GeneDoctor

Biotech Investing - Genetic Medicine, Rare Disease, Translational Innovation, AI-Powered Target Discovery and Validation, Not Investment Advice

[GeneDoctor @GeneDoctorB]

@DesertDweller93 @uniQure_NV To really make progress, we need to take the critical pathobiology learnings of the field and apply them appropriately to therapeutic design.

[GeneDoctor @GeneDoctorB]

@DesertDweller93 @uniQure_NV From the investment perspective, need to discuss SKY-0515’s mechanistic gap in symptomatic HD. By the time of symptom onset, two massive molecular events have already occurred: somatic expansion & robust HTT1a truncated transcript expression.

[GeneDoctor @GeneDoctorB]

@DesertDweller93 @uniQure_NV Part 2 is PMS1 lowering to stall somatic expansion—but this appears to be too little, too late. At symptom onset, somatic expansion has already occurred, leaving a mosaic of CAG expansions (from 50 to >>150) peppered throughout the CNS.

[GeneDoctor @GeneDoctorB]

@DesertDweller93 @uniQure_NV SKY-0515 is a dual-target splice modifier. Part 1 binds pseudoexon 49b in HTT pre-mRNA to trigger NMD. The problem? Exon 49b doesn’t exist in the truncated HTT1a transcript driving disease. This risks exclusive lowering of full-length HTT (WT >>> mutant) missing the key driver.

[GeneDoctor @GeneDoctorB]

@ClearPath100 Part 2 is PMS1 lowering to stall somatic expansion—but this appears to be too little, too late. At symptom onset, somatic expansion has already occurred, leaving a mosaic of CAG expansions (from 50 to >>150) peppered throughout the CNS.

[GeneDoctor @GeneDoctorB]

@ClearPath100 Another under-discussed story with SKY-0515 is its mechanistic gap in symptomatic HD. By the time of symptom onset, two critical molecular events have ALREADY occurred: somatic expansion & robust HTT1a truncated transcript expression.

[GeneDoctor @GeneDoctorB]

@ClearPath100 SKY-0515 is a dual-target splice modifier. Part 1 binds pseudoexon 49b in HTT pre-mRNA to trigger NMD. The problem? Exon 49b doesn’t exist in the truncated HTT1a transcript driving disease. This achieves only lowering of full-length HTT (WT >> mutant) missing the HTT1a driver.

[John Maraganore 🇺🇸🇬🇷🇺🇦 @JMaraganore]

Vinay Prasad Is Out at the FDA—Again https://t.co/v96TUSfa8i

[John Maraganore 🇺🇸🇬🇷🇺🇦 @JMaraganore]

“The FDA official responded, “You all know that as background, I’m a professor and I’m a practicing [hematology-oncology] doctor. I do miss my clinic and I miss teaching, and I miss being able to run my podcast and speak freely.”
https://t.co/iFfo6R957K

[John Maraganore 🇺🇸🇬🇷🇺🇦 @JMaraganore]

BRAVO!

[Eric Topol @EricTopol]

For Alzheimer's disease, it's no longer a debate of amyloid (Aβ) versus tau. They are interactive drivers and this new, optimistic review maps out a path towards disease-halting therapies @CellCellPress
https://t.co/xl3IUSe2IX

[John Maraganore 🇺🇸🇬🇷🇺🇦 @JMaraganore]

Super cool @zhangf!

[John LaMattina @John_LaMattina]

I’m the former head of Pfizer R&D. I’m very worried about biopharma’s future https://t.co/QKPH0ov5tF via @statnews

[John Maraganore 🇺🇸🇬🇷🇺🇦 @JMaraganore]

Good to see these type of combos to build critical mass in areas like rare disease!

[John Maraganore 🇺🇸🇬🇷🇺🇦 @JMaraganore]

“For decades, the U.S. has been the pinnacle of global science. Now experts fear it may have lost some of its luster, and that budding international researchers won’t… take their next career step in the U.S.”

Not MAGA or MAHA.

[Eric Topol @EricTopol]

A discovery of a gene underpinning the perception of pain with implications for treating the chronic condition that affects 600 million people globally
https://t.co/weJyuzgXab
https://t.co/JJQ0sJWBkI

[GeneDoctor @GeneDoctorB]

@adamfeuerstein @Jasonmmast It turns out that the “arduous and treacherous” path to re-shipping the drug took 7 days! No new trial and no new safety data required. Seems the FDA source or reporting is off here. #FDA $SRPT

[GeneDoctor @GeneDoctorB]

@adamfeuerstein @Jasonmmast FDA calls the pathway for reviewing a safety signal and death "arduous and treacherous." Odd choice of words for a scientific process - why the drama? #FDA $SRPT

[GeneDoctor @GeneDoctorB]

#Starlink down right now GLOBALLY! Wow! That’s a quick way to clear the rest of my zoom calendar for the day!

[GeneDoctor @GeneDoctorB]

#SpaceX #Starship major explosion here in the Ragged Islands Bahamas. Taking cover.

[GeneDoctor @GeneDoctorB]

@adamfeuerstein Most likely path forward is that the FDA label safety section is updated by end-Aug, possible REMS… then dosing continues in ambulatory DMD. No reason for another clinical trial when you have substantial real world data in-hand.

[GeneDoctor @GeneDoctorB]

@adamfeuerstein @Jasonmmast After-all, this was a voluntary halt. $SRPT could still restart with a robust internal PV / safety plan (e.g. sirolimus) in ambulatory. FDA did not require an aligned REMS (yet?)?