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Analisten over UniQure

243 Posts
Pagina: «« 1 ... 7 8 9 10 11 ... 13 »» | Laatste | Omlaag ↓
  6. flosz 31 oktober 2016 10:59
    RBC CM

    ASH: Hemophilia deep dive preview and upcoming datasets to watch?BMRN, ONCE, Roche, SGMO, DMTX, QURE


    Uniqure (QURE) may have updated data for HemB at a "higher dose" cohort but initial data has not impressed, in our view. Prior five patients saw improvements and reached a median FIX activity increase of 5.4% (range 3.1-6.7%). All five patients developed anti-AAV5 antibodies, none had developed inhibitory antibodies, but two serious adverse events (SAEs) occurred and one patient had a mild elevation of liver enzymes that disappeared after steroid. In general we don't think competitor data for Factor 9 by other Phase I companies will have data as clean, consistent, or as potent as Spark data and ONCE is best positioned as ahead of competitors with cleanest data.

    research.rbccm.com/sellside/EmailDocV...
    twitter.com/cfdna_ctdna/status/793008...

    Bijlage:
  13. flosz 5 december 2016 15:39
    $QURE gene therapy delivers lasting efficacy in #hemophiliaB
    www.fiercebiotech.com/biotech/uniqure...

    Here’s Why We Think There’s Opportunity In Uniqure NV (NASDAQ:QURE) $QURE $ONCE marketexclusive.com/heres-think-there...

    Chardan twitter.com/_b_i_o_t_e_c_h_/status/80...

    Wedbush twitter.com/_b_i_o_t_e_c_h_/status/80...

    $QURE related GS $ONCE Updated SPK-9001 data remain positive but more variable than initial cut – steroids (cont) twitter.com/_b_i_o_t_e_c_h_/status/80...
    twitter.com/_b_i_o_t_e_c_h_/status/80...
    twitter.com/vlad33301/status/80578086...
  14. flosz 18 maart 2017 10:49
    Flarden uit Piper Jaffray's note, d.d.17032017:Biopharma Gene Therapy 2017 Outlook: Moving Right Along

    Gene therapy for Hemophilia (QURE, Spark) continues to be an area of focus for the field. Both uniQure and Spark are seeing success in converting hemophilia B patients to a mild phenotype (>5% Factor IX levels) with elimination of spontaneous bleeding and durable results up to 1 year, while BMRN is similarly demonstrating robust Factor VIII expression in hemophilia A (even well above physiologic levels) that appear generally durable, though more time will be required for all of these programs to assess the durability of effects. All three of these programs continue to advance, and registration-enabling trials may begin as early as 2H17 – positioning the products for approval before 2020, though dependent on the size of the safety database required by regulators. Both QURE and Spark have received Breakthrough Designation. Dimension Therapeutics has struggled with its hemophilia B gene therapy efforts (described below), with waning of benefit and LFT elevation noted in early dosing; however, the company is working methodically to figure out if/why it may be seeing different results than peers.

    UniQure discontinued development (i.e., chosen not to pursue in-licensing of the program from academic collaborators) of the Sanfilippo B gene therapy program following analysis of two patients who have been followed for 30 months. While we had been previously encouraged by NaGlu enzyme activity, a meaningful clinical signal was not seen that would warrant further development. This experience highlights the fact that in some disease settings (particularly degenerative ones), it can take a long time before a treatment benefit may (or may not) be discerned from natural history.

    While 2016 was another strong step forward for the field, the field continues to evolve and mature, and several important themes have emerged, in our view, as follows: 1) Increasing investor interest in viable programs vs. just platform potential: As gene therapy matures as a platform (particularly AAV and lentivirus), investors are beginning to focus in on specific product profiles and their potential to address unmet need, as opposed to valuation on the pipeline potential and R&D engine alone. Hemophilia is the most noticeable example of such a shift, where both QURE and Dimension Therapeutics are broadly viewed (right or wrong) as having non-competitive products, and as such, shares trade with minimal value despite pipeline programs and potentially attractive shots on goal in the pipeline. However, in the gene editing space, which is in a much earlier evolution vis-à-vis AAV / lentivirus, we note that companies employing the CRSPR technology are still viewed based on platform potential, though in the coming years a similar transition to product focus may ultimately emerge. Whether each is able to chart its own independent path forward remains to be seen, and some of the companies generally appear to be on this path. 2) Gene therapy is competitive with other modalities: Gene therapy is now beginning to clearly have a unique and differentiated impact in diseases where other therapeutic modalities have demonstrated benefit. Most prominently, this dynamic is seen in hemophilia A and B with now multiple datasets demonstrating a clearly mild phenotype with expression / activity >5% and in the case of BMRN and Spark, 15%+ FVIII and FIX levels. Importantly, most patients respond and no inhibitors or major serious adverse events are seen (besides LFT elevations). Though durability continues to evolve, the academic St. Jude’s data indicates durability out to 5+ years and commercial datasets from Spark, QURE and BMRN appear to be durable, at least early on. That said, hemophilia highlights some of the emerging challenges for gene therapy such as an established high bar with factor replacement, which we view as a “gold standard” of care. In addition, other disruptive treatment modalities (e.g., Roche / Chugai bispecific ACE910 / emiciziumab, RNAi, super long-acting, etc.) are emerging as well with competitive profiles, so how gene therapy evolves vs. enzyme / factor replacement and bi-specifics remains to be seen. 3) Preclinical results can be translated into the clinic: In our view, we are beginning to see improvements in translating preclinical animal models into humans, which has historically been challenging for gene therapy. Near term we believe it will lead to more clinical successes (e.g., VYGR, BOLD, etc.) and long term, we expect this should improve valuations across the sector as investors begin to give more credit to “platforms” and pipelines, unlike many of the current valuations which largely reflect only a specific program (or cash in certain cases). That said, the onus will be on companies in the space to clearly define strategies and pipeline programs that resonate with investors. 4) There’s still a lot we don’t know: While the field continues to move forward, questions still remain on key issues, including inter-patient responses, waning expression, and the mysterious LFT elevations. Though some believe an immune response is to blame, the emerging data is still not conclusive, and in fact the LFT elevations may be a result of different etiology in different patients, which may explain why steroids work in some patients and not in others. We are hopeful that over time the field continues to work through these issues.
    Bijlage:
  15. flosz 18 maart 2017 10:51
    CNS continues to be one of the most exciting areas for gene therapy, and one therapeutic area in which gene therapy can differentiate from other therapeutic modalities. 2016 was a generally positive year for the CNS field with positive data from AveXis’ SMA gene therapy stealing the spotlight given the magnitude of clinical benefit in SMA; VYGR in Parkinson’s disease was highly encouraging as well and we believe, overlooked. Discontinuation of the QURE program last year in Sanfilippo B (MPS IIB) was disappointing given early encouraging signs, as it appears that with additional follow-up the clinical data was not differentiated from natural history. Overall, CNS is an attractive area for gene therapy due to the immune privilege, potential one-time administration and minimal turnover of neuronal cells. While many CNS diseases present substantial challenges for gene therapy, (e.g., poorly defined etiologies and genetics, and degenerative processes represent a high bar for treatments), gene therapy’s unique single administration is particularly advantageous.

    QURE has de-prioritized its own Parkinson’s program, which is an investigator-sponsored Phase 1 Parkinson’s trial of glial cell line-derived neurotrophic factor (GDNF) delivered to the brain. In our view, this was not a major surprise given equivocal prior data and what appeared to be limited investor interest and enrollment.

    Companies continue to advance gene therapy programs beyond SMA and Parkinson’s, including Huntington’s disease and ALS. VYGR is advancing a gene therapy approach targeting the ALS subset of patients with SOD1 mutations, with an IND expected in 4Q17. This is an intrathecal RNAi-based gene therapy approach with impressive preclinical data demonstrating robust knockdown of SOD1 which correlates substantially with improved survival in animal models. VYGR recently selected the clinical candidate, and we look forward to further details on the profile of this program, including the capsid serotype. QURE is similarly using gene therapy to silence aberrant protein and is advancing a preclinical candidate for Huntington’s disease. Preclinical data in mice indicates encouraging silencing of HTT (the protein culprit in Huntington’s) in the brain with AAV5 with a well-tolerated profile. Progress towards an IND filing is expected by in 2017 and we look forward to additional details on the program.

    Hemophilia gene therapy programs continue to provide much of the gene therapy clinical data, and the last 12 months featured important updates from many of the relevant players. The field continues to be increasingly competitive with four programs (QURE, Spark, Dimension Therapeutics and SGMO) in the clinic for hemophilia B, three of which (QURE, Spark, recently Dimension Therapeutics) have provided clinical data. Though factor activity levels of 5%+ are widely cited as the relevant goalpost having shown the ability to ameliorate the bleeding phenotype and allow some (but not all) patients to eliminate the need for Factor IX prophylaxis, the true goalposts may ultimately be relative as some approaches are achieving levels well above 5% and a broader competitive landscape which may be able to achieve comparable results (longer acting therapeutics, RNAi, bispecifics). In addition, there is evidence that suggests levels above 5% may provide additional protection, particularly in the case of joint bleeds or pre-existing arthropathy. In addition, investors have increasingly taken a “winner take all” mindset and awarded Spark pole position given robust Factor IX activity levels and lower dose along with lower use of steroids (only 2/9 patients, required on demand steroid use. Spark’s high activity levels are driven by use of the Padua variant which provides a 5-6 fold boost in activity per unit expression; see below for further details. Over the past year, Spark and QURE provided updates from first in man clinical trials. QURE has treated patients at two dose cohorts (5 x 1012 vg/kg and 2 x 1013 vg/kg). Data from the first lower dose cohort indicated durable expression (up to 1 year) with the AAV5, wild-type transgene (same as the St. Jude’s trial) was seen with a median of ~5% FIX (range: <2%-6.9%), resulting in elimination of prophylactic Factor IX in 4/5 patients. In this trial, the first patient treated exhibited LFT elevation but expression was rescued by corticosteroid administration (patient continues to express stable Factor IX). At the higher dose cohort, mean expression was seen of ~7% (range: 2.5%-13%) up to 6 months of follow up. 4/4 patients with available historical bleed data were able to discontinue prophylaxis, and only one spontaneous bleed was reported in a total of 96 weeks of cumulative observation. Steroids were required in 4/5 patients, though did not appear to correlate with loss of expression. We expect further clinical updates throughout the year on the progress of these patients. The company plans to meet with the FDA and define a path forward for a pivotal study, and believes the higher dose of 2 x 1013 vg/kg is appropriate. Of note, the rate of detection of pre-existing neutralizing antibodies to AAV5 continues to be extremely low, which may become a point of differentiation. At WFH, BMRN presented a poster describing a 20-25% neutralizing antibodies to AAV5 in a population of hemophilia patients, though the actual rates of screening failures in both QURE and BMRN’s trials appear to be lower than this.
  16. flosz 18 maart 2017 10:52
    In contract, Spark’s approach utilizes a novel capsid, Spark-100, optimized for the liver, combined with a Padua variant trasgene, which provides a ~5-6 fold improvement in activity relative to expression. Initially discovered from a family in Italy who had abnormally high levels of Factor IX activity (~6 fold normal) with normal Factor IX levels with a mutation causing a single amino acid switch, gene therapy developers SHPG (via BXLT and Chatham) took this knowledge and cleverly installed this Padua variant into the gene therapy construct. Initial data was first presented at EHA which was followed by an additional update at WFH, and most recently at ASH. Nine patients have been treated at the same relatively low dose of 5 x 1011 vg/kg, and patients are demonstrating 15-70% Factor IX activity. Two out of the nine patients required on-demand treatment with steroids following LFT elevation, which coincided with a drop in expression. That said, in one of these two patients expression was “rescued” at 15% and appears durable, while the other continues to express at 68%. Overall, the majority of patients are between 20% and 50%. The company will likely provide continued updates in 2017 and Pfizer will be taking over development as the program enters the pivotal stage. We look for further updates on the potential regulatory and clinical strategy going forward. Dimension Therapeutics is using a “middle of the fairway approach” with the AAVrh10 vector (licensed from RGNX), and a codon optimized transgene along with a liver specific enhancerpromoter combination. The company utilizes a mammalian manufacturing process. In January, Dimension Therapeutics reported preliminary results from the hemophilia B gene therapy study of DTX101, showing robust Factor IX expression particularly at the middle dose level, but with waning effect coincident with LFT elevation. In the low-dose cohort (1.6 x 1012 vg/kg), FIX expression levels reached 10-11% normal and then stabilized at 3-4% of normal. In the high-dose cohort (5 x 1012 vg/kg), peak Factor IX expression reached 12-20% normal and seems to be stabilizing in the 5-8% range. LFT elevation was seen in most patients, and one experienced a Grade 4 elevation but in an unusual time course which might suggest a different type of pathology in that patient. According to recent commentary on the most recent earnings call, the company does not believe this is an immune response. LFT elevation has resolved (or is resolving) in all patients. Dimension Therapeutics continues to strategize over next steps in continuing its clinical trial, considering prophylactic steroids, a longer infusion period and a middle dose level. SGMO continues to advance its gene editing program, which is unique in that the company employs an integrating approach enabled by its zinc finger nuclease platform (see gene editing) combined with AAV6 for in vitro delivery of the FIX transgene to the liver in the albumin locus. Preliminary data is expected in early 2018. In a unique but promising approach, recent upstart LogicBio from Mark Kay’s lab at Stanford is working on a “promoterless” approach along with new AAV vectors, which would similarly utilize the albumin locus as a safe harbor for the FIX gene but a unique integration mechanism; early preclinical studies are encouraging. UCL recently created new AAV spin-out Freeline Therapeutics with hemophilia gene therapy pioneer Amit Nathwani as CSO; we look forward to additional details on the approach. Bioverativ (BIVV; transferred from parent Biogen) licensed an early in vivo lentivirus approach from TIGET, though data presented as ASGCT this year was a bit lower than we had anticipated, with very low levels of expression seen. It’s not clear if this is the approach being advanced or if other more optimized approaches are in development. SHPG (via Baxalta) previously reported data indicated that one out of three patients in the “middose” cohort had seen durable 20-25% Factor IX activity levels. However, at high doses, LFT elevation occurred and employing on-demand steroid treatment did not succeed in rescuing expression. SHPG indicated it will no longer be pursuing this clinical candidate but will evaluate preclinical candidates. We look forward to additional details and how the approach may differentiate in what is an increasingly crowded field.

    Taken together, these approaches are pulling multiple levers (promoters, transgene, vector capsids, dose, immune suppression, etc.) and learning from each other's datasets to achieve high levels of durable activity. While it is early to declare winners and losers, Spark appears in the lead given the efficacy and lack of immunosuppression. Again, other parameters will be important (baseline immunogenicity, response rate, safety, Padua vs. wildtype, etc.). We note that the totality of experience dosing patients with gene therapy systemically is still small, and just one serious complication in one trial could reverberate across the broader field. We expect updates throughout 2017 from all these programs as well as clues from QURE and potentially Spark (and partner PFE now that development will be transitioned to them) on the scope of the registration-enabling trial, including number of patients treated and for how long.
  17. flosz 18 maart 2017 10:54
    Gene Therapy for MPS III diseases (Sanfilippo): Overall, MPS III diseases are proving to be quite challenging, with QURE de-emphasizing its program and next-gen ERT SBC-103 from ALXN being paused to see how data develops. However, Abeona and BMRN are advancing different gene therapy and ERT approaches which are different, and we look forward to seeing how these approaches differentiate and ultimately impact cognitive function. While QURE’s preliminary results last year in Sanfilippo B (MPS IIIB) showed NaGlu enzyme levels (the missing enzyme in MPS IIIB) in the CSF reaching 14-17% of normal (0% expression at baseline) and sustained for a year, many had believed this may be indicative of a potentially even stronger benefit in the brain. Following the company’s strategic review last fall, the company is deprioritizing the Sanfilippo B gene therapy program. While we had been cautiously optimistic on the potential for this program it appears that emerging clinical data over time did not justify further investment in comparison to natural history. While no further data has been presented, the company indicated that 2 of the 4 patients completed their 30-month evaluations, and the 30month data on all four patients in the study is expected to be available for presentation in 1Q17.

    4D Molecular (private): 4D Molecular continues to be at the forefront of gene therapy R&D with both extensive partnerships and a growing pipeline of proprietary programs. The company has a unique and proprietary system of vector optimization which allows for more potent approaches with high tropism via rapid selection in non human primates (which we believe is differentiating), and has attracted Roche, Benitec, AGTC, QURE and PFE as partners. The company’s own pipeline programs are targeting heart failure and other cardiac diseases, Choroideremia, and others. By developing and screening a large library of novel AAV vectors, 4D may be able to establish a platform that competes with the NAV portfolio from U Penn.

    Synpromics (private): Synpromics is a UK based company that is optimizing promoters similar to Encoded Genomics. The company uses synthetic promoters, which may offer both higher expression with a smaller size (which may allow for incorporation of larger transgenes in vectors), and therefore represents another important lever to improve gene therapy results and address higher hanging fruit in the future. Synpromics has collaborations with ADVM, QURE and AGTC and Sartorius / GE for bioprocessing. In addition to these partnerships and enabling others, Synpromics is looking to develop its own portfolio of gene therapy products as well.

    As we have consistently highlighted, many of the companies and players in the broader field of gene therapy as a whole continue to evolve and optimize their approaches by developing new vectors, capsids and promoters. We see this rapid cycle of optimization and pulling multiple levers as accelerating development and ultimately allowing for more challenging diseases to be treated that may require significantly higher levels of expression. Many of the current approaches in the clinic are showing promising and exciting results, which continues to validate the approaches, particularly safety, administration and manufacturing, while setting the foundation for newer, more potent and optimized approaches. To this end, many companies have substantial internal efforts geared towards optimizing promoters and vectors as well as partnerships with outside companies, such as Synpromics or 4D Molecular, highlighted above. Synpromics is working with both QURE and AGTC. 4D Molecular has partnerships with Roche, Benitec, AGTC, QURE and PFE. For vectors, some are approaching the problem by selectively making small changes to the capsid, which can often have a profound impact on the binding, immunogenicity, and other parameters. Others are utilizing directed evolution, which involves generating huge libraries and selecting vectors which are thus optimized based on the selection assay. Some are doing both. Generally we are agnostic and see both as promising. Encoded Genomics is taking a rational approach to promoter selection, by identifying which enhancers are most active in specific cell types and creating cell-specific promoters that take advantage of these findings. Preclinical results with the Encoded Genomics approach are striking. Recent startup from Apple Tree Partners Limelight Bio hopes to expand the carrying capacity of AAV vectors as well as address diseases caused by autosomal dominant inheritance patterns, both unmet needs today, and we look forward to additional details on the approach as they become available. Many of these advances are modular, allowing companies to rapidly advance candidates into trials based on prior datasets, rather than de novo development for each new preclinical program. Many other companies as well as academic labs are evaluating novel vectors as well. We look forward to additional details on these approaches and how they compare to some of the earlier gene therapy efforts.
  18. flosz 18 maart 2017 10:55
    With one major theme of 2016 being an investor focus on companies with clear proof of concept and programs with the potential to be differentiated products vs those without (and bifurcation in valuation), we currently rate gene therapy companies CLLS, BLUE, VYGR, RGNX, BOLD and ADVM as Overweight. We view companies as well positioned either with differentiated programs with proof of concept already, or clear potential to do so in the context of attractive valuations. We view them as attractive platform technology plays with R&D engines that will continue to generate attractive shots on goal. On the other hand, we rate QURE shares as Neutral given multiple setbacks and a portfolio of gene therapies that does not resonate with us given the competitive landscape. Broadly speaking, many gene therapy companies feature strong balance sheets that should serve to limit further downside and continue to allow the companies to execute on their strategies, and in the cases of companies which have struggled, should allow for the opportunity to right the ship and get back on track in the eyes of investors. In our view, we believe a closer look at the space is warranted as the rewards for clinical success are significant ($1B+ valuation), particularly those with catalysts (e.g., VYGR, BOLD), though with binary risk. While each company faces unique challenges, competitive dynamics, opportunities and risks, we believe it is still early days for many of these companies with the best years ahead of them, and for investors with a long-term time horizon, we encourage a closer look at the space.
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