Krzysztof Potempa Profile picture
Oct 19, 2022 32 tweets 18 min read Read on X
🧵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

• • •

Missing some Tweet in this thread? You can try to force a refresh
 

Keep Current with Krzysztof Potempa

Krzysztof Potempa Profile picture

Stay in touch and get notified when new unrolls are available from this author!

Read all threads

This Thread may be Removed Anytime!

PDF

Twitter may remove this content at anytime! Save it as PDF for later use!

Try unrolling a thread yourself!

how to unroll video
  1. Follow @ThreadReaderApp to mention us!

  2. From a Twitter thread mention us with a keyword "unroll"
@threadreaderapp unroll

Practice here first or read more on our help page!

More from @BRAINCURES

Sep 3
🧵 The founder of a successful public biotechnology company once told me that the secret to his company's success was neither the idea nor the concept, but the management team: from day one the company had excellent managers and the best mid-level managers
nature.com/articles/nbt06…
The challenge for the manager of a biotechnology startup, especially in Europe, is to foster a transition within the founding biotech team from science-oriented to commerce-oriented thinking and action
—Andreas Föller @NatureBiotech
nature.com/articles/nbt06…
Biotech requires people who are willing to take risks, conquer new science, and have endurance for the many years it takes to develop a medicine. In addition, professionals who thrive have the know-how, confidence and guts to tackle complex business goals
lifescivc.com/2019/01/2421/
Read 17 tweets
Jul 3
🧵 Don Selkoe, a whistleblower expert and author of Don't Kill the Messenger, says that whistleblowers are ready to endure all forms of retaliation for the sake of truth, as the truth-telling part of their brain seems to override the health and safety part
linkedin.com/pulse/survivor…
Whistleblowers are not being protected enough within the academic environment. Somebody should feel comfortable to be able to raise issues without fearing retaliation or damage to their own career says @skleinert1 to @edyong209 @heidiledford @Richvn
nature.com/articles/50345…
Image
@edyong209 @heidiledford @Richvn When asked about the two careers that have been broken by his investigations, Uri Simonsohn @uri_sohn pauses. I don’t feel bad about it. If I’m going to the same conferences as these people, and publishing in these journals, I can’t just look the other way
linkedin.com/posts/krzyszto…
Read 17 tweets
May 25
🧵1. Genetic support for FDA-approved drugs over the past decade
@PoRusina Maria Falaguera, Juan María Roldán Romero, Ellen McDonagh @DunhamReal @d0choa

2. Human Genetics & Genomics for Drug Target Identification & Prioritization: @OpenTargets' Perspective nature.com/articles/d4157…
Image
Human Genetics and Genomics for Drug Target Identification and Prioritization: Open Targets @OpenTargets' Perspective

Ellen McDonagh, @GosiaTrynka @markmccarthyoxf @emilyroseholz @kshameer, Nikolina Nakic, Xinli Hu, @HelenaCornu, Ian Dunham, @DavidHulcoop
linkedin.com/posts/krzyszto…
Further target relevant biotech posts:
1) Big pharma productivity frameworks
2) Unexplored therapeutic opportunities in the human genome
3) Resources for G-protein coupled receptors (GPCRs) value analyses in drug discovery and development
linkedin.com/posts/krzyszto…
Read 4 tweets
Aug 18, 2023
🧵 A neonatal nurse has been found guilty of murdering seven babies and attempting to kill 6 more, making her the worst child serial killer in modern British history and raising urgent questions over whether her crimes could have been stopped
@joshhalliday
theguardian.com/uk-news/2023/a…
Lucy Letby guilty of murdering seven babies as Angel of Death nurse at NHS hospital. She was working as a nurse at the neonatal unit at the Countess of Chester Hospital, where she was accused of murdering seven babies and trying to kill 10 others
mirror.co.uk/news/uk-news/b…
Nigel Scawn @scawn_nigel, medical director @theCountessNHS, walked away without answering as a journalist asked him: 'Why did hospital managers try to stop Letby from being investigated?’

—Stewart Carr, Rory Tingle, Nigel Bunyan, Liz Hull, Elizabeth Haigh
dailymail.co.uk/news/article-1…
Read 100 tweets
Mar 14, 2023
Can you imagine applying biological intelligence-BI to achieve a 3 to 5-fold increase on AstraZeneca’s reported 19% success rate in the proportion of pipeline molecules that advance from preclinical investigation to completion of Phase III clinical trials?
bioindustry.org/news-listing/m…
@BraincuresLTD's biological intelligence (BI) approach eliminated 59 of 72 target-compound pairs associated with Phase III clinical failures to enable 60 to 100% likelihood of clinical success rates across compounds that target 13 different protein classes
bioindustry.org/news-listing/m…
While there are nearly 400 companies that apply artificial intelligence (AI) to de-risk certain parts of the drug development cycle, @BraincuresLTD are the only company actively using the notion of biological intelligence (BI) in research and development
bioindustry.org/news-listing/m…
Read 9 tweets
Mar 13, 2023
🧵@KQLabs is a major initiative, delivered by @TheCrick supported by funding from @InnovateUK, and with collaboration from the @KQ_London @HDR_UK @GenomicsEngland, which aims to bring together a powerful eco-system in support of data-driven health startups
knowledgequarter.london/kq-labs/
Providing critical support to early stage data-driven health science startups, @KqLabs offers a customised framework with a 16-week accelerator programme. The program also includes workshops to inspire and nurture the next generation of start-ups
@TheCrick
crick.ac.uk/news/2018-09-1…
Veronique Birault, Head of Translation at the Francis Crick Institute, said: “This is the start of a very exciting journey for the ten start-ups, and also a great contribution towards building the ecosystem for data-driven health in the Kings Cross area”
crick.ac.uk/news/2018-10-2…
Read 16 tweets

Did Thread Reader help you today?

Support us! We are indie developers!


This site is made by just two indie developers on a laptop doing marketing, support and development! Read more about the story.

Become a Premium Member ($3/month or $30/year) and get exclusive features!

Become Premium

Don't want to be a Premium member but still want to support us?

Make a small donation by buying us coffee ($5) or help with server cost ($10)

Donate via Paypal

Or Donate anonymously using crypto!

Ethereum

0xfe58350B80634f60Fa6Dc149a72b4DFbc17D341E copy

Bitcoin

3ATGMxNzCUFzxpMCHL5sWSt4DVtS8UqXpi copy

Thank you for your support!

Follow Us!

:(