Here are my brief notes from the ISIS presentation by CEO Crooke on 3/14/11 and Q&A session
Mipomersin
Pipeline/other comments
Mipomersin
- "Look forward to Mipomersin being available in 2012"
- Mipo lowers ApoB, LDL, LPa, triglycerides, and vLDL- each of these are independent CV risk factors
- HoFH and severe HeFH are fatal cardiovascular disease
- Most HoFH patients are not treated by lipidologists because there isn't much they can do- only option is apheresis (requires driving to one of few centers, spending a day there, and then feeling crappy for a few days afterwards)
- Every bit of mipo data shown to date is on most rigorous ITT basis, additional p3 data to be presented in 2011 at ACC meeting
- Decreasing LDL results in a linear reduction in CV risk- this applies as high up the LDL scale as has been measured. 100 mg/dL reduction would correspond to a 50% decreased heart attack risk w/o taking into account the other factors in the 2nd bullet above
- 45% of heFH pts achieved <100 mg/dl LDL levels, a result that no prior CV drug tested would have dreamed of achieving in this population
- 8% of mipo pts have elevated ALT liver enzymes - but no damage has been seen. ALT elevation and liver fat deposits are correlated with greatest reduction in LDL (aka life-saving efficacy)
- 22% discontinuation rate is comparable to other sub-cutaneous drugs
- 2 carcinogenicity studies which will be part of HoFH filing have already been completed
- Mipo partnership with SNY/GENZ- development and commercial milestones each total ~$1 billion
- Royalties increase linearly from 30% to 50% as go from zero to $2b in sales, additional "kickers" for 3,4,5b
- Estimate market size by 20-30k pts in US/EU at $50-100k per year (gives a range of $1b to $3b)- this product would make ISIS sustainably profitable
- ISIS will do commercial manufacturing, plant is ready and has been inspected multiple times. ISIS also makes money on the manufacturing
- Animal data (paper will be published soon) showing "stunning" elimination of plaques in transgenic mice that develop atherosclerosis
Pipeline/other comments
- Hope to create a franchise for lipidologists with mipo, PCSK9, ApoCIII (finishing p1 now)
- The world needs a safer insulij sensitizer (ie, PTP1b inhibitor candidate- but I guess they don't need it bad enough to keep advancing the lead compound after 18 months of blustering and misleading)
- FGFR4 would be peripherally acting obesity drug, much safer than centrally acting
- LLY is finishing p2 trials of survivin drug, hope they move to p3 "before too long"
- Stat3 cancer drug hope to be in clinic in 2012
- Neurological franchise- all have to be administered intrathecally (into spinal column)- so clearly for very severe diseases only
- SOD1 drug is finishing p1 pgm now, p2 on schedule for 2011
- CRP p1 results were first demonstration of a selective CRP inhibitor working in man
- sub-cutaneous drug sales over the next 10 years are expected to be greater than oral drugs (due to their growth and patent expiration of oral blockbusters)...so antisense are constricted solely to Orphan indications
- Will be very cautious in integrating generation 2.5 chemistry into current programs
- Gen 2.5 would be orally bioavailable, but not actively transported- still get into cells by binding to cell surface proteins and membrane inverting
- Can get 12-15% oral bioavailability in man with Gen 2.0 by adding nonspecific penetration enhancers, but cost (10x higher dose vs 2.5) and size of oral pill are prohibitive
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