- Notes in bold indicate new information (to my knowledge)
- INFI will host a CC on June 1st to review pipeline and discuss ASCO abstracts that will be released May 18th
- Accruing patients in the pancreatic cancer trial for IPI-926 is a top priority. Company believes that they will complete enrollment by ye2011.
- Also will initiate investigator-sponsored trial program for IPI-926 for range of potential indications and in combination w/ commonly used and emerging treatments. First is head and neck cancer p1 combo w/ erbitux in 24 pts, expect others this year
- ASCO June 2011: p1b data for IPI-926, including pancreatic cancer patients and followup data from basal cell carcinoma pts
- ASCO June 2011: IPI-504 combo w/ taxotere data
- In the process of evaluating data from IPI-493 p1 trials, on track for HSP90 inhibitor program udpdate by this summer
- $91.2m cash on hand 3/31/11
- $24.3m r&d expenses in 1q2011, up $5m from 1q2010
- net loss $2.3m 1q2011
- expect cash burn $30-40m in 2011. $90-95m rev (reimbursed expenses $85m and recognition of deferred upfront fees). $120-130m expenses, net loss $30-40m. ye cash $60-70m w/o $50m line of credit. Expect to access credit line in full by end of 1q2012
- cash runway into 2014
- q&a session:
- Only one question re revenue components (analyst wasn't listening to CFO earlier on the call I guess)
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I've obtained the full abstracts that Isis presented at the ATVB conference April 28-30, 2011 (previously only the titles were available)
Poster P170 4/28/11 ANTISENSE OLIGONUCLEOTIDES TARGETING SR-BI AND CD36: CONCENTRATION, DISTRIBUTION, AND ACTIVITY WITHIN ATHEROSCLEROTIC TISSUE Aaron J Donner, Wuxia Fu, Mark J Graham, Rosanne M Crooke, Adam E Mullick, ISIS Pharmaceuticals, Carlsbad, CA In order to quantify the accumulation, distribution and activity of 2’-O-methoxyethyl (MOE) 20mer gapmer antisense oligonucleotides (ASOs) in atherosclerotic aortic tissue, ASOs targeting the class B scavenger receptors, CD36 and SR-BI, were evaluated in mouse models of atherosclerosis. The ASOs were administrated for 3 weeks at 25, 50 or 100 mg/kg/wk. RT-PCR analysis of target gene inhibition revealed potent dose-dependent reductions of CD36 and SR-BI (see table below). ASO tissue concentrations were measured by LC/MS and demonstrated dose-dependent increases in both the liver and atherosclerotic aortic tissue. For example, liver ASO concentrations were 228±28, 270±18 and 346±30 and aortic ASO concentrations were 31±6, 51±2 and 88±7 ug/g for the 25, 50 and 100 mg/kg/wk doses, respectively. Thus, at each higher dose, there was an enrichment of atherosclerotic aortic tissue ASO accumulation relative to the liver, and at the highest dose, the liver:aortic ASO tissue concentrations were approximately 4:1. Immunohistochemistry of atherosclerotic tissue from micetreated with 50 mg/kg/wk of an ASO demonstrated drug localization and accumulation within endothelial cells and macrophages in early plaque deposits and the adventitia. CD36 ASO treatment demonstrated anti-atherosclerotic activity in two murine models of atherosclerosis. In summary, these data demonstrate robust ASO distribution, activity and pharmacology within atherosclerotic tissue suggesting that these regions may represent another opportunity for antisense therapeutic intervention. Poster P138 4/28/11 A PHASE 1 STUDY IN HEALTHY VOLUNTEERS TO EVALUATE THE PHARMACOKINETICS, SAFETY, AND TOLERABILITY OF MIPOMERSEN IN 3 DOSING REGIMENS JoAnn D Flaim, Isis Pharmaceuticals, Inc, Carlsbad, CA; Marjie Hard, Genzyme Corp, Cambridge, MA; John Grundy, John Su, Isis Pharmaceuticals, Inc, Carlsbad, CA; Joanne Donovan, Genzyme Corp, Cambridge, MA Mipomersen (ISIS 301012) is an investigational apolipoprotein (apo) B synthesis inhibitor, which has demonstrated significant reductions in LDL-C, non-HDL-C, apo B and Lp(a) in four Phase 3 studies at a dose of 200 mg subcutaneous (SC) once weekly when added to stable lipid-lowering therapy. With a goal to provide prescribers and patients dosing alternatives as needed in the future, the current study investigated 3 SC dosing regimens for PK, safety and tolerability, including assessment of biomarkers for a number of inflammatory pathways: IL-1β (activation of inflammasomes), IL-6 (Toll-like receptor stimulation), hsCRP (acute phase response), IL-13 (mast cell activation), IFN-α and IFN-β (type 1 interferon signaling), MCP-1 and MIP-1α (chemokine release), and C5a and Bb (complement activation). Healthy volunteers were randomized to 1 of 3 cohorts (n=28/cohort) – 30 mg daily (QD), 70 mg 3x/wk (TIW) or 200 mg once weekly (QW) – with each cohort further randomized to receive either mipomersen or volume-matched placebo (saline) in a 3:1 ratio for 3 weeks. The primary PK objective was to evaluate the relative bioavailability of the two test regimens (30 mg QD and 70mg TIW) to the reference regimen (200 mg QW) by comparison of the post-distribution phase plasma concentrations. Comparable post-distribution phase concentrations were observed 7 days after the last dose across the 3 dose regimens (geometric mean test:reference ratios [90% CI] were 0.92 [0.75, 1.13] for 30 mg QD and 1.02 [0.83, 1.25] for 70 mg TIW) suggesting the two test regimens resulted in similar tissue exposure to the 200 mg QW regimen. Injection site reactions were frequently reported, but were mild in severity and did not lead to treatment discontinuation. In general, there were no differences in inflammatory biomarker signals between treatment groups and placebo with the exception of transient post-dose elevations of hsCRP in the mipomersen 200 mg QW group (week 1, median +3.8 mg/L) that tended to decrease with continued dosing (week 3, median +2.3 mg/L). These results support assessment of these dose regimens in longer-term studies. Poster P405 4/29/11 ANTISENSE INHIBITION OF APOLIPOPROTEIN C-III REDUCES PLASMA LIPIDS AND INCREASES HDL FUNCTIONALITY IN CETP TRANSGENIC, LDL RECEPTOR NULL MICE Thomas A Bell, Rosanne Crooke, Mark Graham, Richard Lee, Adam Mullick, Wuxia Fu, ISIS Pharmaceuticals, Carlsbad, CA Inhibition of apoC-III with an antisense oligonucleotide significantly reduced plasma cholesterol and triglyceride while increasing HDL, apoA1 protein and PON1 activity Mice given the apoC-III ASO also displayed reductions in CETP protein and activity. Treatment with apoC-III ASO enhanced HDL cholesterol clearance. The results from these studies suggest that in a process facilitated by CETP, the apoC-III ASO mediated lowering of plasma lipids can have positive effects on HDL metabolism and function. Numerous epidemiological studies have associated elevated plasma triglycerides (TG) with an increase in cardiovascular disease risk. Apolipoprotein C-III (apoC-III) is a key regulator of plasma TG levels via modulation of lipoprotein lipase. In humans, plasma TG is primarily associated with VLDL and LDL and can readily exchange with cholesteryl ester (CE) from HDL in a process mediated by cholesteryl ester transfer protein (CETP). The primary focus of these studies was to examine the effects of an apoC-III antisense inhibitor (ASO) on plasma lipids and lipoprotein metabolism in hyperlipidemic LDLr-deficient mice that express human CETP. These mice were fed a western diet (42% calories from fat, 0.2% cholesterol) and administered either saline, a control ASO, or anapoC-III ASO at 12.5 mg/kg/wk for 4 weeks. At the end of treatment, mice that were administered the apoC-III ASO displayed dramatic reductions in plasma cholesterol and TG when compared to either saline or control ASO groups. Mice in the apoC-III ASO group also had an increase in apoA1 protein, paraoxonase-1 activity, and HDL cholesterol levels as well as significant reductions in CETP protein and activity relative to the control groups. To directly evaluate the effects of apoC-III inhibition on HDL metabolism, CETP tg, LDLr-deficient mice were also treated with the apoC-III ASO for 6 weeks, then injected with radiolabeled HDL, and clearance of labeled HDL was monitored over 24 hours. When compared to the control groups, mice treated with the apoC-III ASO displayed an enhanced rate of radiolabeled HDL clearance of from plasma that was associated with a greater accumulation of label in the liver, suggesting that inhibition of apoC-III in these mice improves reverse cholesterol transport. These preliminary studies suggest that the apoC-III ASO-mediated lowering of plasma lipids can exert downstream changes in HDL metabolism and function. These effects on HDL appear to result from lowering of CETP protein and activity and additional studies will be required to delineate the interplay between plasma lipid, apoC-III, CETP and atherosclerosis. P517 4/30/11 AN INTRAVITAL MICROSCOPIC ANALYSIS OF ANTISENSE OLIGONUCLEOTIDE DEPLETION OF FXI, PLAVIX® TREATMENT, AND THEIR COMBINATION ON PLATELET AGGREGATION AND FIBRIN FORMATION Dacao Gao, Jeff Crosby, Alexey Revenko, Gourab Bhattacharjee, Chenguang Zhao, Chris May, Robert Macleod, Brett Monia, Isis Pharmaceutical, Carlsbad, CA During pathogenic intravascular thrombosis, platelet aggregation and fibrin formation occur simultaneously. Platelets detect injury through the collagen receptor, aggregate in response to activation, and contribute to thrombus propagation via the secretion of soluble agonists. Fibrin formation creates a meshwork to stabilize the propagating thrombus. We have previously demonstrated that Antisense Oligonucleotides (ASOs) targeting coagulation factor XI (fXI) demonstrate potent antithrombotic effects in several mouse models with no bleeding risk. Plavix® is a widely used anti-platelet treatment targeting the P2Y12 receptor. In this study we address how a combination of our anticoagulant antisense drug and an existing anti-platelet therapy can impact thrombus formation in live mice using intravital microscopy. Independently, fXI ASO and Plavix® both demonstrate inhibition of platelet aggregation and fibrin formation in a dose dependent manner. At low doses, Plavix® shows only inhibition of platelet aggregation with no effect on fibrin formation. Interestingly, the opposite effect is observed with fXI ASO. Combination of low doses of both fXI ASO and Plavix® effects potent inhibition of both platelet aggregation and fibrin deposition. Our results support the combination of fXI ASO and Plavix® as a potent antithrombotic strategy in the treatment of cardiovascular pathologies. P597 4/30/11 ADMINISTRATION OF AN APOLIPOPROTEIN C-III ANTISENSE OLIGONUCLEOTIDE LOWERS PLASMA TRIGLYCERIDE AND POSTPRANDIAL HYPERTRIGLYCERIDEMIA IN C57BL/6 BUT NOT APOLIPOPROTEIN C-III -/- MICE Richard Lee, Wuxia Fu, Adam Mullick, Alex Bell, Mark Graham, Rosanne Crooke, Isis Pharmaceuticals, Carlsbad, CA Hypertriglyceridemia, one of the components of the metabolic syndrome, has been positively associated with coronary heart disease and insulin resistance. Apolipoprotein C-III (apoC-III), a 79 aa protein secreted from the liver and small intestine, modulates plasma triglyceride(TG) levels by inhibiting the actions of lipoprotein lipase. Our study aim was to compare/contrast the effects of apoC-III antisense oligonucleotide (ASO) mediated inhibition to systemic apoC-III knockout using apoC-III deficient (-/-) mice. Chow fed C57BL/6 mouse and apoC-III -/- mice were treated for six weeks with either a control ASO (12.5 mg/kg/wk), which has no sequence homology to any annotated gene in the mouse genome, or a mousespecific apoC-III ASO (12.5 mg/kg/wk). After five weeks, mice were fasted overnight, gavaged with a TG bolus, and plasma TG levels were quantified in 1 hour increments over a 4 hour period. Relative to control ASO treated mice, hepatic apoC-III mRNA expression was significantly reduced in apoC-III ASO treated mice as well as apoC-III -/- mice treated with either control or apoC-III ASO. In the proximal third of the small intestine (SI), apoC-III mRNA reduction in apoC-III ASO treated wildtype mice was less than in apoC-III -/- mice treated with either control ASO or apoC-III ASO. Plasma TG concentrations were also significantly reduced in apoC-III treated C57BL/6 mice, control ASO treated apoC-III -/- mice, and apoC-III ASO treated apoC-III -/- mice compared to the control ASO C57BL/6 mice. Finally, plasma TG area under the curve after administration of a TG bolus was significantly reduced in apoC-III ASO treated wildtype mice, relative to the control groups. Therefore, apoC-III ASO treatment effectively replicated the phenotype observed in apoC-III -/- mice. Additionally, apoC-III ASO treatment had no effect on apoC-III -/- mice, demonstrating that the effects of the apoC-III ASO are target specific. These data suggest that pharmacologic inhibition of apoC-III may be an important therapeutic intervention for hypertriglyceridemia in man. Isis will make the following oral presentation at the ASGCT meeting to be held May 18-21, 2011 in Seattle, Washington [85] Systemic Delivery of RNase H-Active Antisense Oligos in a Transgenic Mouse Model of Myotonic Dystrophy Type 1 Thurman M. Wheeler, Andrew J. Leger, Sanjay K. Pandey, A. Robert MacLeod, Masayuki Nakamori, Seng H. Cheng, C. Frank Bennett, Bruce M. Wentworth, Charles A. Thornton. Department of Neurology, University of Rochester, Rochester, NY; Genzyme Corporation, Framingham, MA; Isis Pharmaceuticals, Carlsbad, CA Objective: To test whether systemic delivery of RNase H-active antisense oligos (ASOs) can reduce or eliminate RNA toxicity in a transgenic mouse model of myotonic dystrophy type 1 (DM1). Background: DM1 is a dominantly inherited degenerative disease caused by expression of an expanded CUG repeat (CUGexp) in the 3′ UTR of the DMPK transcript. CUGexp RNA accumulates in the nucleus, sequesters poly(CUG) binding proteins, and forms nuclear inclusions. Trans-dominant effects of the mutant transcript include aberrant pre-mRNA splicing, dysregulated gene expression, myotonia, and muscular dystrophy. Human skeletal actin-long repeat (HSA-LR) transgenic mice express CUGexp RNA in the 3′ UTR of an hACTA1 transgene. In this model, the toxic RNA is retained in the nucleus and induces splicing changes similar to DM1. Antisense knockdown of pathogenic RNA would be expected to mitigate clinical features of DM1. However, skeletal muscle is less sensitive to ASO effects because distribution of ASOs to muscle tissue is low. In previous studies in rodents (n = 10), systemic ASOs failed to produce target knockdown in muscle, despite strong effects in liver. Design/methods: ASOs were 2′ methoxyethyl gapmers that were designed to work by recruiting the nuclear enzyme RNase H to the ASO-RNA heteroduplex. ASOs targeting the hACTA1 mRNA were screened in cell culture. Active ASOs then were tested by subcutaneous injection in mice (25 mg/kg biweekly for 4 weeks). Control mice were treated with saline. Treatment assignments were randomized and analysis was blinded. Control ASOs targeted Malat1, Pten, and Srb1. Results: Two hACTA1-targeting ASOs reduced transgene levels by up to 80%. Control ASOs had no effect. Serum chemistries and histopathology showed no evidence of toxicity. Knockdown of toxic RNA was associated with elimination of myotonia and correction of RNA mis-splicing in all muscles examined. These effects persisted at least 15 weeks after the final dose. By microarray analysis, > 85% of changes in gene expression were normalized or improved. Another nuclear-retained non-coding RNA, Malat1, was also sensitive to knockdown in muscle (up to 80%) using similar RNase H ASO designs. However, ASOs targeting endogenous mRNAs (Pten, Srb1) did not produce knockdown in muscle, and the distribution of ASOs to skeletal muscle in the DM1 model was not higher than in WT mice. Conclusions: Systemic delivery of RNase H-active ASOs was surprisingly effective at reducing RNA toxicity in a transgenic mouse model of DM1. Nuclear-retained transcripts may display increased sensitivity to RNase H-active ASOs and enable RNA knockdown in muscle tissue where biodistribution is low. The mechanism may relate to residence time of transcripts in the nucleus, the cellular compartment in which RNase H1 is also located. ASOs that act through the RNase H pathway may exploit the nuclear retention phenomenon to gain a therapeutic advantage in DM1. Keywords: Oligonucleotide Based Therapies; RNA; Genetic Diseases Date: Thursday, May 19, 2011 Session Info: Simultaneous Oral Abstract Sessions: Small RNA and Oligonucleotide Based Therapeutics (2:30 PM-4:30 PM) Presentation Time: 2:30 pm Room: 606-607
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