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Re: GBT buyout !!!!Congrats! I missed the final ride holding zero shares at the time of the announcement, though as you may know I was once a big believer and once held a sizeable position. I was basically discouraged by a very lukewarm Raymond James report from May that I had read: >> Takeaways From Our KOL Panel on Emerging Sickle Cell Disease Therapeutics Raymond James May 18, 2022 This week, we hosted a KOL (Key Opinion Leaders) panel to discuss existing and emerging therapeutics for the treatment of Sickle Cell Disease (SCD). In addition to discussing the ongoing Oxbryta pediatric launch and commercial implications, our experts examined the validity of emerging mechanisms of action (MoA), with an emphasis on Hb polymerization inhibitors (Oxbryta & GBT-601, GBT), PKR activators (mitapivat, AGIO; etavopivat, FMTX), HbF Inducers (FTX-6058, FULC) and gene therapy approaches (CTX001, VRTX/CRSP; LOVO-CEL, BLUE). Small Molecule Therapeutics: ● Oxbryta: While KOLs do use Oxbryta, they think the drug’s utility is modest, and noted that it has no observable benefits on clinically relevant endpoints (e.g., no change in required transfusions or VOC events). KOLs were mixed on whether Oxbryta will have broader benefits for the recently approved pediatric population aged 4-11y/o. One KOL noted that children with Hb<9 g/dL are at a higher risk of stroke, so raising Hb levels above 9 g/dL could have an outsized benefit in this pediatric population; the counterpoint to this is that there is still no definitive supportive data. Also, tolerability and compliance are still an issue. ● GBT-601: KOLs took a cautious view of GBT-601 data which showed improved hemolytic metrics (Ph 1, n=6) vs Oxbryta, and warned against comparing the two datasets. GBT previously released post-hoc analysis of the Oxbryta data suggesting higher Hb Occupancy correlated with a lower rate of annual VOCs, but KOLs felt the data provided are insufficient to support this conclusion, noting the effects are driven by a small number of patients. KOLs were overall skeptical on whether Hb polymerization inhibition can produce tangible benefits in SCD. They noted that the quality of blood maintained by Oxbryta/’601 by preventing hemolysis is not necessarily the same as transfused blood, and is likely worse. KOLs also opined that increasing O2 affinity to prevent sickling may also prevent O2 offloading, a potential explanation for why Oxbryta does not prevent VOCs. ● PKR Activators: KOLs views on the potential of PKR agonists were mixed. Mechanistically, these drugs may leJ-shiJ the oxygenation curve (similar to Oxbryta) and provide an improvement in RBC health by increasing ATP levels. KOLs recognized the potential to improve oxygen delivery over current therapies; however, these drugs clear the body quickly (faster than Oxbryta) and 1-2 days without treatment may precipitate a VOC rebound, which did seem to occur in the respective trials upon drug cessation/tapering. ● HbF Inducers: KOLs noted HbF is an attractive SCD target, but exercised a cautious view of FULC’s FTX-6058 given 1) the limited amount of data generated which are 2) difficult to interpret/ show questionable benefit over current standard-of-care, Hydroxyurea (HU). One KOL noted the CD34+ cell assay data only shows an additive benefit over HU at 1/5 the normal HU dose, when given with the clinically-relevant HU dose, no clear additive benefit was observed. It reasons that exclusion of HU use in trials may be necessary to see separation from placebo. Gene Editing Efficacy Approaches: KOL’s value eliminating VOCs owing to HbF induction, and one specifically said “efficacy was good in CTX001 trial, can’t deny it”. But a thorough discussion ensued raising the following points/questions: 1) is elevated HbF better than normal Hb?, 2) Don’t really know long term effect, 3) patients still have elevated reticulocyte count and there is evidence of hemolysis, thus patients might be achieving very mild hemolytic anemia (something like HbS β+ thalassemia phenotype wherein those patients have normal lifespan but occasionally can get complications of sickle cell under physiologic stress), 4) patients that are outliers on hydroxyurea approach these levels of HbF (achieved by CTX001) and they are pain free but not completely cured, therefore it is important to distinguish between being free of VOC vs. having normal hemoglobin function. Interestingly, KOLs mentioned we don’t even really know outcomes for allo transplant and how well patients recover from all the years of damage pre-transplant so the same is true for gene therapy/editing HSCT approaches. Thus, maybe low level of hemolysis seems acceptable but unclear if completely normal red cells should be the goal (low level hemolysis is a clue that the red cells aren’t “fixed”). Lastly, one KOL noted that looking at F cell proportion and declaring pan-cellularity can be deceptive given it does not clarify if there is uniform distribution of various hemoglobins. Red cell function assays to determine which therapeutic approach “makes most flexible, least adherent, least dense red cells” could be helpful to differentiate therapies going forward. Gene Editing Safety Discussion ● Cancer risk: Although insertional mutagenesis inherent to lentiviral vector was a specific concern of one KOL (see below for lentiviral/ LOVOCEL specific commentary), the other two cited various factors potentially contributing to cancer risk of HSC transplants on SCD patients that would be true of both gene therapy or gene editing approaches, including: 1) stressing HSCs which are already compromised (e.g., accumulated mutations) in SCD patients, 2) expanding HSCs in an SCD patient’s bone marrow (where bone marrow niche may also be suboptimal or impacted by busulfan), collectively leading to elevated AML risk, up to 6% (cited by one KOL), higher than implied by SEER data in SCD patients without transplants. Moreover, oxidative stress accrued over lifetime of SCD patient having unknown consequential cancer risk. ● Delayed engraftment: We specifically asked about ~25 day median time to neutrophil engraftment in CRSP’s EHA 2021 data (N=7) and if stem cell impairment owing to electroporation and DNA damage/cell cycle arrest could cause delayed engraftment and manifest in safety issues. KOL’s generally said yes this is a concern, could be caused by manipulation impacting quality/number of stem cells or simply inability to use GMCSF, but nonetheless people will be hospitalized and have neutropenic fevers, and 25 days to neutrophil engraftment is longer than expected with allo transplant. One KOL noted other approaches with shorter leukopenia will be easier to adopt. KOLs generally agreed companies should be thinking about different chemo-ablative approaches as one way to mitigate risk (i.e., not bulsufan), including 1) treosulfan or 2) CD117 antibody (although one KOL cited a mouse study they published showing no beneficial effect). ● Erythroid lineage impairment. During our screening calls, the hypothesis that editing BCL11a erythroid enhanced can impair erythroid lineage potential (put forth by Editas at ASH 2019) generally wasn’t on KOL’s radar. During our panel discussion, one noted it is now and raises a concern about BCL11a (i.e., Crispr, Sangamo approaches) and puts more weight on gamma globin promoter editing strategy (i.e., Editas approach). However, while the mouse data on impaired erythroid lineage potential from BCL11a e.e. editing in NBSGW mice were “interesting”, no mouse model is that good at studying erythroid lineage engraftment, hence long term efficacy/safety data in patients is paramount. Uncertainties about long term effects will impact how physicians ultimately use HSCT therapies. Lentiviral gene editing discussion: ● LOVO-CEL (BLUE): Concerns around Bluebird Bio’s lentiviral approach with LOVO-CEL focused on the risk of MDS/AML, and the panelists debated the relative contribution of insertional mutagenesis versus use of high dose busulfan as the cause of increased risk. If LOVO-CEL was FDA approved for commercial use the KOLs agreed that target patients would be adults with substantially high disease burden and high risk of mortality in the next five years. The panelists would also consider kids/adolescents with extremely high disease burden and no transplant options if families are comfortable taking on the risk. All the experts on our panel agreed that matched sibling HSCT would remain their preferred approach when possible. When comparing LOVO-CEL to haploidentical HSCT, the panel was mixed with some believing the risk of patient harm is actually lower with LOVO-CEL. The bar for LOVO-CEL will be to show good safety and eIicacy compared to haplo HSC. The major barrier to LOVO-CEL commercial use will likely be price as the gene therapy is expected to be extremely expensive (on par with CAR T cell therapy) and many SCD patients are on Medicaid which may be hesitant to cover LOVO-CEL. Additionally, if Bluebird’s distribution model focuses on administering LOVO-CEL at centers of excellence as previously guided, this could be problematic for patient access, social support, and follow up. KOLs believe that any transplant center that has experience with SCD should be readily able to adopt LOVO-CEL. |
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Msg # | Subject | Author | Recs | Date Posted |
42459 | Re: GBT buyout !!!! | minxmrphd | 1 | 8/8/2022 12:26:27 PM |