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2012 is a big year for clinical data from HSP90 inhibitors, and you’ll continue to find more updates on both of the sites, as well as detailed analysis for Chimera Research subscribers as we go through the year.

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What does the settlement mean for AIS? Keep in mind that TEVA and AIS are seeking approval for a generic (ANDA pathway) device that closely resembles the branded product, while the Intelliject auto-injector is vastly different (link). Therefore the degree to which the two products potentially infringe on the branded epi-pen is dramatically different. 

Certainly a settlement between PFE and TEVA/AIS is still possible, but one shouldn’t read much into the terms (especially negotiated launch date) in the settlement announced today as an example. For now, the trial is underway and we will await further developments. Launch of the epi-pen or another Teva-partnered injector product is a crucial milestone on the path to profitability for Antares Pharma that has been repeatedly delayed.

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From prepared remarks (transcript and slide deck available on MRK website – I’ve corrected transcription issues in the excerpts below):

“The second potentially transformative candidate in our pipeline is our BACE inhibitor for the treatment of Alzheimer’s disease. BACE has been a very difficult target for the entire pharmaceutical industry and our chemists have made incredible progress. Today we are delighted to show you exciting data demonstrating an unprecedented reduction of CSFA data levels in humans with MK8931, our lead BACE inhibitor which is in Phase I of development

Here’s one example of where modeling assimilation has enhanced our decision making.You will hear more about our base inhibitor program for Alzheimer’s disease later from Darryle Schoepp.When we initially took our lead BACE inhibitor into humans, we found that the molecule was much more efficacious than we had anticipated. As a result, at all doses studied,
we observed very robust lowering of CSFA beta line.This is illustrated in the boxed area on the graph. Traditionally, to ensure that we would have a good dose response in our Phase II study, we would have needed to conduct an additional Phase I study at lower doses before selecting doses to manufacturer for Phase II. However our modeling and simulation experts were able to create mechanistic models to predict the CSFA beta response at lower doses. This allowed us to select doses for Phase II drug supply manufacturing without delay while we conducted a confirmatory Phase I study in parallel, enabling an early Phase II start.”

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—-
“So I will end by giving you an update in an important and exciting Merck program, BACE inhibitors for Alzheimer’s disease progression. Alzheimer’s disease is an irreversible neurodegenerative brain disease that leads to dementia with cognitive behavioral changes
that are associated with functional impairments of activities of daily living and ultimately death.Today, there are no treatments available to stop of slow disease progression over the long term or to prevent it. Brains of Alzheimer’s patients are characterized by amyloid plaques, neurofibulatory tangles, inflammation and neuronal death. About 35 million people live with dementia around the world. In the United States there are over 5 million patients with
Alzheimer’s disease. About one out of every eight persons, 65 years of age or older, suffers from Alzheimer’s diseases.The costs to payers are staggering, estimated to be $183 billion in the US during 2011. Worse, the prevalence of Alzheimer’s disease is growing rapidly, due to the aging population, creating an unsustainable burden on patients, caregivers and the economy. If no effective treatments are found by 2050, its estimated there will be over 13 million
Alzheimer patients in the United States, payer costs will grow to over $1 trillion. These statistics do not begin to capture the emotional and physical toll Alzheimer’s disease takes on patients and their families.

The amyloid hypothesis is a leading therapy of what causes Alzheimer’s disease. A positive role of amyloid is supported by genetic studies in patients to familiar Alzheimer’s disease who get early onset disease.These patients have gene mutation that lead to overproduction of amyloidogenic A beta peptide and amyloid plaques.The presence of amyloid plaques was originally observed at autopsy in the brains of Alzheimer patients over 100 years ago.
Now been show are people at high risk for Alzheimer dementia using brain imaging with amyloid PET labeling. The two key enzymes that generate A beta peptide and the amyloidogenic pathway, beta secretase (BACE) and gamma secretase. These enzymes process amyloid precursor protein, APP to produce short peptide forms A beta 1-40 and 1-42, which then aggregate and produce amyloid plaques. Amyloid is associated with loss of neurons, brain atrophy and ultimately clinical symptoms. Inhibitors of gamma secretase have been tested in Alzheimer disease trials, but cannot be administered at doses which substantially reduce A beta peptides in the human brain.The enzyme gamma secretase also processes other substrates, in particular Notch A protein that’s needed for normal function of tissues throughout the body. This has limited doses of these compounds in the clinic only to those which have very modest effects on formation of A beta peptide in the brain. Merck has been working on BACE — BACE inhibitors as a way to more robustly inhibit the amyloidogenic pathway while potentially avoiding the safety and tolerability concerns of the gamma secretase inhibitors.Discovery and identification of a small molecule BACE inhibitor that readily enters the brain to reduce amyloid has been a major challenge. This has been a difficult target for several reasons. BACE is an aspartic protease enzyme compartmentalized to the inner membranes of neurons.
Its active site is relatively large in order to provide access to the proteins of processes. Such as amyloid precursor protein, or APP. The active side of the enzyme is illustrated on the right, showing a peptide substrate docking to a shallow active site. A small molecule must not only [?? word] the active site to inhibit the enzyme, but must enter into the CNS and inside of the
neuron with sufficient concentration. Despite over 10 years of intense effort to discover such molecules, there’s still no BACE inhibitor in clinical development with substantial [senis] A beta lowering in humans. Merck who’s been pioneering the design of brain penetrate molecules optimized for in vivo senis A beta lowering activities.

The orange and the red regions are the enzyme active site in the figure represents critical regions where small molecule inhibitors bind. Unique insights from the use of structural modeling by our chemists were keyed in the success of our program.As a result of these efforts, extremely pleased to now show you clinical data with our lead BACE inhibitor molecule. Our lead Merck BACE inhibitor, known as MK8931, greatly suppressed A beta peptide levels in the human brain.These are the results of our multiple dose Phase I study with MK8931.These studies are intended to find doses that reduce A beta peptides in the brain, using the cerebral spinal fluid, that’s CSF compartment and examine the safety and tolerability of these doses in humans. Volunteers were given the compound or placebo orally once per day for 14 consecutive days. A baseline value of A beta peptide includes SAPP beta, A beta 1-4, MA beta 1-42 was determined prior to the first dose by lumbar puncture of the CSF. Subsequent data is calculated as a percentage of that value. On day 13 of dosing, a few hours prior to dose 14, the last dose, the catheter was inserted in the lumbar space with serial CSF samples. Last dose is given and CSF samples were collected every two hours for 36 hours.When compared to placebo, both a lower dose A and a higher dose B of our compound markedly inhibited the formation of A beta 1-40 in the CSF were up to 36 hours past the last dose. Very similar reductions, not shown here, were also observed for SAPP beta and A beta 1-42 peptide. This study shows the Merck base inhibitor, MK8931 reduced CSF A beta peptide by greater than 90% in healthy volunteers without observing dose limiting side effects in this study. Details of these Phase I studies will be presented at scientific meetings in 2012.

Alzheimer’s disease therapeutics, the priority area for Merck, the amyloid hypothesis remains a leading approach for disease modification for Alzheimer’s disease. Based on our study BACE inhibition is a very promising means to inhibit amyloidogenic A beta production with a goal of preventing or delaying Alzheimer’s disease progression. Phase one studies with our lead first
BACE inhibitor, MK8931, showed potent lower of A beta peptides in the CNS and it was generally well tolerated in those studies. We also have multiple back up compounds and I’m pleased to announce that we expect to initiate our Phase II studies in patients
with Alzheimer’s disease in 2012.”

From Q&A session:
“And then last question is on Alzheimer’s disease. I know you guys have kind of behind the scenes been doing mechanistic work for a number of years on Alzheimer’s and the compound you highlighted is a BACE inhibitor which is small molecule and can go into neurons for example and target A beta. Can you speak in your opinion about the validity of the approach of targeting
A beta accumulation outside of the neuron, and where do you think that’s a valid approach? Because that’s essentially what the monoclonals do?
I don’t really think that we want to comment on the other methods for removing A beta, in particular the antibodies that are being used to remove A beta. As you know, we’ll see some of the results of the trials that are ongoing in the next few years and it’ll be interesting to see what happens. I will say that we’re just extremely excited about the degree of inhibition that we’re getting with BACE.We’ve never seen anything like it and like I said, in my remarks, we grossly overshot it when we first did the Phase I experiments, because we just never expected to see that. And as Darryle said, we’re able to get greater than 90% inhibition of CSFA beta, SAPP as well as 1 to 40 and 1 to 42 with our drug, without having a dose limiting toxicity.
And so we think that this is the molecule that will definitively provide the best test of the A beta hypothesis for Alzheimer’s disease as we move forward and as Darryle mentioned and I also mentioned, when you just look at what the chemists had to do to get this, it is an unbelievably impressive story and it really just a complete chemical structural biological tour de force to
get this molecule to the point where it is and it’s something that we’re really excited about and as Darryle said, we have backups in the series that also are showing very nice efficacy”

“Now Europe first introduced a biosimilar pathway in 2005 for three molecules including human growth hormone, erythropoietin and the colony stimulating factors, granulocyte colony stimulating factors.These three were among the earliest biotech products and they’re the simplest in size and structure. In the EU the approval packages using this new pathway required analytical, preclinical, clinical and immunogenicity studies and draft guidelines for the regulatory approval of the important monoclonal antibody biosimilars in Europe are currently in discussion and we’re waiting for those guidelines to be formally approved and issued. In the United States, the biologics price competition and innovation act of 2010 created a legal pathway for approval of biosimilars, but it did not detail the regulatory requirements for the development and licensure steps. So we’re also waiting for these guidelines to be issued, hopefully before the end of this year”“Now, while waiting for this forma guidance, we continue to discuss our specific programs with the regulators. We’ve had numerous meetings to date, we’ve gotten some feedback from them, we extrapolate from those learning’s to all of our development programs. So we desperately need the overview, both from the US and Europe to understand what the full requirements for this business are going to be”We’ve committed over 200 people in R&D to the development of the Merck bioventures portfolio.We’ve established partnerships to obtain critical molecules, such as the deal already mentioned with Hanwha to obtain a biosimilar version of Enbrel. We’ve invested over $200 million in building our internal manufacturing infrastructure for biosimilar and novel programs.
Internally we have six facilities that we’re making our biological products in. And then, recently, we concluded a partnership with a MedImmune — with MedImmune for their manufacturing capacity in their brand new facility in Frederick Maryland. Finally, for clinical development we’ve partnered with Parexel in an exclusive biosimilars deal. They’re working to provide us
with access to approximately 500 worldwide clinical sites to do our biosimilar clinical work.”

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“Now, because Enbrel is one of the earliest freedom to operate dates for Merck we believe it’s going to be the lynchpin in this new business. This portfolio also allows us to continually prioritize our investments behind the best opportunities. Using the strategies outlined earlier by Peter, we’ll select from these molecules that have the highest potential relative to the development
costs, highest probability of technical success and those molecules for which we have the highest probability of being a first mover.”

“Now, while we won’t wait for the formal global guidance on biosimilars to be issued, before moving to late stage development, we do need formal clarity around a number of crucial issues. For example, the apparent requirement for using only locally sourced comparator material for our Phase III studies that are intended for global registration.That’s a challenge. In this context
of regulatory ambiguity, we don’t expect to have five molecules in Phase III by the end of 2012.
Instead, the timing of Phase III starts will be determined by the regulatory guidance and the ongoing prioritization of our portfolio.That said, I’ll remind you that it’s the freedom to operate dates that are most critical in the timing of the launch of our products.”

“Finally, biosimilar — the market opportunity for biosimilars is large, with important patent expiry starting in the middle of this decade. Merck BioVentures has made progress in developing a portfolio of biosimilar targets, securing partnerships to enhance the portfolio and capabilities while actively engaging with regulators as they develop the final pathways. All of this is with a
goal of pursuing the highest potential molecules and making them ready to enter the market when we have the freedom to operate.”

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Abstract #213 (Infinity Pharma) Friday 1/20 1145 am to 145 pm
A phase Ib trial of IPI-926, a hedgehog pathway inhibitor, plus gemcitabine in patients with metastatic pancreatic cancer.
Donald A. Richards, MD, PhD
Poster Board: #B21

Abstract #467 (Synta Pharma) Saturday 1/21
Phase II study of ganetespib, an hsp-90 inhibitor, in patients with refractory metastatic colorectal cancer.
Andrea Cercek, MD
Poster Board: #B38

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Research White Paper by ARWR on RNAi Delivery – November 2011For Perspective – June 2011 interview with ARWR CEO

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• 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

1. Initiate phase 1 for Factor XI drug
2. Update on CRP drug, initiate phase 2 in multiple myeloma
3. Move SGLT2 drug towards phase 2
4. Some insight into timing of PTP1b inhibitor phase 2b trial “as we round the bend in long-term toxicology studies”
5. 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