Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma.

Background In pancreatic ductal adenocarcinoma (PDAC), the chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) axis plays a key role in immunosuppressive properties of the tumor microenvironment, patient prognosis, and chemoresistance. This phase Ib study assessed the effects of the orally administered CCR2 inhibitor PF-04136309 in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic PDAC. Methods Patients received PF-04136309 twice daily (BID) continuously plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) administered on days 1, 8, and 15 of each 28-day cycle. The primary objectives were to evaluate safety and tolerability, characterize dose-limiting toxicities (DLTs), and determine the recommended phase II dose (RP2D) of PF-04136309. Results In all, 21 patients received PF-04136309 at a starting dose of 500 mg or 750 mg BID. The RP2D was identified to be 500 mg BID. Of 17 patients treated at the 500 mg BID starting dose, three (17.6%) experienced a total of four DLTs, including grade 3 dysesthesia, diarrhea, and hypokalemia and one event of grade 4 hypoxia. Relative to the small number of patients (n = 21), a high incidence (24%) of pulmonary toxicity was observed in this study. The objective response rate for 21 patients was 23.8% (95% confidence interval: 8.2-47.2%). Levels of CD14 + CCR2+ inflammatory monocytes (IM) decreased in the peripheral blood, but did not accumulate in the bone marrow. Conclusions PF-04136309 in combination with nab-paclitaxel plus gemcitabine had a safety profile that raises concern for synergistic pulmonary toxicity and did not show an efficacy signal above nab-paclitaxel and gemcitabine. ClinicalTrials.gov identifier: NCT02732938.

A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients with Locally Advanced or Metastatic Cancers.

PURPOSE: Stimulation of effector T cells is an appealing immunotherapeutic approach in oncology. OX40 (CD134) is a costimulatory receptor expressed on activated CD4+ and CD8+ T cells. Induction of OX40 following antigen recognition results in enhanced T-cell activation, proliferation, and survival, and OX40 targeting shows therapeutic efficacy in preclinical studies. We report the monotherapy dose-escalation portion of a multicenter, phase I trial (NCT02315066) of ivuxolimab (PF-04518600), a fully human immunoglobulin G2 agonistic monoclonal antibody specific for human OX40. PATIENTS AND METHODS: Adult patients (N = 52) with selected locally advanced or metastatic cancers received ivuxolimab 0.01 to 10 mg/kg. Primary endpoints were safety and tolerability. Secondary/exploratory endpoints included preliminary assessment of antitumor activity and biomarker analyses. RESULTS: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade ≤2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at ≥0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4+ central memory T-cell proliferation and activation, and clonal expansion of CD4+ and CD8+ T cells in peripheral blood were observed at 0.1 to 3.0 mg/kg. Increased immune cell infiltrate and OX40 expression were evident in on-treatment tumor biopsies. CONCLUSIONS: Ivuxolimab was generally well tolerated with on-target immune activation at clinically relevant doses, showed preliminary antitumor activity, and may serve as a partner for combination studies.

Molecular Characterization of Familial Hypercholesterolemia in a North American Cohort.

BACKGROUND: Familial hypercholesterolemia (FH) confers a very high risk of premature cardiovascular disease and is commonly caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) and very rarely in LDLR adaptor protein 1 (LDLRAP1) genes. OBJECTIVE: To determine the prevalence of pathogenic mutations in the LDLR, APOB, and PCSK9 in a cohort of subjects who met Simon Broome criteria for FH and compare the clinical characteristics of mutation-positive and mutation-negative subjects. METHODS: Ninety-three men and 107 women aged 19 to 80 years from lipid clinics in the United States and Canada participated. Demographic and historical data were collected, physical examination performed, and serum lipids/lipoproteins analyzed. Targeted sequencing analyses of LDLR and PCSK9 coding regions and exon 26 of APOB were performed followed by detection of LDLR deletions and duplications. RESULTS: Disease-causing LDLR and APOB variants were identified in 114 and 6 subjects, respectively. Of the 58 LDLR variants, 8 were novel mutations. Compared with mutation-positive subjects, mutation-negative subjects were older (mean 49 years vs 57 years, respectively) and had a higher proportion of African Americans (1% vs 12.5%), higher prevalence of hypertension (21% vs 46%), and higher serum triglycerides (median 86 mg/dL vs 122 mg/dL) levels. CONCLUSIONS: LDLR mutations were the most common cause of heterozygous FH in this North American cohort. A strikingly high proportion of FH subjects (40%) lacked mutations in known culprit genes. Identification of underlying genetic and environmental factors in mutation-negative patients is important to further our understanding of the metabolic basis of FH and other forms of severe hypercholesterolemia.

Model-Based Characterization of the Pharmacokinetics, Target Engagement Biomarkers, and Immunomodulatory Activity of PF-06342674, a Humanized mAb Against IL-7 Receptor-α, in Adults with Type 1 Diabetes.

IL-7 receptor-α (IL-7Rα) blockade has been shown to reverse autoimmune diabetes in the non-obese diabetic mouse by promoting inhibition of effector T cells and consequently altering the balance of regulatory T (Treg) and effector memory (TEM) cells. PF-06342674 is a humanized monoclonal antibody that binds to and inhibits the function of IL-7Rα. In the current phase 1b study, subjects with type 1 diabetes (T1D) received subcutaneous doses of either placebo or PF-06342674 (1, 3, 8 mg/kg/q2w or 6 mg/kg/q1w) for 10 weeks and were followed up to 18 weeks. Nonlinear mixed effects models were developed to characterize the pharmacokinetics (PK), target engagement biomarkers, and immunomodulatory activity. PF-06342674 was estimated to have 20-fold more potent inhibitory effect on TEM cells relative to Treg cells resulting in a non-monotonic dose-response relationship for the Treg:TEM ratio, reaching maximum at ~ 3 mg/kg/q2w dose. Target-mediated elimination led to nonlinear PK with accelerated clearance at lower doses due to high affinity binding and rapid clearance of the drug-target complex. Doses ≥ 3 mg/kg q2w result in sustained PF-06342674 concentrations higher than the concentration of cellular IL-7 receptor and, in turn, maintain near maximal receptor occupancy over the dosing interval. The results provide important insight into the mechanism of IL-7Rα blockade and immunomodulatory activity of PF-06342674 and establish a rational framework for dose selection for subsequent clinical trials of PF-06342674. Furthermore, this analysis serves as an example of mechanistic modeling to support dose selection of a drug candidate in the early phases of development.

Immunomodulatory activity of humanized anti-IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes.

BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS: Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS: This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION: NCT02038764. FUNDING: Pfizer Inc.

Single and multiple ascending-dose study of glucagon-receptor antagonist RN909 in type 2 diabetes: a phase 1, randomized, double-blind, placebo-controlled trial.

PURPOSE: This first-in-human study assessed safety, immunogenicity, pharmacokinetics, and pharmacodynamics of RN909, a monoclonal antibody antagonist of the glucagon receptor, in type 2 diabetes (T2DM) subjects. METHODS: This study enrolled 84 T2DM subjects receiving stable metformin regimens. Forty-four subjects were randomized to receive single escalating doses of RN909 (0.3 to 6 mg/kg subcutaneously (SC), or 1 mg/kg intravenously (IV)), or placebo; 40 subjects were randomized to receive multiple escalating doses (50 to 150 mg SC) or placebo every 4 weeks for 12 weeks. RESULTS: RN909 was well tolerated; treatment-related elevated liver function tests (LFTs) were observed in 4/33 (12.1%) and 5/32 (15.6%) subjects treated with single and multiple doses, respectively, versus 1/10 (10%) and 0 in the respective placebo groups. RN909 dose-normalized AUCinf increased more than dose-proportionally following single SC doses, and after multiple doses, accumulation ratios ranged from 1.3 to 3.4. The incidence of antidrug antibodies (ADA) was 33% after single doses and 50% after multiple doses. RN909 produced dose-dependent, durable fasting plasma glucose (FPG)-lowering at day 29 (mean change -20.6 to -97.5 mg/dL) and day 85 (mean change; -27.2 to -43.5 mg/dL) after single and multiple doses, respectively. HbA1c also was reduced after single (mean change -0.30% to -1.44%), and multiple doses (-0.83% to -1.56%). CONCLUSION: RN909 was well tolerated after single and multiple doses in T2DM subjects, with diarrhea and elevated LFTs the most frequent adverse events. The appearance of ADA did not affect pharmacokinetics or efficacy. Robust lowering of FPG and HbA1c was observed.

The effects of single- and multiple-dose administration of bococizumab (RN316/PF-04950615), a humanized IgG2Δa monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin: Results from four phase I studies.

AIMS: Three single-dose and one multiple-dose phase I studies were conducted in subjects with primary hypercholesterolemia to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. METHODS: The dosing schedules for hypercholesterolemic subjects randomized in the four phase I studies were (1) ascending, single, intravenous (IV) bococizumab (0.3, 1, 3, 6, 12, or 18 mg/kg), or placebo (N = 48; baseline low-density lipoprotein cholesterol [LDL-C] ≥130 mg/dL); (2) single, IV bococizumab (0.5 or 4 mg/kg; no placebo) added to ongoing atorvastatin 40 mg/day (N = 24); (3) single, fixed, subcutaneous (SC) bococizumab (100 or 200 mg), or IV bococizumab (200 mg; no placebo; N = 49; baseline LDL-C ≥130 mg/dL); and (4) weekly IV bococizumab (0.25, 0.5, 1, or 1.5 mg/kg) or placebo for 4 weeks (N = 67; baseline LDL-C ≥130 mg/dL). RESULTS: Bococizumab pharmacokinetics were well characterized following single IV or SC doses and following multiple IV doses. Exposure to single-dose bococizumab increased slightly greater than dose-proportionally and clearance decreased with increasing dose. In the single-dose studies, maximal mean percent reductions from baseline in LDL-C ranged from 43% (0.3 mg/kg) to 84% (18 mg/kg) in bococizumab-treated subjects, compared with 2% for placebo. For the multiple-dose study, maximal reductions in LDL-C ranged from 55% (0.25 mg/kg) to 66% (1 mg/kg) in bococizumab-treated subjects, compared with 9% for placebo. In all studies, adverse events were infrequent, transient, and not dose-related. CONCLUSIONS: Bococizumab was generally safe and well tolerated. Bococizumab lowered LDL-C levels substantially in all four studies.

Effects of 12 weeks of treatment with intravenously administered bococizumab, a humanized monoclonal antibody blocking proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects on high-dose statin.

AIMS: Two multiple-dose phase II studies were conducted in subjects with primary hypercholesterolemia to evaluate the LDL-C lowering efficacy, safety, and tolerability of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. METHODS: The results from the two phase II, double-blinded, randomized, placebo-controlled, multicenter studies conducted in the USA and Canada were combined. In Study 1, 90 subjects with LDL-C ≥100 mg/dL received intravenous (IV) placebo or bococizumab 0.25, 1, 3, or 6 mg/kg. In Study 2, 45 subjects with LDL-C ≥80 mg/dL received IV placebo or bococizumab 1 or 3 mg/kg. Subjects were treated every 4 weeks for 12 weeks. Dosing was interrupted if LDL-C dipped to ≤25 mg/dL and resumed if LDL-C returned to ≥40 mg/dL. The primary endpoint was percent LDL-C reduction from baseline at Week 12. RESULTS: At Week 12, the reductions from baseline in LDL-C vs placebo in the bococizumab 0.25, 1, 3, and 6 mg/kg groups were 9.3%, 10.2%, 41.6%, and 52.0%, respectively (P < .001 vs placebo for all). LDL-C reductions were greater (69.9%) in subjects who received all three doses of bococizumab 6 mg/kg (P < .001 vs placebo). Pharmacogenomic analysis revealed that 15% of hyperlipidemic subjects carried polymorphisms associated with familial hypercholesterolemia, with maximal LDL-C reductions being similar between carriers and noncarriers. Adverse events were mild, unrelated to bococizumab, and resolved by Week 12. CONCLUSIONS: These studies demonstrated that bococizumab safely and effectively lowered LDL-C in hypercholesterolemic subjects on high doses of statin.

Effects of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition with Bococizumab on Lipoprotein Particles in Hypercholesterolemic Subjects.

PURPOSE: Monoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) elicit significant reductions in serum LDL-C levels. However, little is known about their effects on lipoprotein particles. The purpose of this analysis was to evaluate the effect of PCSK9 inhibition with bococizumab (RN316/PF-04950615), a humanized monoclonal antibody to PCSK9, on LDL, VLDL, and HDL particle concentration and size in hypercholesterolemic subjects. METHODS: Data from 3 double-blind, placebo-controlled, randomized studies were analyzed. In study 1, a total of 67 hypercholesterolemic subjects received IV placebo or bococizumab 0.25, 0.5, 1, or 1.5 mg/kg weekly for 4 weeks. In studies 2 and 3, a total of 135 hypercholesterolemic subjects taking statins received IV placebo or bococizumab 0.25, 1, 3, or 6 mg/kg monthly for 12 weeks. Lipoprotein particle concentration and size were measured by using nuclear magnetic resonance spectroscopy. FINDINGS: Overall, the majority of subjects were men (51.9%) aged >50 years of age and of white ethnic origin. In total, 189 subjects with both baseline and 2-week posttreatment data were included in the analysis. After PCSK9 inhibition with bococizumab 0.5, 1, 1.5, 3, and 6 mg/kg, concentrations of total LDL, total small LDL, and small VLDL particles decreased significantly versus baseline and placebo (P < 0.05), whereas concentrations of HDL particles increased (P < 0.05). The size of the LDL, VLDL, and HDL particles increased after PCSK9 inhibition. Reductions in LDL-C and total LDL particle concentrations were highly correlated. IMPLICATIONS: The effect of inhibiting PCSK9 with bococizumab on lipoprotein particle concentration and size are consistent with the general mechanism of PCSK9 inhibitors in blocking PCSK9-mediated downregulation of LDL receptors. PCSK9 inhibition has the potential to provide a clinical benefit through the modulation of atherogenic lipoprotein particles in addition to LDL-C lowering, and this effect will likely be assessed in future analyses of data from cardiovascular outcomes trials of PCSK9 monoclonal antibodies that are currently being conducted. ClinicalTrials.gov identifiers: NCT01243151, NCT01342211, and NCT01350141.

A Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for Bococizumab, a Humanized Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, and Its Application in Early Clinical Development.

Bococizumab (RN316/PF-04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low-density lipoprotein receptor, leading to improved clearance and reduction of low-density lipoprotein cholesterol (LDL-C) in plasma. A mechanism-based drug-target binding model was developed, accounting for bococizumab, PCSK9, and LDL-C concentrations and the effects of concomitant administration of statins. This model was utilized to better understand the pharmacokinetic/pharmacodynamic (PK/PD) data obtained from 3 phase 1 and 2 phase 2a clinical studies. First, simulations performed with this model demonstrated that the conventional method of the area-under-the-curve ratio for bioavailability determination underestimated the subcutaneous bioavailability of bococizumab due to its target-mediated disposition. Second, a covariate model component for statin effects on bococizumab PK/PD was characterized, including a description of the decreased baseline LDL-C, increased baseline PCSK9, and increased LDL-C lowering with concomitant use of statins. Last, the impact of the dosing regimens with and without a dose holiday on bococizumab's LDL-C-lowering effectiveness was shown to be predictable due to the well-characterized PK-PD relationship.

Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial.

OBJECTIVE: To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti-double-stranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare. METHODS: We conducted a randomized, placebo-controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti-dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent-to-treat (ITT) population (145 abetimus, 153 placebo), based on the presence of high-affinity antibodies for the oligonucleotide epitope of abetimus at baseline screening. RESULTS: Abetimus did not significantly prolong time to renal flare, time to initiation of high-dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus-treated patients [12%] versus 24 of 153 placebo-treated patients [16%]). Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced > or =50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated. CONCLUSION: Abetimus at 100 mg/week significantly reduced anti-dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.

Relationship between anti-double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus.

OBJECTIVE: To examine the relationship between changes in anti-double-stranded DNA (anti-dsDNA) antibody levels and the risk of renal flare in patients with systemic lupus erythematosus (SLE), using data from 2 randomized, controlled trials. METHODS: Analyses were based on 487 patients with SLE and a history of lupus nephritis who had an anti-dsDNA antibody titer >/=15 IU/ml at baseline, as measured by Farr assay. Results are presented for the combined population of patients, the placebo arms, and the drug treatment arms in which a dsDNA-based bioconjugate (abetimus sodium; LJP 394) was used. RESULTS: Changes in anti-dsDNA antibody levels were inversely correlated with changes in the C3 level (P < 0.0001 in both trials). Cox proportional hazards regression models showed that changes in anti-dsDNA antibody levels correlated with the risk of renal flare. The models predicted that a point estimate of a 50% reduction in anti-dsDNA antibody levels is associated with a 52% reduction (95% confidence interval [95% CI] 26-68%, nominal P = 0.0007) and a 53% reduction (95% CI 33-69%, nominal P < 0.0001) in the risk of renal flare in the 2 trials, respectively. In the 2 trials, the incidence of renal flare was lower in patients with sustained reductions in anti-dsDNA antibodies (3.0% and 4.1%, respectively) than in patients with stable or increasing antibody levels (21.3% and 20.3%, respectively). CONCLUSION: Changes in anti-dsDNA antibody levels were directly correlated with the risk of renal flare and inversely correlated with changes in the C3 level. Reducing anti-dsDNA antibody levels may represent a therapeutic objective in SLE patients with lupus nephritis, because it is associated with a reduced risk of renal flare.

Concomitant medication use in a large, international, multicenter, placebo controlled trial of anakinra, a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis.

OBJECTIVE: To examine the safety of anakinra when added to a background of standard rheumatoid arthritis (RA) medications in patients with RA with active disease. METHODS: This analysis further evaluates data from the first 6 months of a blinded, placebo controlled safety trial that had a subsequent 30 month, open label portion (not reported here). Patients with RA with a wide range of comorbid conditions, disease activity, and background medications were randomly assigned in a 4:1 allocation ratio to treatment with anakinra 100 mg or placebo administered daily by injection. Safety was assessed by comparing adverse event profiles between anakinra and placebo patients according to concomitant medications received. RESULTS: Anakinra patients (n = 1116) showed no difference in the incidence of upper respiratory infections or overall serious adverse events compared with placebo patients (n = 283). The anakinra group had more injection site reactions (72.6% vs 32.9% in placebo) and a small increase in serious infections (2.1% vs 0.4% in placebo). Anakinra's safety profile did not differ in patients receiving antihypertensive, antidiabetic, or statin drugs. CONCLUSION: This study indicates that anakinra has a good safety profile in patients typically seen in a rheumatology practice who are considered candidates for therapy with agents that are immunomodulatory and disease modifying. Except for injection site reactions and a nonstatistically although potentially clinically significant increase in serious infections in the anakinra versus the placebo groups, the addition of anakinra to a stable background regimen of RA medications introduced no other important safety risk in patients with RA.