11/30/2010 webcast
- 2 of the 4 Mipo phase 3 trials are for the first indication- homozygous FH and severe heterozygous FH/severe high cholesterol
- Benchmark for Mipo pricing is apheresis, which is about $100k per year in the US, slightly lower in EU
- BMS-PCSK9 drug also lowers LDL levels, but by different mechanism than mipomersin
- PTP1b inhibitor- two short term studies of this insulin sensitizer complete so far. Good activity in multiple endpoints but not H1bAc (but changes in this often not seen until 6 month duration studies- slow effects). Goal is long term studies (6-12 months next). In parallel with long term tox of this drug, also moving forward a more potent backup compound. Also see LDL lowering with this drug- not enough as a stand-alone, but a nice complement for treating diabetes
- SGLT2 phase 2 trials in 2011
- GCCR and GCGR in preclinical tox now, phase 1 trials in 2011
- eIF-4E start p2 trials in 2010 in prostate cancer and NSCLC. $LLY has the right to take these drugs back after positive phase 2 data at dramatically better terms. ISIS had re-taken over the compounds to accelerate their development
- Success of any one drug in the pipeline moves the company to be sustainably cash flow positive
- Since ISIS has much more cash on hand now vs a few year ago, they can keep drug longer, through phase 2 to capture more of the value
12/7/2010 Webcast
- CRP p2 trials to start late 2010 or in 2011
- FXI p1 trial to begin early 2011
- PTP1b "getting ready" for p2b trials
- Survivin inhibitor "about ready" for phase 3
- eIF4E inhibitor p2 trials to start any day now
- 2011, will add 3-5 more drugs to pipeline and transition to gen 2.5 chemistry
1/6/2011 Pipeline Update webcast
- Next week there will be an update with info from pre-NDA meeting Genzyme had with FDA re mipomersen
- No other Stat3 drugs in development. Top cancer targets are lung, liver, myeloma
- Current obesity drugs- attempt to suppress appetite in CNS, ISIS goal is drugs that act peripherally to increase metabolism
- Have evaluated scores of obesity targets before selecting FGFR4 as first one- toxicology and PK studies underway to allow IND for this 1h2011
- Gen 2.2 chemistry is basically same as 2.0, but use knowledge to improve potency
- No plans to convert current pipeline to Gen 2.5 chemistry
- Will introduce Gen 2.5 cautiously, first in cancer and serious diseases- will select first candidate in 2011 and several more in 2012, follow later with chronic disease drugs
- Events coming up in near future (by the time of spring 2011 conference call to discuss pipeline
- Initiate phase 1 for Factor XI drug
- Update on CRP drug, initiate phase 2 in multiple myeloma
- Move SGLT2 drug towards phase 2
- Some insight into timing of PTP1b inhibitor phase 2b trial "as we round the bend in long-term toxicology studies"
- Excalliard EXC001 phase 2 data so far are "thrillingly positive", rest will be released soon
- ISIS has sufficient manufacturing capacity to launch mipomersen and to supply the entire pipeline for teh foreseeable future- they expanded the facility in 2010
- 4q2010 conference call will include a comprehensive list of events/milestones for 2011
- ISIS does not anticipate new discovery partnerships, but looking at more option deals like done with GSK
- Do not expect any data on oral delivery in 2011- ISIS is working on formulations now that have the selected chemistry
- Stat3 drug- IND enabling studies in 2011, phase 1 in 2012
- SOD drug p2 later in 2011
- SMA drug p1 2011
- GSK1 (undisclosed) drug phase 1 2011
- EXC001- elective abdominal surgery trial- reduced fines at 12 weeks and maintained this at 24 weeks, in 32 pts
- EXC001- elective scar revision: 21 pts, significant improvement at 24 weeks
- EXC001- elective abdominal surgery- 28 pts, 13 weeks tx, showed reduction of CTGF target gene, other genes, and of scarring
1/10/2011 Conference call notes re Mipomersen regulatory pathway
- The recent meeting was the first time $GENZ discussed the severe heterozygous familial hypercholesterolemia (HeFH) population with the FDA. In the US, will need a separate filing for this indication
- The severe HeFH indication will not require an outcome study, but will require an additional study with 12 month exposure to the drug (previous studies were 6 month only, some pts were on for >1 yr, but FDA wants larger database
- The required trial is "within the scope of the planned development program" and will be of "reasonable size" [not disclosed specifics], currently preparing the clinical trial design
- FDA is pleased with quality of current 12 month safety database (107 total pts), is more than enough info for homozygouse FH population, just wants more data for severe HeFH- still only need to look at lowering of LDL cholesterol endpoint
- Analyst question referred to ICH guideline re trial size, ISIS mgmt indicated this was in the right range (anyone know what this is?)
- HoFH US NDA filing may be delayed to 2nd half 2011 because now is different vs European filing (hoFH and severe HeFH are treated as a single continuum and can combine the filings in EU)
- HoFH indication would include up to about 3000 pts in US- this depends on the precise definition for labeling as negotiated with FDA
- HeFH represents 1 in 500 of the US population (~600,000)
- ISIS will finish their funding commitment for the GENZ partnership sometime in 2011, costs are split equally after that
2/28/2011 4q2011 earnings conference call
- 2010 loss of $36.2m, much better than guidance of mid to high $40m's
- ye2010 cash $475m, >$25m better than guidance
- 2010 added 3 new drugs to pipeline (FGFR4 obesity, Stat3 cancer, undisclosed GSK1); started p2 trials for 2 pgms
- Selected Gen 2.5 chemistry and will have first candidate using this in 2011
- 2011: expect revenue to increase by >$10m vs 2010
- Starting p1 trial w/ GSK would trigger a second milestone (earned $5m preclinical milestone in 2010)
- $GENZ submission of Mipomersen NDA will trigger $25m milestone payment (EU filing will be 1h11, US may shift to 2h)
- 2011 expect operating expenses to increase ~$15m over 2010 ($5m associated with moving to new R&D building in mid-2011)
- Later in 2011 will start sharing Mipo expenses equally with GENZ/SNY
- 2011 Guidance: net loss of low $40m's and year end cash balance greater than $350m (is conservative but includes above mipo milestone)
- HoFH- 300 pts in US by genetics, 3000 by clinical definition
- "I'll compare all Phase 3 program to that of the MTP inhibitor. The MTP inhibitor being developed by Integreon has reported a single uncontrolled study with 29 patients individually dose titrated to maximally tolerated dose, while on a very restricted diet to avoid exasperating diarrhea caused by the drug. Clearly the overall profile of Mipomersen demonstrates that Mipomersen is a cut above the competition including anything on the horizon and of course we have completed a much more thorough Phase 3 program than the MTP inhibitor."
- Detailed data from final 2 phase 3 mipo trials will be presented at ACC April 2011
- SGLT2 data 2011
- $25m additional milestone for US approval. No milestones for EU submission/approval
- Statins reduce CRP by 15-30%, hope that can get much more than that w/ antisense in p2
- "We set up Regulus to be successful and what that would mean eventually is that it would become a public company"...no comment on when/how to monetize stake
- Unless we hear otherwise, EU mipo filing will include severe HeFH
- CRP program: "So initially, and for this year, we are planning to move into two Phase 2 programs, one in rheumatoid arthritis in which the endpoints will be of course CRP but also symptomology in the disease and the second is in multiple myeloma for which we will be looking at not only the reduction of CRP but also symptomology and chemosensitization. "
- Initial US filing based on 733 pts, inc 107 for > 1 yr, would expect label to require similar liver monitoring as statins
3/1/2011 Citi webcast
- Gray fuzzy line exists between HoFH and severe HeFH
- HoFH- 700 different mutations identified in LDL receptor
- HoFH- in US and EU, this condition is not diagnosed by genetic testing, but instead clinically/phenotypically based on exceedingly high LDL >300 while on maximally tolerated statins
- Severe HeFH- present clinically with very high LDL, in US are eligible for apheresis (but fewer than 30 centers exist in nation). Market of 10,000-16,000 pts in US. EU sees a continuum of disease, does not segregate HoFH and severe HeFH
- GENZ is in conversations to define the protocol for a 1 year controlled severe HeFH safety and efficacy trial (only 9 severe HeFH pts are among those that have been on therapy over 1 yr)
- Over 100 pts have been on mipo over 1 yr, over 50 pts are still on the extension study being managed by Genzyme
- Observations of liver fat deposits and liver enzyme elevations are related to the target of mipo, not antisense in general
- In Europe, their advice and feedback suggests they look at the population differently vs FDA. Much of the discussion is related to the 2nd filing to expand mipomersen to all HeFH patients
- Mipomersen is contained within the rare diseases unit of Genzyme that SNY has said would not be changed- so don't think SNY would return rights to drug
- Competing candidate (Adurion sp?)- NDA filed this year with only 29 pts, mipomersen has much larger population
3/16/2011 Barclays webcast
- Mipomersen- seen moderate increases in liver fat deposits, doing further work now to assess the clinical significance
- Injection site reactions are largely consmetic, but working on new mipo dosing regimens to alleviate this
- Finalizing design of 12 month mipo study needed for severe HeFH population NDA filing in US
- On track for 1h2011 European filing for mipo in HoFH and severe HeFh
- Phase 2 around midyear 2011 for CRP program, more to say at upcoming pipeline update conference call
- Diabetes program seek 1) insulin sensitizer 2) increase glucose excretion
- Stat3 cancer drug is in IND-enabling studies now
- SOD drug will move into multiple ascending dose p1 trial later this year
- More details and p1 initiation on GSK1 later this year
- Goal is to add 3-5 new drugs to pipeline in 2011, including one with generation 2.5 chemistry
- ACC conference April 3rd-4th will present Mipomersen data
4/6/11 Needham webcast
- Mipomersen- 100mg/dl reduction in LDL corresponds to up to 50% decrease in CV risk
- Now said FDA mipo filing definitely 2h11
- new 12 month mipo study for severe HeFH population is planned to begin 2h11
- CRP begin p2 very shortly
- p2 apoc3 late 2011 or early 2012
- p2 FXI late 2011 or early 2012
- PCSK9 program "moving forward"
- FGFR4 is in IND-enabling studies
- LLY Survivin drug "finishing up p2"
- STAT3 in IND-enabling studies, p1 late 2011 or early 2012
- SOD1 p2 2011
- SMN p1 2011
- GSK1 p1 near middle of this yr- can't talk about target/indication just yet
- Well on track for adding 3-5 new drugs to pipeline 2011
- injection site reactions are mainly cosmetic: 70-90% of pts get them, but not with every injection, resolve in 36-48 hrs, sometimes get tenderness too
- during mipo study conduct, physician and pts are both blinded to patient's ongoing LDL levels
- all commerical/sales/marketing expenses currently paid by genz
- ISIS pays up to $125m development work, will reach in 2011, then 50/50 split
- once there is commercial revenue, becomes profit share, so subtract all expenses then split whatever is leftover
- glad when SNY-GENZ buyout went thru to remove uncertainly
- would be happy if SNY gave back because is valuable. Mipo would be first drug to market for SNY after GENZ merger
- apheresis annual cost is $75-125k. for Mipo, expect "typical orhphan pricing for fatal disease", pharamcoeconomics good for preventing heart attaaks.
- very few people get apheresis in US
4/13/2011 Pipeline Update conference call
- mipomersen-ALT increases (seen in 8% of pts) and liver fat deposits associated with rapid and profound LDL reduction--these plateau or decrease w/ continued tx, decrease when stop tx
- exc001 represents a "major new commercial opp"
- "making real progress towards initiation of longterm ptp1b trial"- glucose control and lipid lowing, trend toward weight loss (uh, sort of...see below re them killin their lead candidate)
- gsk first cancidate was selected in <1yr
- ISIS has the first drug to lower CRP in man. p2 this yr
- satellite company strategy-expertise outside of core focus. little investment
- EXC001for local tx of fibrotic diseases in scarring:
- 10's of millions of surgical procedures per yr in US (1.5m cosmetic, 5m reconstructive. $5b breast comsetic)
- mkt survey- opportunity possible several $B/yr
- dose dependent MOA studies show mRNA decrease, plus decreased collagen and other pathways activated by CTGR (the target of exc-001)
- hypertrophic breast scars can reoccur after revision surgery. other study was in fine line tummytuck scars- product is versatile
- next- p2 dose ranging scar revision study to determine plan for p3 trial (a bit unfortunate...I thought it was ready for phase 3)
- about 5% equity ownership in Excalliard, milestones typical of early partnering deals
- PTP1b (Sanjay)
- late 2009 positive p2 study
- efforts on this program over last yr "invisble to those outside ISIS"
- diabetes is 7th leading US cause of death. 60% of pts poorly controlled. half of type 2 pts progress and need insulin (goal to extend the time before this is necessary)
- insulin sensitizer- can help body's own or exogenous insulin
- small molecule PTP1b inhibitors have off target effects on closely related proteins
- ptp1b inhib also reduces LDL- seen in p2 studies
- many advantages over PPARs
- 2 p2 trials completed w/ 715 give POC and safety
- next step: longterm clinical studies
- in the process of preclinical studies needed, discovered new more potent drug. 5x inc potency should result in better clinical activity- will move this drug forward instead- IND-enabling studies done. complete p1 and move into p2 studies 2012 combo with insulin and metformin. accel path based on 715 experience. significantly longer patent life (this announcement has been a long time coming and was clear as day- they have weasel worded around this program for over a year before officially admitting this today- finally switched the pipeline to show as preclinical instead of phase2 asset)
- GSK1 now disclosed and will be known as TTRrx
- inhibit transthyretin (TTR) for TTR amyloidosis
- no current tx, incidence 1 in 100,000, so 50k pts worldwide
- mutant form of protein- accumulates slowly in tissues, impairing function
- FAC- familial- buildup in heart. life exptacny 5-6 yrs after diagnosis. onset age 60-70
- FAP- destroy peripheral nerves and wasting (intestinal buildup). life expectancy 9-11 yrs after diag. age of onset 30-50yrs. most effective tx is liver transplant ($500k)
- can tx all known types of TTR w/ antisense
- first devel for FAP- hope to halt accumulation
- preclinical efficacy in mouse and monkey studies
- plan to start p1 in normal vol in next few weeks and complete rapidly
- still planning the design for a 9-12 month p2 study to start 2012. neuropathy and wasting endpts
- CRP
- RA- chronic elevation of CRP. well established endpts. active disease for at least 6 months, stable doses of typical meds, elevated CRP. p2 will include short duration of tx, placebo controlled, dose escalation 40-90 pts
- autologous stem cell transplant for MM- acute elevation for 3-4 weeks, associated w/ malaise and myalgia. randomized, placebo controlled. receive before and after transplant. look at CRP levels and symptoms
- any one opportunity in which lowering CRP helps clinically could be $1b mkt
- "ready to begin these p2 studies" finish first two trials 2012 and expand to additional indications then
- 1q earnings in 2 weeks.
- Q&A
- Needham
- each satellite deal is slightly different. but typically some equity, license fee, milestones (similar to early discovery partnership because usually ISIS has not done any work yet when partnered). royalties typically 5-10%
- exception-30% owenerhship in OGXI drug.
- TTR- FoldRx and Amicus related competing pgms.-these attempt to stabilize mutant fibriles and make clusters soluble. best can hope for is some fraction of protein is prevented from forming these
- Normal form of TTR protein also participates in the disease
- TTR excreted from lvier to blood- could measure reductions of this early on in p1
- Morgan Joseph
- 715 not going to continue developing. may seek to license (this statement was very half-hearted...not going to happen). one of earliest generation 2.0 compounds
- backup more potent and longer halflife. expect to move much faster due to experience, didnt have the funding early to do the 26wk studies knew were necessary (this is annoying for an investor to hear). move quickly thru p1 then directly into 6 month studies in diabetics. long term toxicology studies will be in place in 2012