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BMS is vooral beroemd omdat een van hun CEO's radical overstapte van 'eigen' R&D die niet rendeerde naar het kopen van molecule bij kleine start-ups. Ik meen dat de man in zijn eerste jaar tinetallen deals deed, die het bedrijf eindelijk weer de zo gewilde innovatieve nieuwe molecule bezorgde en het bedrijf uit het skop haalde. Dat ze dus met QURE in zee gaan is een zeer groot teken van erkenning!
Sorry voor alle typo's maar ik heb vaak last van trage en stroperige omzetting van wat ik intik naar tekst op IEX. Weet iemand hoe dat kan komen?
En nog even de nadruk op TexMex zijn analyse van vorige maand. Iedereen kijkt met argusogen naar de resultaten van Celladon's fase 2B trial met de AAV1 vector in harfalen die in April worden verwacht. Ik denk dat we allemaal moeten hopen dat deze trial POSITIEF is. Dan gaat QURE/gentherapie ook weer een stukje omhoog....Die markt is echt groot genoeg voor twee spelers.
@psuvafan007:Congestive Heart Failure #genetherapy $QURE S100A Better target, better retrograde delivery than $CLDN SERCA2a. t.co/agnORRygd6 @mhrob: @psuvafan007 I'm seeing some serious disadvantages with the QURE method that might be avoided with CLDN. Both have pros & cons, depends,
Bristol-Myers Squibb L.Andreotti on Q1 2015 Results - Earnings Call Transcript We are also expanding our specialty portfolio through business development. Our recent agreement with uniQure brings us exclusive access to uniQure's gene therapy technology platform for multiple targets in cardiovascular diseases, including a program for congestive heart failure. The agreement also allows us to collaborate in other therapeutic areas. And obviously, as you know, cardiovascular is one of our priority areas. We have a number of early programs in cardiovascular disease. We actually, as Charlie mentioned, signed an agreement with uniQure, which has a potential target in heart failure. So Eliquis is one product, but we are committed to the area.seekingalpha.com/article/3111956-bris...
InoCard – an exercise towards the translation of a novel therapy against chronic heart failure tinyurl.com/n9wyg94 AAV-S100A1 $QURE
twitter.com/ogut_ozgur/status/6141675... Uniqure and the Celladon Legacy June 25, 2015 Virus-based gene therapies are demonstrating strong proof-of-concept primarily for hematological diseases. To date, however, the data targeting solid organs has been weak. This was best exemplified by the recent results for Celladon’s Mydicar therapy providing AAV-mediated SERCA protein expression for heart failure (HF) patients. As readers might recall, prior posts outlined that Celladon’s preclinical data were exceptionally weak and failed to show increased target protein expression. Without this, there was little reason to expect success in their randomized CUPID-2 trial regardless of the results in the dose-finding CUPID-1 trial. CUPID-2 ended with a hazard ratio of 0.93 in a modified intent-to-treat population, confirming that the “therapy” was effectively a placebo. This outcome strongly encourages future investors in HF-targeted gene therapies to ensure that the preclinical data achieves one fundamental observation: verifiable change in expression of the targeted protein. In addition to their hematological programs, European outfit Uniqure is also directing their AAV efforts to address heart failure. Based on their preclinical publications, Uniqure have seemingly come out ahead where Celladon clearly failed. Uniqure’s proof-of-concept studies in pigs receiving their AAV9-based construct to increase S100A1 protein expression seems both reliable and conclusive. At multiple points throughout this publication, the authors are able to show convincing evidence of S100A1 protein at levels above and beyond baseline. Why have Uniqure succeeded in providing convincing proof-of-concept where Celladon have failed? Although Uniqure is using an AAV2/9 construct whereas Celladon opted for AAV2/1, I do not think this makes a material impact. Preclinical data testing the tropism of these vectors have shown that both can target the heart efficiently in rodents, suggesting that the choice of capsid type is not the discriminator. Rather, Uniqure’s retroinfusion with accompanying left anterior descending (LAD) coronary occlusion is likely the key factor. Celladon’s preclinical and clinical data have conclusively shown that intracoronary infusion of AAV is not sufficient to transduce the myocardium, and Uniqure’s modification of working in a retrograde fashion is a novel and effective means of addressing delivery. Although not as simple and convenient as a daily pill, the infusion / temporary LAD occlusion method used by Uniqure is achievable and, given the state of the technology, necessary to achieve transduction of the myocardium and target protein expression. Although Uniqure and their team are to be commended for their technical achievement and thorough preclinical work, I remain skeptical of the S100A1 program and, by extension, their collaboration with Bristol-Myers Squibb. Although this blog attempts to be as quantitative and data-driven as possible, the reservations surrounding these programs are, admittedly, qualitative and a “gut” feeling. To add context to the gut feeling, we can set the stage for what these programs are attempting to achieve. Simply put, both programs from Uniqure and Celladon were attempting to restore what was once abundant. In the case of Celladon, they were attempting to capitalize on literature observations that the expression of SERCA2a declines in the context of the failing heart. Similarly, Uniqure is pointing to a decrease in S100A1 in the failing heart as a point of intervention. Simply put, this approach relies on an underlying belief that restoring something to the levels found in the “normal” heart will allow the failing heart to recover some or all of its lost function. In effect, the strategy treats heart failure as if it was analogous to the pathophysiological settings wherein enzyme replacement therapies succeed. Missing glucocerebrosidase because you have Gaucher’s disease? We can provide the enzyme to attempt to restore it to physiological levels. Is your failing heart low on S100A1? We have an AAV for you. Unfortunately, I think this strategy is very flawed when applied to heart failure. It is very well established that heart failure impacts the heart in a myriad of ways. At the molecular level, we can observe changes in protein signaling and protein abundance. But at a more macro level, there are clear structural changes that occur. The figure from Wikipedia does a good job of showing representative structural changes and remodeling that are evident in various pathophysiological states. Simply put, this figure is the backbone for my skepticism. If we take the example of S100A1, the preclinical data suggest that ischemia-induced HF (which often takes a first step through hypertrophy) induces a state of the heart wherein S100A1 expression level is less than it was under normal conditions. Therefore, the presumption is that increasing S100A1 in the hypertrophic or failing / remodeled heart will allow the heart to return to normal. This, in my view, is a logical flaw. In effect, I believe this reflects a cognitive dissonance that treats the remodeled heart as simply a normal heart with reduced S100A1 (or reduced SERCA2a, or reduced protein X) expression. However, this simply isn’t true. The remodeled heart has altered structure including myocyte disarray, aberrant signaling, and changes in the expression level of a myriad number of proteins. In effect, the context has changed. As a simple analogy, consider the case of the smoker who develops emphysema. At the point of emphysema diagnosis, quitting smoking will not simply reverse the course of disease. The damage is done, alveoli and capillary beds have expired. In effect, cessation of smoking by an emphysematic patient does not have the same effect as cessation of smoking for someone who has not yet developed emphysema. The contexts have changed, and therefore the treatment and care strategies are not simply interchangeable. Similarly, my contention is attempting to “restore” a singular protein level to that found in the normal heart provides no guarantee of recovery for a remodeled heart. In support of this argument for S100A1 specifically, human heart tissue from nonfailing, failing and left ventricular assist device (LVAD) supported hearts show that although there is a decrease in inotropic response and S100A1 protein in failing hearts, LVAD supported hearts demonstrated restored inotropic response yet no restoration of S100A1. In that respect, these human tissue data suggest a peripheral rather than pivotal role for S100A1. The counterpoint to this is, obviously, the hundreds of mouse and porcine studies showing that restoration of intracellular protein X to the failing heart restores function and rescues the model. But the level of success of each and every one of these studies is reason to be highly skeptical and, to a certain extent, dismissive of the “restoration of protein X rescues the heart” narrative. Additionally, consider the drugs used in the clinic for patients with / developing heart failure. By and large, they impact whole intracellular signaling cascades through modulation of surface receptors rather than focus on restoration of a single intracellular protein. Even in that context, the HR benefit is around 20%. Therefore, if manipulation of a whole signaling pathway in the heart yields a 20% benefit, what can reasonably be expected from focusing on an individual intracellular protein?www.ozgurogut.com/thoughts/
twitter.com/srqstockpicker/status/614... Cardiomyocytes, endothelial cells and cardiac fibroblasts: S100A1’s triple action in cardiovascular pathophysiology Full text:www.futuremedicine.com/doi/pdfplus/10...
flosz schreef op 25 juni 2015 22:56 :
twitter.com/ogut_ozgur/status/6141675... Uniqure and the Celladon Legacy
Comment 1: www.ozgurogut.com/thoughts/2015/6/25/... Thanks for sharing your thoughts so clearly. In essence you say that the truly stunning animal results of S100A1 bare no relevance to any category of human CHF. I find that heart (!?) to believe. In my opinion it's all be about selection of the relevant subcategory of humans. Aldag mentioned one important factor to consider for a lot gene herapy clinical trials: the trial can only be run in the worst category of patients (e.g. Parkinson or CHF for that matter), while an effect can maybe be better seen if GT were applied early in the disease. My solution: do an orientational phase 1 in different categories of CHF patients and see where you pick up a signal and develop it from there. That might be a way around the risk that you point out. Because indeed: CHF is a mixed bag and and S100A will probably not work in all. Comment2=reply comment 1 It does sound harsh doesn't it? After brushing aside Celladon's human data in CUPID-1 as a fluke, I'm not too shy about ignoring preclinical data from animal HF models. But in seriousness, I think preclinical data are necessary to analyze more because they're predictive for failure rather than for success. If I'm to value Uniqure's animal data so highly and accept them as indications for future clinical success, I would have had to do it with dozens and dozens of prior programs that showed similar preclinical success but failed in the clinic. Development history suggests that there are many reasons to be skeptical or, at the least, very guarded about the relevance and reliability of these models. Uniqure may prove the exception, and their technical achievement is to be lauded. But right now their data package is tracking similarly to other efforts that failed in the clinic. My general view is that manipulating single intracellular proteins in the heart is, by and large, a losing proposition. I think it can work if you start playing with cell cycle related proteins, but not ones that are generally accessory proteins such as S100A1. Finally, I agree with your comment regarding earlier treatment. For the sake of brevity, I did not write it up but I think it is the implied message from the post. However, the clinical setting is what it is, and Uniqure faces the same challenge as everyone else in this regard. I think the most apt clinical situation is early treatment of people with confirmed familial cardiomyopathy gene mutations. In that circumstance, you have a defined population and, depending on the severity of the specific mutation, a strong clinical rationale to treat early. This is likely a direction they'll pursue with Bristol-Myers. I appreciate your comment.
In May, Bristol-Myers Squibb (BMS) nailed down the exclusive access to uniQure’s gene therapy platform to treat cardiovascular diseases. Everything seems to work out fine as BMS paid $53M (€47M) for three new targets and additional shares to own nearly 10% of the company. UniQure is a Dutch pioneer in the field of gene therapy. It has the first and only approved gene therapy on the European market, which has a stiff price of €1.1M. Its unique technology platform makes it a promising partner for pharma companies. One month after Edinburg-based Synpromics joined forces with uniQure to develop a delivery system that gets the replacing DNA to the liver, BMS snared uniQure’s gene therapy technology for cardiovascular diseases. The strategic collaboration included uniQure’s gene technology platform for congestive heart failure that is designed to restore the heart’s ability to synthesize a calcium sensor. The master regulator of heart function is crucial for the adjustment of the heart’s ejection performance. Beyond that, BMS had left the door open for up to ten target-exclusive collaborations in other disease areas. 4 of them are nominated until now, including the three it purchased today for $15M in cash. The deal bolsters uniQure in a big way. Until now, BMS has made total payments of $140M (€125M) and $471M (€421M) could be on its way if everything works out well. Additional to the milestone payments, BMS bought $38M (€34M) of new shares to increase its shareholding to 9.9%. All in all, the partnership between BMS and uniQure resembles to a lovestory. When will be the marriage-aquisition? A Tale of Love for $QURE and Bristol-Myers Squibb twitter.com/labiotech_eu/status/63149... m.youtube.com/watch?v=ks_qOI0lzho
wat QURE nog doet op een schamele 500 mln$ marktcap is me een raadsel...en anders wel de marktcap van andere peers! IMO zijn we getuige van een takeover in slowmotion!
Tja, zou best kunnen. Vind de markt steeds moeilijker te snappen. Duidelijk is (helaas) dat vooral de peers als BLUE EN ONCE in waarde dalen ipv dat QURE in waarde stijgt! Maar zekfs dan is de marktwaarde laag en het aandeel volatiel. Daarom prefereer ik een overname, ook al zou de koers meer kunnen stijgen in een multiple partner model. Ik ben ook niet helemaal zeker van voorkeur voor een overname scenario binnen de QURE leiding. Volgens mij willen ze CNS aan Shire slijten......en ik verwacht redelijk goede data op Sanfilippo B. Indien ja dan wordt 2015 idd transformational....
DrMedicalValue schreef op 14 augustus 2015 14:02 :
Volgens mij willen ze CNS aan Shire slijten......
twitter.com/globerobw/status/63288038...
Phase 2 Trial Results of Single-dose Gene Therapy for HF twitter.com/srqstockpicker/status/646... Let op: Renova, geen Qure.
Designing a Heart of gold: S100A1 P.48 issuu.com/biocom/docs/ebm2015_autumn
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