25.6 (10.9)23.8 (10.0)11.7 (5.3)0.5 (0.24)6.1 (3.5)
There was a statistically, but not clinically, significant reduction (17%) in midazolam exposure (AUC) in the presence of deferasirox in comparison with midazolam administered alone. Similarly, Cmax was decreased on average by 23%.
Conclusion: An increase in midazolam exposure, which would have been expected for an inhibitory effect of deferasirox on the CYP3A4-mediated metabolic pathway, was not observed. A decrease in midazolam exposure is suggestive of an induction effect, albeit weak in nature. Drugs that are substrates for CYP3A4 can be co-administered with deferasirox if necessary.
The microbiological hydroxylation of some 3α,5-cycloandrostanes by the fungus,
Cephalosporium aphidicola has been shown to take place at C-2α and C-14α and a 6β-alcohol was oxidized to the 6-ketone.
The microbiological hydroxylation of 4,4-dimethylandrost-5-en-3-ones by the fungus, Cephalosporium aphidicola, takes place at C-7 rather than in a biosynthetically patterned sense on the C-4 dimethyl ...groups.
The hydroxylation of ring B of des-ring D androstanes by Cephalosporium aphidicola follows the pattern of normal steroids, but that of ring C differs from this, suggesting that the nature of ring D ...is important in determining the hydroxylation of ring C.
Some 4
β-hydroxy-4
α-methyl-5
α-androstanes were synthesized and their microbiological hydroxylation by
Cephalosporium aphidicola was examined in order to explore the possibility of a ...biosynthetically patterned methylcarbinol: vicinal glycol biotransformation; however the substrates were hydroxylated mainly at C-7.
Whereas the major hydroxylation product of 3
β-hydroxy-5
α-androstan-17-one by
Cephalosporium aphidicola is the 11
α-alcohol, the presence of a Δ
5-double bond in the substrate leads to ...non-stereospecific allylic hydroxylation at C–7. Hydroxylation at C–11 became a minor transformation and there was no detectable hydroxylation at C–14.
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