The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines) encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family.

Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL.

The results confirm that this approach to chemical discovery could identify compounds that escape traditional screens. The complexity of the system means that a panel of single and multiple gene knockdown transgenic lines may be required.

Background:Patients (pts) with lower risk myelodysplastic syndromes (LR-MDS) and anemia experience severe fatigue that negatively impacts overall functioning and daily life. Fatigue can also be commonly reported with treatments for LR-MDS, the goals of which are to minimize transfusions and improve pt-reported outcomes (PRO). In the IMerge Phase 3 (Ph3) study (NCT02598661), imetelstat, a first-in-class telomerase inhibitor, demonstrated statistically significant and meaningfully improved 8-and 24-wk transfusion independence (TI) rates, durable TI, and increased hemoglobin levels compared with placebo in heavily red blood cell (RBC) transfusion-dependent (TD) non-del(5q) LR-MDS pts who were ineligible/relapsed/refractory to ESA and naive to lenalidomide/hypomethylating agents. We also evaluated pt reported fatigue (rate of deterioration/improvement) during treatment with imetelstat or placebo.

Background The combination of the immunomodulatory drug lenalidomide (LEN) with the proteasome inhibitor bortezomib (BORT) and dexamethasone (DEX) has demonstrated substantial preclinical and clinical activity in patients with MM (Richardson PG, et al. Blood. 2010; Kumar S, et al. Blood. 2012). Pomalidomide (POM), a distinct immunomodulatory agent, has been approved by the US FDA for patients with RRMM with ≥ 2 prior therapies, including LEN and BORT, and progressive disease (PD) on or within 60 days of completion of the last line of treatment (Tx). POM with low-dose DEX (LoDEX) has demonstrated efficacy in patients with RRMM treated with prior LEN and BORT (San Miguel, EHA 2013; Leleu X, et al. Blood. 2013; Richardson PG, et al. Blood 2013; Lacy MQ, et al. Blood. 2011). MM-005 was designed to identify the optimal dose of POM-BORT-DEX (PVD) combination Tx for a phase 3 trial comparing PVD vs BORT + LoDEX (VD) in patients with RRMM (MM-007). Methods Eligible patients had RRMM with 1-4 prior lines of Tx including ≥ 2 consecutive cycles of LEN and a proteasome inhibitor. Patients must have been refractory to LEN (PD during or within 60 days of LEN Tx) but not refractory to BORT (at 1.3 mg/m2 twice weekly). The maximum tolerated dose (MTD) was determined using a 3 + 3 design in 5 cohorts. Each cohort received 21-day cycles of POM (1-4 mg/day on days 1-14); intravenous BORT (1-1.3 mg/m2 on days 1, 4, 8, and 11); and LoDEX (20 mg/day on days 1-2, 4-5, 8-9, and 11-12; patients aged > 75 years received 10 mg/day on days 1-2, 4-5, 8-9, 11-12). The study protocol was revised to include a 6-patient cohort receiving subcutaneous BORT. Thromboprophylaxis was given to all patients as either aspirin or low-molecular-weight heparin. Once established, an expansion cohort was enrolled at the MTD. Tx was continued until PD or unacceptable toxicity. Dose-limiting toxicities (DLTs) were assessed during cycle 1. MTD was the primary endpoint; secondary endpoints included safety, overall response rate (ORR; ≥ partial response), duration of response, and time to response (TTR). Results A total of 28 patients across all Tx cohorts is planned. As of April 2013, 22 patients have been enrolled, 21 patients were evaluable for baseline characteristics and safety, and 20 patients were evaluable for response. The median age was 57 years (range, 36-75 years). The median number of prior Tx lines was 2 (range, 1-4). All patients were refractory to LEN and had received prior BORT. 67% of patients had progressed on LEN as their last prior Tx and an additional 2 patients never responded to LEN. At the time of analysis, 14 of 22 (64%) patients remain on study. The primary reason for discontinuation was PD (27%). No DLTs have been observed during cycle 1 at any dose level; thus, the MTD/maximum planned PVD dose is POM 4 mg (days 1-14); intravenous BORT 1.3 mg/m2 (days 1, 4, 8, and 11 for cycles 1-8; days 1 and 8 for cycles 9+); and LoDEX 20 mg/day (days 1-2, 4-5, 8-9, and 11-12 for cycles 1-8; days 1-2, 8-9 for cycles 9+). The most common grade 3/4 adverse events (AEs) were neutropenia (29%) and thrombocytopenia (19%). With thromboprophylaxis, no deep vein thrombosis was observed. Despite 62% of patients having a history of peripheral neuropathy (PN) at baseline, only 29% developed grade 1 and 14% developed grade 2 PN; no grade 3/4 PN was observed. Only 1 patient has discontinued due to AE (Tx-unrelated metastatic pancreatic cancer). Thus far, the ORR is 75% (15 of 20 evaluable), 30% achieving very good partial response (VGPR) or better (including 1 patient in stringent complete response). Responses were rapid (median TTR of 1 cycle [range 1-3]). Many responses are ongoing and may improve with longer follow-up. Responses were also observed in patients with adverse cytogenetics. Updated and pharmacokinetic data on all 28 patients are planned for presentation at the meeting. Conclusions PVD was generally well tolerated in this population of LEN-refractory and BORT-exposed patients with RRMM, with no DLTs and no discontinuations due to Tx-related AEs to date. PVD had promising activity in this population of LEN-refractory and BORT-exposed RRMM pts with an ORR of 75% and 30% ≥ VGPR. The maximum planned dose of POM 4 mg/day on days 1-14; BORT 1.3 mg/m2 on days 1, 4, 8, and 11; and LoDEX 20 mg on days 1-2, 4-5, 8-9, and 11-12 (21-day cycles) has been incorporated into the ongoing MM-007 randomized, prospective phase 3 trial comparing PVD with VD in patients with RRMM (N = 782). Disclosures: Richardson: Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: POM is approved in the US but not in Europe. Hofmeister:Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Siegel:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Lonial:Sanofi: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Onyx: Consultancy. Vesole:Millennium: Honoraria; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Raje:Millennium: Consultancy; Onyx: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding. Zaki:Celgene: Employment, Equity Ownership. Hua:Celgene: Employment, Equity Ownership. Li:Celgene Corporation: Employment, Equity Ownership. Shah:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment, Equity Ownership. Anderson:Acetylon: Equity Ownership; Gilead: Consultancy; Sanofi Aventis: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Oncopop: Equity Ownership.