Potent Pharmacodynamic Activity Research Articles

LATE BREAKING NEWS E-POSTER PRESENTATION: LBP 7 Characterization of Novel Exon-51 Skipping Oligonucleotides that Safely Rescues Dystrophin Expression in a Severe Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy is a severe childhood degenerative muscle disorder, caused by the absence of functional dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping aims to restore the disrupted dystrophin reading frame, leading to synthesis of internally deleted, partially functional dystrophin. B152869 and B152575 are exon-51 targeting 2′-O-methyl phosphorothioate AONs, designed to improve pharmacodynamics and safety via length optimization, chemical modifications and targeting capabilities. In transgenic dystrophic del52hDMD/mdx mice, lacking both human and mouse dystrophin, intravenous (IV) administration of B152869 or B152575 (13 weekly doses; 18 mg/kg) induced increases in dystrophin, reaching up to ∼50% and ∼6% of normal controls in quadriceps and heart, respectively, as determined by capillary Western immunoassay. Dystrophin increases were accompanied by correction of disease pathogenic markers, including neuronal nitric oxide synthase, and improvement in motor function. AON treatments did not result in adverse renal effects, known to be a clinically translatable endpoint in mice. Absence of renal findings were confirmed in CD-1 mice (13 weekly IV doses at 9-18 mg/kg). Cynomolgus monkeys treated IV with B152869 and B152575 for 8-13 weeks at dose levels of 1-3 mg/kg, demonstrated a lack of kidney or major organ toxicity. Unlike previous generations of AONs these candidates exhibited minimal activation of the alternative complement pathway that was transient and at sub-clinical levels; coagulation effects were also mild and transient (< 5 sec prolongation of APTT). B152869 and B152575, with highly potent pharmacodynamic activity and an improved safety profile, are promising next generation exon-51 skipping therapeutics, warranting further evaluation.

Abstract 5535: SEA-CD40 is a non-fucosylated anti-CD40 antibody with potent pharmacodynamic activity in preclinical models and patients with advanced solid tumors

Abstract CD40 is a co-stimulatory receptor of the TNF receptor superfamily expressed on antigen presenting cells (APCs). Antibodies targeting CD40 may have therapeutic benefit via multiple mechanisms including innate immune activation that can support generation of antigen-specific, antitumor T cell responses, and binding to CD40-expressing cancer cells leading to antibody-mediated target cell killing. Multiple CD40-directed antibodies are in clinical development and differ by immunoglobulin isotype, affinity to CD40, and selectivity for FcγR-binding. These alterations could lead to differences in pharmacodynamic and antitumor activity. SEA-CD40 is an agonistic non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40. SEA-CD40 has enhanced FcγRIIIa binding (~10x greater than parent IgG1 antibody) that drives increased effector function, resulting in more potent immune stimulatory activity than antibodies with muted or selective FcγR binding. The enhanced effector function of SEA-CD40 may confer greater immune stimulation and antitumor activity relative to other CD40-directed therapeutics. Preclinically, SEA-CD40 exposure results in a distinct signature of responses including activation of APCs, CD8+ and CD4+ T cells and NK cells, and targeted depletion of CD40+ B cells. SEA-CD40 demonstrates superior activity compared to other CD40-targeted antibodies in vitro and in vivo, suggesting that the enhanced effector function is critical for optimal immune cell agonism. For example, SEA-CD40 drove in vitro ADCC activity 100-fold above the parent antibody and exhibited robust ADCC with the low and high affinity FcγRIIIA genotype. At matched dose levels in cynomolgus monkeys, SEA-CD40 induced circulating cytokines and sustained B cell depletion that were up to 50-fold above that induced with the parent antibody. The SEA-CD40 signature of activation translates to increased antitumor activity as a single agent and in combination with standard of care treatments in preclinical models, suggesting the potential for beneficial combination therapy in the clinic. The SEA-CD40 immune signature was confirmed by pharmacodynamic changes in an ongoing phase 1 clinical trial in patients with relapsed/refractory metastatic solid tumors (NCT02376699). SEA-CD40 treatment induced dose-dependent increases in circulating cytokines and chemokines associated with myeloid and lymphoid immune activation and trafficking. SEA-CD40 treatment also resulted in activation of CD4+ and CD8+ T cells and CD40-targeted B cell depletion in the periphery. These findings support continued clinical evaluation of SEA-CD40. The ongoing phase 1 clinical trial is actively enrolling and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab. Citation Format: Haley Neff-LaFord, Juneko E. Grilley-Olson, David C. Smith, Brendan Curti, Sanjay Goel, Timothy M. Kuzel, Svetomir N. Markovic, Olivier Rixe, David L. Bajor, Thomas F. Gajewski, Martin Gutierrez, Elisabeth I. Heath, John Thompson, Sahar Ansari, Shyra Gardai, Celine Jacquemont, Michael Schmitt, Andrew L. Coveler. SEA-CD40 is a non-fucosylated anti-CD40 antibody with potent pharmacodynamic activity in preclinical models and patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5535.

Preliminary Results from a Phase 1b Study of TAK-079, an Investigational Anti-CD38 Monoclonal Antibody (mAb) in Patients with Relapsed/ Refractory Multiple Myeloma (RRMM)

Preliminary Results from a Phase 1b Study of TAK-079, an Investigational Anti-CD38 Monoclonal Antibody (mAb) in Patients with Relapsed/ Refractory Multiple Myeloma (RRMM)

Pseudosaccharin amines as potent and selective KV1.5 blockers.

Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects.

Abstract PD5-7: Phase Ib study of LCL161, an oral antagonist of inhibitor of apoptosis proteins, in combination with weekly paclitaxel in patients with advanced solid tumors: Safety and efficacy results, including breast cancer cohort

Abstract Background: LCL161 is a small molecule that triggers tumor cell apoptosis by selectively antagonizing inhibitor of apoptosis proteins (IAPs). Preclinical studies demonstrated antitumor efficacy of LCL161 alone or in combination with chemotherapeutic agents, acting synergistically with paclitaxel in breast cancer models. A Phase I study confirmed potent pharmacodynamic (PD) effects at well-tolerated doses of 1800 mg once weekly. The purpose of this Phase Ib study was to determine the maximum tolerated dose (MTD)/recommended phase II dose (RP2D), safety, pharmacokinetics (PK), PD, and preliminary antitumor activity of LCL161 in combination with weekly paclitaxel. Methods: Patients with advanced/metastatic solid tumors were treated with paclitaxel 80 mg/m2 each week, immediately followed by escalating doses of LCL161 administered once weekly. PK and biomarker sampling was performed. Patients with breast or ovarian cancer were treated at the MTD/R2PD in the dose-expansion phase of the study. Results: As of 4 June 2013, 61 patients have received LCL161 doses of 600 mg (n = 3), 1200 mg (n = 5), 1500 mg (n = 5), and 1800 mg (n = 48), including 26 patients with breast cancer and 19 patients with ovarian cancer. Median duration of exposure was 10 weeks. The most common LCL161-related adverse events (AEs) were diarrhea (53%), anemia (36%), and neutropenia (34%). Eleven patients experienced AEs indicated by the principal investigator as a toxicity requiring dose reduction or a change to a 3 week on/1 week off schedule (ten at 1800 mg and one at 1200 mg), seven of which were neutropenia or febrile neutropenia. The MTD was not reached, and 1800 mg was selected as the RP2D. In the safety expansion group of patients with breast cancer treated at 1800 mg, 17 (out of 20) patients were evaluable for response by investigator assessment using RECIST criteria; of these, 47% achieved a partial response, 35% had stable disease, and 18% developed progressive disease. Interestingly, responses were seen in patients with documented progression to prior taxane-based regimens. Of note, in the ovarian cancer cohort, one patient achieved a complete response. In the study overall, 26% achieved a partial response, and 30% experienced stable disease. No PK interaction between LCL161 and paclitaxel was observed. Discussion: Combination therapy with LCL161 and paclitaxel is well tolerated, with manageable toxicities and encouraging clinical efficacy in breast cancer. Enrollment of additional patients with breast cancer resistant to paclitaxel is ongoing. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-7.

Abstract 2452: ONO-4059, a novel oral Bruton's tyrosine kinase (Btk) inhibitor that demonstrates potent pharmacodynamic activity through Phosphorylated Btk (P-Btk) inhibition, in addition to effective anti-tumour activity in a TMD-8 (DLBCL) xenograft model.

Abstract Purpose: The B-cell receptor (BCR) pathway plays a central role in signal transduction pathways that regulate survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. Btk is a key regulator of the BCR signaling pathway and abberant BCR signaling has been implicated in the survival of malignant B-cells. Recent studies indicate that targeting Btk may be effective in the treatment of B-cell malignancies. ONO-4059 is a highly potent and selective oral Btk inhibitor with an IC50 in the sub-nmol/L range. Previous studies with ONO-4059 (formerly known as ONO-WG-307; AACR 2012) demonstrated that Btk-mediated signaling through Akt and PKD is a critical role for the survival of activated B-cell-like (ABC) sub-type of diffuse large B cell lymphoma (DLBCL) cell lines [TMD-8]. It was also of interest to determine the extent of gene expression changes induced in TMD-8 cells after treatment with ONO-4059. To understand the effects of ONO-4059 on gene transcription, we analyzed the gene expression patterns of ONO-4059 in the TMD-8 xenograft model. Methods: TMD-8 cells were implanted subcutaneously into SCID mice and ONO-4059 was administered orally, twice a day (BID) in two groups of animals, at doses of 3 and 10 mg/kg. When the mean tumour volumes reached 100-200mm3, treatment was initiated daily for 14 days. After the final treatment of ONO-4059, the total RNAs were extracted from frozen re-sected tumour tissue specimens, which comprised of 10 samples at each dose, along with 10 vehicle tissue samples. Microarray analysis was conducted by Agilent technology. Results: The inhibitory level of P-Btk achieved indicates profound anti-proliferative activity of ONO-4059 in the TMD-8 model. Gene expression studies demonstrated that ONO-4059 affects a core set of genes which contains 9 down-regulated and 8 up-regulated genes in a dose-dependent manner. CXCL-10 is the prominent regulated gene that is down-regulated after ONO-4059 treatment and CXCL-10 has been shown to be involved in the pathological processes of human disorders, such as, infectious diseases, inflammatory and autoimmune diseases as well as cancer. From a publicly available microarray database, CXCL-10 expression has been shown to be up-regulated in lymphoma patients, suggesting that CXCL-10 may be a potential biomarker for ONO-4059 in the treatment of B-cell malignancies. Conclusion: Our data show that ONO-4059 has potent anti-tumour activity in a ABC-DLBCL xenograft model and that ONO-4059 achieves active tumor exposures as measured by P-Btk in vivo. ONO-4059 is currently being developed in a Phase I clinical trial for the treatment of B-cell malignancies. Additional work is now underway to determine whether the combining ONO-4059 with other targeted agents affects CXCL-10 expression. Citation Format: Tomoko Yasuhiro, Toshio Yoshizawa, Shingo Hotta, Yuko Ariza, Yoshiko Ueda, Ryohei Kozaki, Joseph Birkett. ONO-4059, a novel oral Bruton's tyrosine kinase (Btk) inhibitor that demonstrates potent pharmacodynamic activity through Phosphorylated Btk (P-Btk) inhibition, in addition to effective anti-tumour activity in a TMD-8 (DLBCL) xenograft model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2452. doi:10.1158/1538-7445.AM2013-2452

Evaluation and prediction of drug permeation.

A major challenge confronting the pharmaceutical scientist is to optimize the selective and efficient delivery of new active entities and drug candidates. Successful drug development requires not only optimization of specific and potent pharmacodynamic activity, but also efficient delivery to the target site. Following advances in rational drug design, combinatorial chemistry and high-throughput screening techniques, the number of newly discovered and promising active compounds has increased dramatically in recent years, often making delivery problems the rate-limiting step in drug research. To overcome these problems, a good knowledge of the pharmacokinetic barriers encountered by bioactive compounds is required. This review gives an overview of the properties of relevant physiological barriers and presents some important biological models for evaluation of drug permeation and transport. Physicochemical determinants in drug permeation and the relevance of quantitative and qualitative approaches to the prediction and evaluation of passive drug absorption are also discussed.

A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765, a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced solid tumors

3502 Background: XL765 is a potent and selective inhibitor of Class I PI3K isoforms, TORC1, and TORC2. XL765 has shown dose-dependent target modulation and tumor growth inhibition or shrinkage in multiple human xenografts. Methods: Pts receive XL765 bid or qd for 28-day cycles. PK and pharmacodynamic analyses are performed. Tumor response is assessed by RECIST every 8 weeks. Results: To date, 34 pts have been dosed with XL765; 26 pts on a bid regimen (15–120mg) and 8 pts on a qd regimen (70–100 mg). Maximum administered doses are 120 mg bid and 100 mg qd. Dose-limiting toxicities (DLTs) occurred at 120 mg bid and 60 mg bid and included elevated hepatic transaminases (2), anorexia/hypophosphatemia (1), rash (1), and nausea/vomiting (1). Grade &gt; 2 increase in transaminases, including one possibly related serious adverse event of Grade 4, occurred in 3 of 7 pts at 120 mg bid. Non-specific neurological complaints (1) and rash (1) were the DLTs that occurred at 100 mg qd. The most common (&gt; 10% of pts) related adverse events were elevated liver enzymes, nausea and diarrhea. XL765 exposure increased with increasing doses (15–120 mg bid). Median tmax was 1–3 h post-dose. Mean t1/2,z ranged from 3 to 9 h at steady-state. Repeat dosing (bid or qd) resulted in moderate to no drug accumulation. XL765 augmented food-induced increases in plasma insulin, but not glucose, in an exposure-dependent fashion. Robust pharmacodynamic modulation of PI3K pathway signaling in PBMCs, hair follicles, skin, and tumors was evident following administration of XL765. These effects were exposure-dependent for some biomarkers in PBMCs and hair. Five pts had durable stable disease (&gt; 3 months): appendiceal cancer (15 mg bid) 8 cycles; RCC (15 mg bid) 4 cycles; NSCLC (30 mg bid) 4 cycles; mesothelioma (60 mg bid) 10 cycles; CRC (100 mg qd) 6 cycles. Conclusions: In this phase I study, XL765 has exhibited potent pharmacodynamic activity at generally well tolerated doses. PI3K pathway inhibition of ∼60–90% in hair and skin was seen at multiple tolerable doses. [Table: see text]