Late-stage Candidates Research Articles

Commencing research students’ expectations and the design of doctoral induction: introducing inflections of collaboration and pleasure

ABSTRACT Current understandings of the expectations and educational needs of commencing PhD students are based on research focusing on the retrospective recollections of middle or late-stage candidates about the extent to which their expectations at entry were met. This article explores the prospective expectations of 199 commencing PhD students at the point of entry into doctoral study. Students’ expectations of PhD study, of being a research student, and of supervisors’ expectations of them were collected at doctoral orientation events in an Australian university. The study found that commencing students reproduce institutional discourse about the doctorate being a high-stakes test of the individual’s preparedness for membership of an academic discipline, and they envisage a difficult trial involving hard work, initiative, self-sacrifice, and intellectual innovation with little outside support. The implication for institutions is that the same narrative does not need to be placed centre-stage within orientation and induction. Rather, institutions need to bring narrative and practices surrounding PhD commencement more into line with the contemporary doctorate emphasising to incoming students that, undertaken within a networked and supportive environment, the doctorate can involve both enjoyment and work-life balance.

Setting up to deliver a therapy for ALS

Neuvivo, a 2-year-old firm with a drug candidate for amyotrophic lateral sclerosis (ALS) poised for Phase 3 clinical trials, has signed on Thermo Fisher Scientific to manufacture the active pharmaceutical ingredient. Selected from a field of seven potential service firms in part for its ability to take the project from clinical to commercial scale in one location, Thermo Fisher has begun manufacturing NP001 in Florence, South Carolina. Meanwhile, Neuvivo is petitioning the US Food and Drug Administration for conditional approval of NP001 for a subset of people before the completion of Phase 3 trials. This forward momentum reflects the high level of interest that any late-stage candidate targeting ALS, a devastating neurodegenerative malady also known as Lou Gehrig’s disease, would generate among patients for whom there is no cure or effective treatment available. Patient advocacy groups are especially interested in Neuvivo’s claim that the therapy arrested the disease’s progress for

WITHDRAWN: The path forward in Alzheimer’s disease therapeutics: Reevaluating the amyloid cascade hypothesis

Development of disease-modifying treatments for Alzheimer's disease (AD) has been challenging, with no drugs approved to date. The failures of several amyloid-targeted programs have led many to dismiss the amyloid beta (Aβ) hypothesis of AD. An antiamyloid antibody aducanumab recently showed modest but significant efficacy in a phase 3 trial, providing important validation of amyloid as a therapeutic target. However, the inconsistent results observed with aducanumab may be explained by the limited brain penetration and lack of selectivity for the soluble Aβ oligomers, which are implicated as upstream drivers of neurodegeneration by multiple studies. Development of agents that can effectively inhibit Aβ oligomer formation or block their toxicity is therefore warranted. An ideal drug would cross the blood-brain barrier efficiently and achieve sustained brain levels that can continuously prevent oligomer formation or inhibit their toxicity. A late-stage candidate with these attributes is ALZ-801, an oral drug with a favorable safety profile and high brain penetration that can robustly inhibit Aβ oligomer formation. An upcoming phase 3 trial with ALZ-801 in APOE4/4 homozygous patients with early AD will effectively test this amyloid oligomer hypothesis.

Evaluation of two lead malaria transmission blocking vaccine candidate antibodies in natural parasite-vector combinations

Transmission blocking vaccines (TBV) which aim to control malaria by inhibiting human-to-mosquito transmission show considerable promise though their utility against naturally circulating parasites remains unknown. The efficacy of two lead candidates targeting Pfs25 and Pfs230 antigens to prevent onwards transmission of naturally occurring parasites to a local mosquito strain is assessed using direct membrane feeding assays and murine antibodies in Burkina Faso. The transmission blocking activity of both candidates depends on the level of parasite exposure (as assessed by the mean number of oocysts in control mosquitoes) and antibody titers. A mathematical framework is devised to allow the efficacy of different candidates to be directly compared and determine the minimal antibody titers required to halt transmission in different settings. The increased efficacy with diminishing parasite exposure indicates that the efficacy of vaccines targeting either Pfs25 or Pfs230 may increase as malaria transmission declines. This has important implications for late-stage candidate selection and assessing how they can support the drive for malaria elimination.

Incentives for Starting Small Companies Focused on Rare and Neglected Diseases.

Starting biotech or pharmaceutical companies is traditionally thought to be based around a scientist, their technology platform or a clinical candidate spun out from another company. Between us we have taken a different approach and formed two small early stage companies after initially leveraging the perspective of a parent with a child with a life-threatening rare disease. Phoenix Nest ( http://www.phoenixnestbiotech.com/ ) was co-founded to work on treatments for Sanfilippo syndrome a devastating neurodegenerative lysosomal storage disorder. In the space of just over 3years we have built up collaborations with leading scientists in academia and industry and been awarded multiple NIH small business grants. The second company, Collaborations Pharmaceuticals Inc. ( http://www.collaborationspharma.com/ ) was founded to address some of the other 7000 or so rare diseases as well as neglected infectious diseases. The Rare Pediatric Disease Priority Review Voucher is likely the most important incentive for companies working on rare diseases with very small populations. This may also be partially responsible for the recent acquisitions of rare disease companies with late stage candidates. Lessons learned in the process of starting our companies are that rare disease parents or patients can readily partner with a scientist and fund research through NIH grants rather than venture capital or angel investors initially. This process may be slow so patience and perseverance is key. We would encourage other pharmaceutical scientists to meet rare disease parents, patients or advocates and work with them to further the science on their diseases and create a source of future drugs.

Unleashing the clinical power of T cells: CD19/CD3 bi-specific T cell engager (BiTE®) antibody construct blinatumomab as a potential therapy.

Multi-agent chemotherapy is the standard treatment for most B cell malignancies. Since chemotherapy can be associated with significant toxicity and since relapses resistant to chemotherapy often develop, new therapies are needed. Blinatumomab (AMG 103 or MT103) is a late-stage candidate in clinical development, which belongs to a novel class of antibody constructs termed bi-specific T cell engager antibodies. This antibody construct has dual specificity for CD19 and CD3 and can re-direct polyclonal cytotoxic T lymphocytes toward the tumor. This review focuses on the pre-clinical and clinical development of blinatumomab as a powerful new tool in the treatment of B cell malignancies.

High-throughput 1,536-well fluorescence polarization assays for α(1)-acid glycoprotein and human serum albumin binding.

Two major plasma proteins in humans are primarily responsible for drug binding, the α1-acid-glycoprotein (AGP) and human serum albumin (HSA). The availability of at least a semiquantitative high-throughput assay for assessment of protein binding is expected to aid in bridging the current gap between high-throughput screening and early lead discovery, where cell-based and biochemical assays are deployed routinely to test up to several million compounds rapidly, as opposed to the late-stage candidate drug profiling methods which test at most dozens of compounds at a time. Here, we describe the miniaturization of a pair of assays based on the binding- and displacement-induced changes in fluorescence polarization (FP) of fluorescent small molecule probes known to specifically target the drug-binding sites of these two proteins. A robust and reproducible assay performance was achieved in ≤4 µL assay volume in 1,536-well format. The assays were tested against a validation set of 10 known protein binders, and the results compared favorably with data obtained using protein-coated beads with high-performance liquid chromatography analysis. The miniaturized assays were taken to a high-throughput level in a screen of the LOPAC1280 collection of 1,280 pharmacologically active compounds. The adaptation of the AGP and HSA FP assays to a 1,536-well format should allow their use in early-stage profiling of large-size compound sets.

Preclinical Strategy to Reduce Clinical Hepatotoxicity Using in Vitro Bioactivation Data for >200 Compounds

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

The Ideal Diabetes Therapy: What Will It Look Like? How Close Are We?

IN BRIEF Although the number of diabetes treatments has substantially increased in the past two decades, today's therapies are considered far from ideal. Yet, what constitutes an ideal therapy is not readily clear, as diabetes drug therapies are regularly judged both by their effects on glycemia and by a wide variety of nonglycemic metrics. This review describes the characteristics of an ideal diabetes therapy from the perspective of patients, physicians, payors, and financial analysts and examines how well currently available therapies and several late-stage candidates meet these guideposts.

Drug Repositioning Using In Silico Compound Profiling

Drug repositioning is a current strategy to find new uses for existing drugs, patented or not, and for late-stage candidates that failed for lack of efficacy. In silico profiling of several marketed drugs (methadone, rapamycin, saquinavir and telmisartan) was performed, exploiting a vast amount of published information. Similar compounds were assessed in terms of target-activity profiles for major drug-target families. In silico profiles were visualized within an interactive heat map and detailed analysis was performed associated with the accessible current knowledge. Based on a basic principle assuming that similar molecules share similar target activity, new potential targets and, therefore, opportunities of potential new indications have been identified and discussed.