Background
Prostate‐specific membrane antigen (PSMA) is a well‐characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibody‐drug conjugate (ADC) is a fully human ...IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA‐positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment‐refractory prostate cancer.
Methods
In this first‐in‐man dose‐escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic castration‐resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate‐specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging.
Results
Fifty‐two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first‐cycle and late dose‐limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose‐proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent.
Conclusions
In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti‐tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer.
Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary ...nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of approximately 1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
Combinations of direct-acting anti-virals offer the potential to improve the efficacy, tolerability and duration of the current treatment regimen for hepatitis C virus (HCV) infection. Viral entry ...represents a distinct therapeutic target that has been validated clinically for a number of pathogenic viruses. To discover novel inhibitors of HCV entry, we conducted a high throughput screen of a proprietary small-molecule compound library using HCV pseudoviral particle (HCVpp) technology. We independently discovered and optimized a series of 1,3,5-triazine compounds that are potent, selective and non-cytotoxic inhibitors of HCV entry. Representative compounds fully suppress both cell-free virus and cell-to-cell spread of HCV in vitro. We demonstrate, for the first time, that long term treatment of an HCV cell culture with a potent entry inhibitor promotes sustained viral clearance in vitro. We have confirmed that a single amino acid variant, V719G, in the transmembrane domain of E2 is sufficient to confer resistance to multiple compounds from the triazine series. Resistance studies were extended by evaluating both the fusogenic properties and growth kinetics of drug-induced and natural amino acid variants in the HCVpp and HCV cell culture assays. Our results indicate that amino acid variations at position 719 incur a significant fitness penalty. Introduction of I719 into a genotype 1b envelope sequence did not affect HCV entry; however, the overall level of HCV replication was reduced compared to the parental genotype 1b/2a HCV strain. Consistent with these findings, I719 represents a significant fraction of the naturally occurring genotype 1b sequences. Importantly, I719, the most relevant natural polymorphism, did not significantly alter the susceptibility of HCV to the triazine compounds. The preclinical properties of these triazine compounds support further investigation of entry inhibitors as a potential novel therapy for HCV infection.
Mu opioid receptors are present throughout the central and peripheral nervous systems. Peripheral inflammation causes an increase in mu receptor levels on peripheral terminals of primary afferent ...neurons. Recent studies indicate that activation of peripheral mu receptors produces antihyperalgesic effects in animals and humans. Here, we describe the in vitro pharmacological and in vivo pharmacokinetic properties of a novel, highly potent, and peripherally restricted mu opioid agonist, 8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro4.5dec-3-yl-acetic acid (DiPOA). In a radioligand binding assay, DiPOA inhibited (3)H-diprenorphine binding to recombinant human mu receptors with a K(i) value of approximately 0.8 nM. The rank order of affinity for DiPOA binding to recombinant human opioid receptors was mu > kappa approximately ORL-1 >> delta. DiPOA showed potent agonist effects in a human mu receptor guanosine 5'-O-(3-(35)Sthio)triphosphate functional assay, with an EC(50) value of approximately 33 nM and efficacy of approximately 85% normalized to the mu agonist, d-Ala2,MePhe4,Gly(ol)5enkephalin. Low potency agonist activity was also seen at ORL-1 and kappa receptors. DiPOA bound competitively to the opioid binding site of human mu receptors as demonstrated by a parallel rightward shift in its concentration-response curve in the presence of increasing concentrations of naltrexone. High and sustained (> or =5 h) plasma levels for DiPOA were achieved following intraperitoneal administration at 3 and 10 mg/kg; central nervous system penetration, however, was < or =4% of the plasma concentration, even at levels exceeding 1500 ng/ml. As such, DiPOA represents a systemically available, peripherally restricted small molecule mu opioid agonist that will aid in understanding the role played by mu opioid receptors in the periphery.
Mu opioid receptors are expressed throughout the central and peripheral nervous systems. Peripheral inflammation leads to an increase in mu receptor present on the peripheral terminals of primary ...sensory neurons. Activation of peripheral mu receptors produces potent antihyperalgesic effects in both humans and animals. Here, we describe the in vivo pharmacological properties of the structurally novel, highly potent, systemically available yet peripherally restricted mu opioid agonist, 8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro4.5dec-3-yl-acetic acid (DiPOA). DiPOA administered i.p. produced naltrexone-sensitive, dose-dependent reversal of Freund's complete adjuvant-induced inflammatory mechanical hyperalgesia (1-10 mg/kg). Maximum percent reversal (67%) was seen 1 h postadministration at 10 mg/kg (the highest dose studied). DiPOA also proved antihyperalgesic in a model of postsurgical pain with a maximum percent reversal of 85% 1 h postadministration at 30 mg/kg i.p. (the highest dose studied). DiPOA administered i.p. had no effect in the tail flick assay of acute pain (0.1-10 mg/kg), produced no ataxia as measured by latency to fall from an accelerating rotarod (3-30 mg/kg), and was not antihyperalgesic in the Seltzer model of neuropathic pain (1-10 mg/kg). This is the first report of a peripherally restricted, small-molecule mu opioid agonist that is nonsedating, antihyperalgesic, and effective against inflammatory and postsurgical pain when administered systemically.
To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. ...However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (∼50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3–100
mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30
mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100
mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology.
Background. PRO 140 is a humanized CCR5 monoclonal antibody that has demonstrated potent antiviral activity when it is administered intravenously to adults infected with CCR5-tropic (R5) human ...immunodeficiency virus type 1 (HIV-1). This study is the first to evaluate subcutaneous administration. Methods. A randomized, double-blind, placebo-controlled study was conducted among 44 subjects with HIV-1 RNA levels of >5000 copies/mL, CD4+ cell counts of >300 cells/µL, no receipt of antiretroviral therapy for ⩾12 weeks, and only R5 HIV-1 detectable. Subjects received placebo, 162 mg of PRO 140, or 324 mg of PRO 140 weekly for 3 weeks or 324 mg of PRO 140 every other week for 2 doses by means of subcutaneous infusion. Subjects were monitored for 58 days for safety, antiviral effects, and PRO 140 serum concentrations. Results. Subcutaneous PRO 140 demonstrated potent and prolonged antiretroviral activity. Mean log10 reductions in HIV-1 RNA level were 0.23, 0.99 ( P = .009), 1.37 (P<.001), and 1.65 (P<.001) for the placebo, 162 mg weekly, 324 mg biweekly, and 324 mg weekly dose groups, respectively. Viral loads remained suppressed between successive doses. Treatment was generally well tolerated. Conclusions. This trial demonstrates proof of concept for a monoclonal antibody administered subcutaneously in HIV-1 infected individuals. Subcutaneous PRO 140 offers the potential for significant dose-dependent HIV-1 RNA suppression and infrequent patient self-administration. Trial registration. ClinicalTrials.gov identifier: NCT00642707.
Aims To assess the pharmacokinetic and pharmacodynamic profile of the novel PDE4 inhibitor V11294A (3‐(3‐cyclopentyloxy‐4‐methoxybenzyl)‐6‐ethylamino‐8‐isopropyl‐3H purine hydrochloride) in healthy ...male volunteers.
Methods This was a double‐blind, single dose, randomized crossover study in eight healthy volunteers who received a single oral, fasting dose of V11294A (300 mg) or placebo. Blood samples were taken before and 0.5, 1, 2, 2.5, 3, 4, 6, 9, 12, 18 and 24 h after oral dosing for determination of plasma concentrations of V11294A. Blood samples were also taken before and 3 and 24 h after dosing for the assessment of the effect of V11294A on mononuclear cell proliferation and tumour necrosis factor (TNF) release in whole blood.
Results Following a single oral dose of 300 mg V11294A, plasma concentrations of V11294A and its active metabolite V10332 reached Cmax (ng ml−1; mean ± s.d.; 1398 ± 298, 1000 ± 400, respectively) after 2.63 ± 0.79 and 5.9 ± 2.3 h, respectively. For V11294A and V10332, t1/2 were 9.7 ± 3.9 and 9.5 ± 1.7 h, and AUC(0,∞) were 18100 ± 6100 and 18600 ± 8500 ng ml−1 h, respectively. At 3 h dosing, plasma concentrations of V11294A and V10332 (3‐(3‐cyclopentyloxy‐4‐methoxy‐benzyl)‐8‐isopropyl‐3H‐purin‐6‐ylamine) were 1300 ± 330 and 860 ± 300 ng ml−1, 7 and 3 times their in vitro IC50s for inhibition of TNF release and proliferation, respectively. Treatment with V11294A resulted in a significant reduction of lipopolysaccharide (LPS)‐induced TNF release at 3 h (P < 0.001) and at 24 h (P < 0.05) post ingestion. The amount of TNF released (pmol ml−1) in response to a submaximal concentration of LPS (4 ng ml−1) was not significantly altered following placebo treatment (before 681 ± 68 vs 3 h postdose 773 ± 109, P = 0.27). In contrast, there was a significant reduction in the amount of TNF released following treatment with V11294A (before 778 ± 87 vs 3 h postdose 566 ± 72, P = 0.02). Phytohaemagluttinin (PHA) stimulated the incorporation of 3H‐thymidine in whole blood prior to drug administration. V11294A inhibited the PHA‐induced proliferation at 3 h (P < 0.05). No adverse reactions were noted following single oral administration of V11294A.
Conclusions A single oral 300 mg dose of V11294A administered to healthy volunteers results in plasma concentrations adequate to inhibit activation of inflammatory cells ex vivo, which persists for at least 24 h without any adverse reactions.
Background. The current goal of human immunodeficiency virus type 1 (HIV-1) therapy is to maximally suppress viral replication. Securing this goal requires new drugs and treatment classes. The ...chemokine receptor CCR5 provides an entry portal for HIV-1, and PRO 140 is a humanized monoclonal antibody that binds to CCR5 and potently inhibits CCR5-tropic (R5) HIV-1 in vitro. Methods. A randomized, double-blind, placebo-controlled, dose-escalating study was conducted in 39 individuals with HIV-1 RNA levels ⩾5000 copies/mL, CD4+ cell counts ⩾250 cells/µL, no antiretroviral therapy for 3 months, and only R5 HIV-1 detectable. Cohorts were randomized 3:10 to receive placebo or doses of PRO 140 of 0.5, 2, or 5 mg/kg. Subjects were monitored for 58 days for safety, antiviral effects, and serum concentrations of PRO 140. Results. PRO 140 was generally well tolerated and demonstrated potent, rapid, prolonged, and dose-dependent antiviral activity. Mean reductions in HIV-1RNAlevel of 0.58 log10, 1.20 log10 (P = .0002) and 1.83 log10 (P < .0001) were observed for the 0.5-, 2-, and 5-mg/kg dose groups, respectively. Reductions in mean viral load of ⩾10-fold were observed within 4 days and persisted for 2–3 weeks after treatment. Conclusions. This trial established clear proof of concept for PRO 140 as a potent antiretroviral agent with extended activity after a single dose. Trial registration. ISRCTN Register: ISRCTN45537485.
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