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Proud to partner w/
@TeamDDP,@CJDFoundation & CJDISA to launch http://prionregistry.org : connecting patients & people at-risk with research!pic.twitter.com/USZLr8Vuig
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Eric Vallabh Minikel Retweeted
"We heard this refrain of 'There’s nothing you can do' [because there was no existing cure]. I have come to feel really strongly that that’s not the case." -Sonia Vallabh http://fal.cn/Vvgc
#priondisease@cureffi via@guardianThanks. Twitter will use this to make your timeline better. UndoUndo -
Eric Vallabh Minikel Retweeted
The lawyer who became a scientist to find a cure for her fatal diseasehttps://trib.al/o8FKxZF
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Eric Vallabh Minikel Retweeted
This is huge - first ever pivotal study of Huntingtin lowering drug launching end of 2018, enrolling patients in 2019!! More details coming via an HDBuzz story shortly. Massive thanks to everyone who got it this far (
@ionispharma,@Roche).https://twitter.com/HDBuzzFeed/status/1041268841567977472 …
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Eric Vallabh Minikel Retweeted
The genetics behind human disease targets: prepare yourself for some hard work, but in a good cause:http://blogs.sciencemag.org/pipeline/archives/2018/09/12/digging-into-the-genetics-of-drug-targets …
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Eric Vallabh Minikel Retweeted
Great blog. “There is no doubt that if you’re developing a drug against gene X, then knowing the effect of human loss-of-function variants in gene X is incredibly valuable.” But it ain’t easy...read on!https://twitter.com/cureffi/status/1039813484136079360 …
New blog post on an analysis I led in the@dgmacarthur lab a few years ago. Q: What can loss-of-function variants in databases like gnomAD tell us about whether it's safe to target a gene with a drug? A: A lot, but it's complicated. Read more
http://www.cureffi.org/2018/09/12/lof-and-drug-safety/ …Show this threadThanks. Twitter will use this to make your timeline better. UndoUndo -
New blog post on an analysis I led in the
@dgmacarthur lab a few years ago. Q: What can loss-of-function variants in databases like gnomAD tell us about whether it's safe to target a gene with a drug? A: A lot, but it's complicated. Read morehttp://www.cureffi.org/2018/09/12/lof-and-drug-safety/ …Thanks. Twitter will use this to make your timeline better. UndoUndo -
Many thanks to
@smead2,@GenomicJanna,@roberchiesa,@UCSFmac,@lttakada,@afiffitalia,@prionalliance, & all the patients and families who contributed data to this study!Show this threadThanks. Twitter will use this to make your timeline better. UndoUndo -
In our new
@biorxivpreprint on genetic prion disease last week https://www.biorxiv.org/content/early/2018/08/29/401406 … we ask 2 questions: 1. When will disease strike? 2. How can we design prevention trials? Read this blog post for the story behind the paper:http://www.cureffi.org/2018/09/06/racing-against-a-clock-we-cant-see/ …Show this threadThanks. Twitter will use this to make your timeline better. UndoUndo -
14/ Final note: public dataset & source code for this study are available on GitHub for your reproducing pleasure: https://github.com/ericminikel/prnp_onset … *END*
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13/ Conclusion: the mandate for us as prion scientists: 1) Develop biomarkers for genetic prion disease, 2) Develop infrastructure for post-marketing surveillance. This give us a route forward in case a drug is effective only at prevention and not in symptomatic patients.
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12/ You get increased power from longer trial duration, large control N, and maybe continuous enrollment, and maybe can recruit larger N for an approved drug than a trial. There are of course issues with use of historical controls, but worth exploring and trying to make it work.
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11/ Answer: of course many possible designs for post-marketing confirmatory studies. We raise one option that merits evaluation: surveil drug-treated people long term and compare their survival to historical controls.
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10/ Final question: if a biomarker could one day get us Accelerated Approval of a preventive drug, how do we ultimately convince ourselves and regulators that the drug really does delay onset?
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9/ Conclusion: if our goal is to develop a drug to delay onset of prion disease, clinical evaluation of that drug will require a biomarker. This motivates our work on biomarkers, e.g. Sonia's recent
@biorxivpreprint on CSF PrP levels:https://www.biorxiv.org/content/early/2018/04/04/295063 …Show this threadThanks. Twitter will use this to make your timeline better. UndoUndo -
8/ That's a v. long and v. expensive trial. Moreover, it's more people than we even *have* in this rare disease. Mutation carrier rate may be ~1 in 100K, but due to underdiagnosis & low genetic testing rates, we think only ~60 ppl in U.S. meet criteria for trial modeled above.
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7/ Power calculation: if a drug reduced annual risk of onset by half, then to have 80% power at P=.05 to show that it delayed onset, you would need to randomize 813 people age 40+ for 5 years.pic.twitter.com/zG22QkvXXN
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6/ To illustrate this, we made this plot, inspired by the legendary Charles Joseph Minard plot of Napoleon's invasion of Russia. Recruit young people - OK numbers but their annual risk is very low. Recruit older people - higher annual risk but very few people.pic.twitter.com/T0xM44wWiR
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5/ Turns out it's very hard to follow people to a clinical endpoint in a trial. Because onset is so variable, you can't identify a decent-sized group of people likely to develop disease in the next five years.
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4/ Our goal is to develop a drug to delay onset of Sonia's disease. So next research question: how can you show that a drug delays onset, if onset is so variable?
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3/ Result: age of onset is incredibly variable (e.g. age 12 to 89 for Sonia's mutation) and as far as we can tell today, nothing predicts it. It seems to be totally random.pic.twitter.com/Wey7IS1TZi
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