Thread by @BRAINCURES

🧵When resources are limited, the question of what knowledge is needed and when — the ‘decision gate’ analogy — becomes the principal strategic consideration in determining the priority of activities during early drug development
@NatRevDrugDisc #biotech
nature.com/articles/nrd11…

Evidence showing ligands & receptors to be variable and discerning instigators of signals, and translators of information, respectively, have illustrated the fallacy of assuming that the surrogate host cell is an inert vessel-Terry Kenakin @NatRevDrugDisc
nature.com/articles/nrd11…

Stepping back from the rather safe HTS paradigm to discovery in virtual space which is still not yet fully developed, certainly needs courageous management decisions not only in terms of financial investments, but also in organizational evolution @Aalanine
nature.com/articles/nrd10…

“The best ideas are simple, practicable with the available resources and novel enough to yield medicines that are likely to be better than probable competitors in ways that will be obvious both to doctors and their patients"-Sir David Jack @NatRevDrugDisc
nature.com/articles/nrd986

Congruence between in vitro and animal models of disease and the corresponding human condition is a fundamental assumption of much biomedical research, but it is one that is rarely critically assessed. Much more open discussion of this issue is required
nature.com/articles/nrd10…

Combinatorial chemistry is best described as the industrialization of chemistry; the chemistry has not changed, just the way in which it is now carried out, which is principally by exploiting instrumentation & robotics coupled to extensive use of computers
nature.com/articles/nrd10…

It can be argued that obtaining data is no longer the key issue facing early drug discovery, and that the challenge has now become selecting the right experiments to run and the right point in the compound optimization process to apply the information #RRI
nature.com/articles/nrd10…

A key question to address at a reasonably early stage of pharmaceutical development (preferably at the same time as, or before, the nomination of a new candidate drug) is the projected future cost of goods
-Hans-Jürgen Federsel @AstraZeneca @NatRevDrugDisc
nature.com/articles/nrd11…

554 new therapeutics approved for marketing in the United States between 1980–2001. Of these therapeutics, 504 were small molecules, 40 were recombinant proteins (rDNA) and 10 were monoclonal antibodies (mAb) based on Janice Reichert @TuftsCSDD data review
nature.com/articles/nrd11…

Depending on the number of concerns raised in the patent, and the number of countries in which patents are sought, the entire patenting process can take up to four-and-a-half years and cost in excess of £40,000-Philip Webber @NatRevDrugDisc #Patent #IPLaw
nature.com/articles/nrd12…

Organizations managing public–private partnership drug R&D:
Medicines for Malaria Venture (MMV) @MedsforMalaria
Global Alliance for Tuberculosis Drug Development (GATB) @TBAlliance #endTB
Drugs for Neglected Diseases Initiative (DNDi) @DNDi
@OneWorldHealth
nature.com/articles/nrd12…

Has the role of serendipity, so important to drug discovery in the past, been supplanted by robots?

What has happened to the role of the medicinal chemist’s intuition and creativity in producing quality drugs?

Joseph Lombardino and John Lowe III @pfizer
nature.com/articles/nrd15…

Pricing medicines: theory and practice, challenges and
opportunities

Nigel Gregson, Keiron Sparrowhawk @KTSparrowhawk, Josephine Mauskopf @jmauskopf & John Paul @NatRevDrugDisc #DrugPricing #PricingMedicines
nature.com/articles/nrd16…

The defining characteristic of any statistical approach is how it deals with uncertainty. Unlike the frequentist approach, in the Bayesian approach all uncertainty is measured by probability. Anything that is unknown has a probability distribution
-D Berry
nature.com/articles/nrd19…

The average cost associated with the discovery & preclinical evaluation of a single drug candidate ranges between US$28-$38 million; a 10% improvement in predicting failure before the initiation of clinical trials could save $100m in development costs/drug
nature.com/articles/nrd23…

A study published in 2003 showed that the average clinical development and approval time was more than 1 year faster for 33 protein therapeutics approved between 1980 and 2002 than for 294 small-molecule drugs approved during the same time period
-D Golan
nature.com/articles/nrd23…

While allowing many of the advantages of an in vitro preparation, brain-slice field recordings, in most instances, remain indistinguishable from their in vivo counterparts. Unlike intracellular recordings, field potentials typically remain stable for hours
nature.com/articles/nrd25…

Below are some of the most critical findings in the review of the clinical part of unapproved marketing authorization applications:
-Proof of the product rationale
-Magnitude of demonstrated clinical effect
-Methodological flaws of the pivotal study design
nature.com/articles/nrd27…

Challenges to effective phenotypic profiling:
-Implementing profiling on relevant cell types
-Using new data-mining methods and finding ways to extract system level information from both drug-induced and genetic perturbations
-Acquiring time-dependent data
nature.com/articles/nrd28…

The use of etanercept, infliximab & adalimumab— which are widely used in the treatment of rheumatoid arthritis and psoriatic arthritis is associated with an increased risk of cancer. @RheumatologyUK has established a register of patients taking these drugs
nature.com/articles/nrd30…

A key challenge for the implementation of tools and techniques which advance the quality, timeliness and efficiency of drug development is the ability to work across disciplines and amongst stakeholders to understand how and when to apply these solutions
nature.com/articles/nrd30…

Based on the free drug hypothesis, Smith & Kerns believe that several common drug discovery drug-plasma binding measurement practices are counterproductive:
The shift assay is not beneficial
-Optimization of the free drug fraction is scientifically unsound
nature.com/articles/nrd32…

Although terms including mitotic catastrophe, anoikis, entosis, pyroptosis, parthanatos, autoschizis are being used by the scientific community, most often they refer to cell death modes that are executed by the molecular machinery of apoptosis or necrosis
nature.com/articles/nrd33…

Using data extracted from the 2000–2010 patent literature Leeson & St-Gallay showed how companies such as Takeda, Lilly, Schering-Plough & AstraZeneca shifted the logP profiles of their compounds in the later part of the decade compared to the earlier part
nature.com/articles/nrd37…

Will the magnitude and duration of the off-target activity in vivo lead to a biologically relevant effect?

Will the off-target-driven #invivo effect negatively affect the safety profile of the drug candidate for the targeted indication?

@NovartisScience
nature.com/articles/nrd38…

Here, for the first time, four major pharmaceutical companies (@AstraZeneca @GSK @Novartis and @pfizer) share their knowledge and experiences of the innovative application of existing screening technologies to detect off-target interactions of compounds
nature.com/articles/nrd38…

Animal models for metabolic-(Fabry’s disease
Gaucher’s, MPS disorders, Niemann–Pick, Pompe's, α‑mannosidosis, Acute intermittent porphyria, Hypophosphatasia), neuromuscular-(ALS, Huntington's, LEMS, EAMG) and ophthalmological-(LCA, Stargardt) rare diseases
nature.com/articles/nrd38…

GPCR dimerization may be common to all 3 classes of GPCRs. It is possible for a modulator binding to the orthosteric binding site of one monomer of a dimer to modulate the binding and/or function of the orthosteric ligand in the other monomer-Wootten et al
nature.com/articles/nrd40…

In trying to understand why the cost per successful drug has risen dramatically, perhaps the most important observation is that less than 5% of the molecules that enter Phase I clinical trials are eventually approved as safe & effective therapeutics by FDA
nature.com/articles/nrd40…

One of the hallmark attributes of academia is PIs who are engaged in curiosity-driven research. Although they may collaborate with other laboratories, they are often accustomed to leading projects in a different manner to that of pharmaceutical companies
nature.com/articles/nrd45…

17 defining principles of disease-relevant assays:
1) Define the translational research objective of the assay
2) Adopt the human physiology assay checklist
3) Retrospectively analyse and measure the predictive value of each assay
@hpke1980 @NathalieAulner
nature.com/articles/nrd.2…

@threadreaderapp please unroll