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Positive phase 1 data - statistically significant reductions in serum TTR protein levels in ATTR patients....the most robust RNAi data ever presented, silencing of disease-causing gene in patients.
Data from ALN-PCS phase 1 trial in the coming weeks - second generation delivery technology, potential to show PCSK9 and LDL cholesterol reductions -same formulation as upcoming TTR02 program.
New drug approval in Europe is a positive for FAP patients and for our program, as we view this as complementary approach. This drug (Vyndaqel aka tafamidis from Pfizer) showed relatively modest effect and new therapies are needed, and ALN-TTR could have more profound clinical impact.
Phase 1 trial in patients in Portugal, Spain, UK and Sweden, 3:1 randomization to drug or placebo at each dose cohort. 31 patients could have any ATTR mutation, but most had common Val30Met mutation.
All patients completely treatment, saw roughly dose proportional increase in plasma exposure levels (PK). Similar to what was seen in ALN-VSP liver cancer program.
Dose dependent reduction in serum TTR levels, statistically significant at highest 1 mg/kg dose (range 25-81% in 5 patients, nadir at 7 days, decrease persists through 21 days). As expected saw parallel declines in Retinol Binding Protein (RBP) and vitamin A levels. Confirms potential for once monthly systemic RNAi delivery.
Committed to advancing out TTR program...in coming weeks will file regulatory documents [IND or European equivalent] for TTR02 at or around yearend 2011 (>10x improvement in preclinical studies vs TTR01). Expect TTR02 data in 2012 and move into later stage trials thereafter [slide makes it look like already assuming later development will be with TTR02].
Dose response curve - hard to interpret, why isn't it more obvious?
Slide 12-13 shows some evidence, look at placebo vs 0.4, 0.7, 1.0 groups, gets too crowded if include all cohorts. Start detecting drug effect at 0.4. Not enough data to test for dose dependency. Just noisy up until 0.7 and especially 1.0, why jump at this point? Mostly just small numbers, not inconsistent with non-human primate data.
Pick up any info on competitive landscape for TTR at the meeting in Japan?
We'll let others comment on their products. Some updates from tafamidis, some updates from Isis from their study in volunteers. Reception we received was very positive.
Where are you on dosing for PSCK9 program?
Moving along quite nicely, not giving specifics at this time. Volunteer study, so quicker than patient study, on track for data around yearend.
Color around remaining 3 patients for 1.0 mg/kg dose level - mean suggests others closer to 25%, is 81% reduction patient an outlier? Baseline characteristics to explain that?
A couple patients at 30-35%, one around 50% reduction. The 81% patient was similar clinically to other patients, but didn't have the Val30Met mutation (75-80% of patients), had position 77 mutation instead, but no knowledge of why that would matter. Spectrum of responses consistent with non-human primates.
Biomarkers - can you distinguish between reductions in wild-type and mutant protein?
Yes, we have total TTR assay, that data presented today. Also have MS/MS assay to look at wild-type versus mutant, we are showing changes in both - still working on that dataset and will release (perhaps with data from additional patients dosed at 1.0 mg/kg - no precise guidance on timing, not by year-end 2011). Will be more presentations and then full peer-reviewed patients.
Would PK be meaningfully affected by BMI?
We don't see a big impact in VSP or TTR studies.
How does plasma data translate to tissue TTR data? What link in animal models - linear link or is there a threshold?
Excellent question. Most animal data show >80-90% circulating reductions in mutant mouse, associated with strong tissue decreases. In human context, we don't know what % knockdown would result in tissue depletion. Other diseases, ~50% knockdown was threshold.
Studies in mice with lower than 3 mg/kg dose?
We are doing those studies currently - mice are allowed to age to 20 months, had to wait for additional mice to be available.
Timing for later trials? Had said chance for phase 2 late 2012 and phase 3 2013? Any changes?
Only that we are more confident. Guidance stands.
Course of TTR over time seems more important than nadir at one point?
Agree. We'll have to do pivotal study to link nadir to outcome. With TTR02 will be aiming for ~75% reductions over time.
Slide 9 - what is definition of early stage disease?
Symptomatic with sensory motor neuropathy (stage 1) - needles, pain, minor weakness. Fully ambulatory and self-caring. Not a measure of how long since diagnosis.
5' RACE or other analysis to demonstrate RNAi mechanism?
We didn't take liver biopsies in this study - viewed to be too aggressive in this population. Can't do those studies here. Can't do more than serum levels unless there is scientific breakthrough going forward.
All were polyneuropathy patients.
Potential for data from 5 further patients - haven't yet mapped out when that data will be shared.
Does it make sense to dose higher with TTR01 or just look for better exposure in TTR02? Both in parallel?
Terrific question. Safety profile with TTR01 was quite good, don't see why we couldn't explore higher dose. But all preclinical data suggest TTR02 is a superior formulation, will update in future. Haven't decided yet whether to do more with TTR01.
Not waiting for any data for TTR02 filing, just assembling reports.
What is pivotal endpoints for trials in this program?
Recent drug approval validates composite endpoint for FAP.
TTR02 with more potent formulation study will teach us a lot for later multiple ascending dose studies and pivotal studies. More guidance to come.
First indication targeting is polyneuropathy subset of patients.
Expand on RBP and vitamin A?
TTR carries RBP and RBP provides hydrophobic pocket for vitamin A to sit in and be carried to tissues around body. Predict that TTR decrease should lead to lower RBP and vitamin A decline. Good independent way to monitor drug activity.
Relatively well patients, but have TTR diagnosis and are symptomatic.
Any connection between knockdown and effect on symptoms?
Single dose study - wouldn't expect to see clinical improvement. Confident that repeat doses would have effect on tissue deposits and lead to clinical benefit. Have data in case report forms but have not analyzed yet.
Similar single dose study for TTR02 or direct into multi-dose?
Haven't given specific guidance - stay tuned until early next year.
Appreciable COGS/economic difference between TTR01 and TTR02?
Real benefit is clinical - improved silencing and far lower doses, therapeutic index is better, clearly a better molecule. Expect to use a lot less drug, but COGS not a factor for either drug. 1/10 dose per month is better idea for chronic lifetime therapy.