Barclays Initiating SGMO Coverage with Overweight Rating PT 20 We are initiating coverage of Sangamo Therapeutics with an Overweight rating and $20 price target. SGMO is at the forefront of both gene editing and gene therapy development. SGMO's gene therapy program in hemophilia A showed impressive data in monkeys and we believe initial clinical data could be compelling despite a competitive landscape. We believe SGMO's zinc finger nuclease (ZFN) technology is a powerful gene editing tool, and has been validated in multiple preclinical and clinical systems. ZFN is the only gene editing technology that is being tested in Phase 1 studies in both ex vivo and in vivo systems. Clinical data from these programs are likely to emerge in 2018, which could provide important clinical proof of concept and generate significant additional interest in the stock.
Barclays - SGMO: Key takeaways from management meeting
Key takeaways: We met with SGMO management earlier today who provided incremental color on ongoing clinical studies as well as development of pipeline/partnership programs. We look for proof of concept data in 1H18 from both the Hemo A and MPS I/II clinical trials.
Update on ongoing clinical programs:
· HemoA program on track for update in 1H18; HemoB enrollment would focus in EU. 1) HemoA: Management disclosed the initial dose in the ongoing Ph1/2 study to be 9E+11 vg/kg. Management highlighted that a total of 6 dose cohorts could be tested with 2 patients in each dose cohort (6 weeks of waiting period in between the patients). So far, 2 patients have been dosed at 9e+11 vg/kg and a third patient has been dosed in a second dose cohort (dose undisclosed). Management highlighted that patient enrolment has not been a problem and reiterated that preliminary meaningful clinical data would be available in 1H18. 2) HemoB: Noting that the enrollment in HemoB study continues to be slow in the US, management submitted CTA and plans to enroll patients in EU.
· Ph1/2 trials ongoing in MPS I/II; preliminary SB-913 Ph1/2 data expected in 1H18. SB-318/913 leverages the in vivo genome editing of albumin to permanently insert correct genes into liver cell genome for the treatment of MPS I/II, respectively. Following dosing of the first MPS II patient with SB-913 in Nov 2017, management believed the second patient would be dosed very soon. There would be 2 patients in each dose cohort, with 4-week waiting period in between patients. Management expected to report preliminary clinical data in 1H18.
· ST-400 Ph1/2 enrollment in beta-thalassemia (BT) expected in 1Q18 with data likely in early-19; BIVV-003 IND filing in sickle cell disease (SCD) in 2018 by partner BIVV. The SGMO/BIVV partnered BT/SCD program uses ex vivo gene editing of BCL11A enhancer locus in hematopoietic stem cells to up-regulate fetal hemoglobin and address the underlying diseases. SGMO would be responsible to run the Ph1/2 trial in BT (IND active) and the first patient is expected to enroll in 1Q18 with clinical data likely in early-19. Partner BIVV would file IND for BIVV-003 in SCD this year. Management emphasized that it is important to possess single-nucleotide resolution for gene editing in the BCL11A enhancer region.
Management perspectives on other pipeline/partnership programs
· ST-920 gene therapy program in Fabry Disease: IND enabling studies are currently ongoing and management expects IND to be filed in mid-18
· ALS/FTLD program utilizing gene regulation technology: Management highlighted recent partnership with Pfizer as further validation of the potential of SGMO’s zinc finger protein technology platform .
· Oncology program: Management highlighted SGMO’s capability to manufacture allogeneic T-cell therapies utilizing their zinc finger nuclease technology platform. Management expects to initiate a partnership in oncology in 2018.
Barclays - SGMO: WORLDSymposium Update: Preliminary safety data incrementally positive; eyes on more meaningful update by mid-2018
Key Takeaway: SGMO reported preliminary safety data from the Ph1/2 CHAMPIONS study in MPS II patients dosed with SB-913 (in vivo therapeutic involving ZFN-based genome editing). Data from the first 2 patients at low dose (5E+12 vg/kg) showed an overall good safety profile after a short follow up, with normal liver function and no drug-related SAE. We see initial safety data encouraging to warrant a higher dose and we look for initial efficacy data by mid-18; specifically, we would look for the trend of biomarkers (GAG and plasma enzyme level) to assess the therapeutic window since the clinical benefits in neurocognitive function might not be detectable in the adult population and the low-dose cohort could potentially be sub-therapeutic based on mouse data.
SB-913 Ph1/2 initial safety data appear good in the first two MPS II patients. The first MPS II patient received a low dose SB-913 at 5E+12 vg/kg on Nov 13, 2017 and the initial safety data (with cutoff of Dec 27, 2017) showed only grade 1 adverse events related to the treatment, including dizziness, weakness and frequent urination, which resolved without treatment. No other adverse events related to SB-913 were noted. One SAE of hospitalization was reported for acute bronchitis due to an upper respiratory tract infection and was clarified as unrelated to the treatment. The patient was reported to have a medical history of chronic pulmonary disease. With prophylactic steroid treatment (to taper for the first 20 week after dosing per protocol), the liver function tests were within normal range. The second patient was treated at the low dose in mid-Jan 2018 and has tolerated the treatment well (based on personal communication from Prof. Harmatz, principle investigator of the CHAMPIONS study). Additional safety and initial efficacy data are expected by mid-18.
Barclays - Gene-editing value in cell therapy highlighted by GILD, more to come in our view (CRSP/EDIT/NTLA/SGMO)
Key takeaways: We believe the strong run of three companies developing CRISPR/Cas9 gene editing technology today was likely due to the comments yesterday from GILD (covered by US Biopharma analyst Geoff Meacham), with CRSP +15%, EDIT +2%, and NTLA +7% vs. IBB +0.6%, as of 12:45 PM ET. On the earnings call yesterday, GILD commented that gene editing represents an additional technology to enhance its capabilities in CAR-T cell therapy and GILD expected to do more collaborative deals in the gene editing space. The comments are consistent with our view that gene-editing will serve as a powerful tool to generate off-the-shelf CAR-T cell therapy, a significant advancement of current autologous CAR-T therapies. We note that multiple companies have shown simultaneous knockout of up to 3 genes and integration of a transgenic cassette (including CAR-T construct) in T cells. Despite a good run recently, we continue to see upside for gene-editing companies under our coverage including CRSP, EDIT, NTLA and SGMO. In addition to transformative potential in cell therapies, initial clinical proof of concept starting in 2018 from multiple companies would likely unlock the clinical potential for the technology platform, providing further upside for the stocks. Of note, CRSP and SGMO have wholly owned off-the-shelf CAR-T programs. NTLA partnered with NVS on CAR-T cell therapy and EDIT collaborated with JUNO (proposed acquisition by CELG) on CAR and TCR cell medicines to treat cancer.
Multiple gene editing approaches are being pursued to augment development of CAR-T cell therapy with largely comparable gene editing efficiencies. All three companies utilizing the CRISPR/Cas9 technology platform have reported preclinical results achieving single/dual knockouts in T-cells while simultaneously inserting a CAR construct. CRSP is carrying out IND-enabling studies for its wholly owned allogeneic CAR-T program for CD-19+ B-cell malignancies while EDIT (in collaboration with JUNO/CELG) has announced T cell therapy to be their next pipeline program to enter the clinic . NTLA’s collaboration with NVS includes CAR-T cell therapy and use of CRISPR/Cas9 in modifications of hematopoietic stem cells, while their eXtellia division is focusing on ex vivo opportunities outside the NVS collaboration (including allogeneic cell therapy, modified T-cell therapy and regulatory T cells) with updates expected in 2H18. Outside of CRISPR/Cas9, SGMO has also recently highlighted the capability of their ZFN technology to manufacture allogeneic T-cell therapies and management expects to initiate a partnership in oncology in 2018.
Barclays - SGMO: Keystone update highlights multiplex editing efficiency of ZFN platform in T cells
Key takeaways: SGMO’s recent presentation at the Keystone Symposium reported the ability of zinc finger nucleases (ZFNs) to achieve efficient multiplex gene editing in T-cells and highlighted ZFNs as a viable technology platform to produce “off-the-shelf” allogeneic CAR-T products. In our view, allo-CAR-T products could be one of the strongest competitors to existing CAR-T therapies in the long run and gene editing technologies would serve as powerful tools in generating these products. We continue to see upside in versatility of SGMO’s ZFN technology.
ZFNs can achieve efficient multiplex editing and targeted insertion in primary T cells. Jain et al presented preclinical data at the Keystone Symposium on Emerging Cell Therapies, which showed simultaneous knockout of up to 3 genes (T-cell receptor, beta 2-microglobulin, and a checkpoint gene) and targeted insertion (GFP) with ~76% efficiency in T-cells. ZFN-mediated gene editing achieved efficient simultaneous knock-outs of the T-cell receptor TRAC (~93% efficiency, to increase safety), Beta-2-microglobulin/β2M (96%, to increase persistence) and CISH checkpoint gene (93%, likely to fine tune T cell potency) along with insertion of GFP (91%) utilizing AAV6 vectors (Figure 1). SGMO also reported achieving ~77% efficiency in inserting a CD19 CAR+ construct in T-cells while simultaneously knocking out TRAC and β2M. CD19+ CAR-T cells (single TRAC KO or double TRAC/ β2M KO) produced using SGMO’s technology were functionally capable to achieve specific lysis of CD19+ K562 cells (chronic myeloid leukemia cell line). Together these data highlight utility of ZFN technology platform to support development of “off-the shelf” allogeneic-CAR-T cells and we look for more functional data (anti-tumor activity) in the future. Of note, CRISPR/Cas9 platform has shown largely comparable results for multiplex editing and most recently CRSP highlighted progress in their allo-CAR-T program with IND filing expected by YE18.
Interesting that they think that editing percent is same when its not..CRISPR percent much lower i though but would have to research further.. Plus i think that YE 2018 filing wont lead to a trial start until 2020 due to having the get through first time safety concerns for CRISPR
Barclays - SGMO: 4Q17 KITE deal another boost to the ZFN platform; Eyes on HemoA data - Increase PT to 30
Key Takeaway: Today’s collaboration with KITE/GILD was not a complete surprise to us after recent GILD comments on gene editing. We view the deal as a significant positive, maximizing the potential of SGMO’s zinc finger nuclease (ZFN) platform in oncology, which was not included in our valuation. We continue to see upside in the stock with emerging clinical data in 2018 from multiple programs. We increase PT to $30 to reflect technology capability and progress in clinical programs.
KITE/GILD to receive exclusive license to use SGMO’s ZFN platform in allogeneic (off-the-shelf) and autologous cell therapies. SGMO would design ZFNs/AAV vectors to edit/insert genes (CAR, TCR and NKR) in T-cells/NK cells for specific targets, while KITE/GILD would focus on clinical/commercial development of resulting products. SGMO would receive $150M upfront and up to $3.01B in milestones for 10 programs (~$1.26B for R&D and first sale milestones, $1.75B for other commercial milestones). SGMO would also be eligible to receive escalating, tiered single digit royalties.
Clinical data from ongoing HemoA and MPS programs expected in mid-18. 1) HemoA: Three patients (2 in 1st dose of 9E+11 vg/kg; 1 in 2nd dose, undisclosed) have been treated in the Ph1/2 Alta trial and efficacy/safety data would be presented at a medical conference by mid-18 (likely 4+ patients). 2) MPS II: Following recent safety data from Ph1/2 CHAMPIONS study (See “WORLDSymposium Update: Preliminary safety data incrementally positive; eyes on more meaningful update by mid-18”, 02/06/2018), initial efficacy data (mid-18) would include IDS activity levels in the serum and urinary GAG reduction from 2+ patients. Of note, Shire’s Elaprase weekly dosing led to 58% reduction in uGAG in MPS II patients.
Other pipeline programs: 1) MPS I: 2 patients passed screening and initial data expected in 2018. 2) BT/SCD: Ph1/2 initiation in BT in 1Q18 with IND filing (by partner BIVV/SNY) in SCD later this year. 3) Fabry Disease: IND filing in mid-18.
Barclays hemophilia gene therapy expert ONCE, BMRN and SGMO/PFE We hosted a hemophilia gene therapy expert lunch during our trip to Philly earlier this week. Our KOL provided comments on the overall gene therapy space and specific hemophilia programs from ONCE, BMRN and SGMO/PFE. Open questions in the field include the differences between mammalian/baculorival based systems and the cause/management of immune responses. For the gene therapy programs in hemoA, we continue to see the market large enough to accommodate multiple players.
Acute toxicities observed in NHPs but lacking in humans could be due to multiple variables; innate immune responses could potentially be related to CpG content. Although cannot be ignored, recent toxicities observed in NHPs at high IV doses were acute and similar side effects were not seen in human clinical trials as evidenced by AVXS Ph1 data (with 2-3 years follow-up). Multiple variables could be in play, including the construct and the manufacturing processes (cell culture systems, purification processes and empty/full capsid ratio). As for the innate immune response (complement activation) observed in the Solid’s DMD program, our KOL noted a combination of factors could lead to complement activation and based on experience from hemophilia gene therapies, high CpG content (might vary for the same amino acid sequence depending on codon optimization) could be one key contributing factor. As an example, Shire/Baxalta hemoB program used AAV8 serotype and enriched the CpG content. Its Ph1/2 data showed only transient expression of factor IX and the immune responses were not controlled by immune suppression.
AAV liver tropism and different manufacturing systems. Based on animal data, our KOL commented that the liver expression was the highest for AAV8, followed by AAV6 and then AAV5. The difference in liver tropism, however, is most pronounced when evaluated in mice and the gap narrows when tested in NHPs. No side by side comparison was performed for the manufacturing based on mammalian cells or the baculoviral system, although our KOL believed AAV viral particles manufactured by the two systems would differ significantly including post-translational modifications.
Overlapping neutralizing antibodies (NAbs). Some patients might be NAbs positive against more than one AAV serotypes, so could be ineligible to multiple gene therapies. Our KOL noted that AAV5 is evolutionarily distant to AAV2/6/8 and a patient is less likely to have overlapping NAbs against both AAV5 and AAV2/6/8. Since AAV6, 7, 8, and 9 are evolutionarily closer, there is a higher chance that a subject could have NAbs against multiple of these serotypes. If a subject has positive NAb against AAV2, it is more likely the subject would have cross reaction against other AAVs.
Difference tissue expression pattern for hemoA and hemoB may explain different factor profile seen so far in gene therapies. According to our KOL, factor IX is mainly generated by hepatocytes, while factor VIII is produced by both liver sinusoidal cells and endothelial cells outside of the liver. Therefore gene therapy for hemoA targeting hepatocytes could be perceived as ectopic expressing of factor VIII. As for the target factor level for gene therapy, our KOL would aim for 50% while no more than 100%.
Comments on specific hemophilia gene therapy programs:
· ONCE – While most gene therapy clinical trials have the neutralizing antibodies (NAbs) cutoff of <1:5, clinical data from ONCE’s hemoB program (partnered with PFE) suggested that even low level of NAbs could impact the transgene expression since the one patient with 1:1 NAbs had lower factor IX activity level compared to other patients (<1:1 NAbs). As for SPK-8011 in hemoA, our KOL consider it too early to draw conclusion on dose response since there were only two patients each in the first and second dose cohorts at ASH 2017. The use of steroid treatment was to prevent complete loss of transgene expression, and our KOL would wait for 4-6 weeks after steroid tapering off to determine the steady state level. When asked about the variation of factor VIII level in patient 2 (from ~10% to ~40%), our KOL noted that factor VIII level in normal individuals could also fluctuate significantly given its half life is determined by a carrier protein (one of the acute phase reactive proteins), although other hypothesis includes low level of Factor VIII could overcome existing antibody against Factor VIII (similar to inhibitor patients).
· BMRN – Our KOL was puzzled by a few observations in BMRN’s valrox Ph1/2 data, including 1) it took more than 28 weeks for the factor VIII level to reach plateau and stabilize (vs. 12 weeks in other gene therapy programs); and 2) the liver enzyme elevation in a few patients was seen in the context of steroid prophylactics and no T-cell mediated responses, while in other gene therapies, liver enzyme elevation, T-cell mediated responses and factor level decrease were seen together, which were responsive to steroid treatment. Therefore the cause of liver enzyme elevation might be different in BMRN’s trial. Our KOL saw high factor VIII level and high AAV dose as potential concerns. Although some patients might prefer to achieve higher factor VIII level, our KOL consider higher dose of gene therapy might not necessarily be better and close monitoring would be required to rule out safety concerns including thrombotic risk, DNA insertion and tumorigenesis. Key advantage of the valrox program was the use of AAV5, where the presence of NAbs appears rare (~20% per BMRN).
· SGMO/PFE – while it could be difficult to predict clinical data for SGMO/PFE’s SB-525 in hemoA, our KOL considered the NHP data as pretty good. The immune-suppression used in the NHP was perceived as normal experimental practice by our KOL since human factor VIII is highly immunogenic in NHPs. In addition, since SB-525 is manufactured based on the baculoviral system, clinical data would add to the dataset to compare different manufacturing systems.
Barclays analyst Gena Wang maintained a Buy rating on Sangamo Biosciences (NASDAQ: SGMO) on February 22 and set a price target of $30. The company’s shares closed on Friday at $24.95, close to its 52-week high of $27.50.
Gena Wang, 5 star ranked analyst.
According to TipRanks.com, Wang is a 5-star analyst with an average return of 29.2% and a 58.6% success rate. Wang covers the Healthcare sector, focusing on stocks such as Dimension Therapeutics Inc, Ionis Pharmaceuticals Inc, and Cascadian Therapeutics.
Barclays - SGMO: Speaking the Science conference call with SGMO Management: Key Takeaways In our last Speaking the Science call with senior management, we spoke with Sangamo President and CEO Sandy Macrae on Thursday, April 12. Our discussion provided incremental color on SGMO’s ongoing clinical programs and management’s expectations regarding the upcoming clinical updates. The company is on track to provide data from the HemoA/MPSII Ph1/2 studies by mid-18 and treat ~3 patients in the Ph1/2 trial for BT by YE18. We continue to see upside for SGMO ahead of multiple data outputs in 2018 and reiterate our OW rating with $30 PT.
Incremental color on SGMO’s hemophilia programs: Recall that SGMO has already dosed 4 patients in the ongoing Ph1/2 study in HemoA (Alta trial) with SB-525 (AAV6 gene therapy) and management reiterated their goal for presenting the data when it is “meaningful and reliable” (by mid-18). In HemoB, SGMO has been pursuing a genome editing approach wherein, using zinc finger nucleases (ZFNs, packaged in AAV6 vectors) a FIX gene would be inserted into the albumin gene in the liver, which would be viewed as favorable in young patients whose livers are still growing.
· Expectations from the initial HemoA data update: Management noted that both ONCE and BMRN’s HemoA data required several months of follow-up to “settle down” and SGMO intends to provide more color on the data after sufficient time has passed to allow for meaningful gene expression. In this regard, venue/timeline for the update would not be driven by conference schedules and data could be presented via press release/conference call. Management reiterated their skepticism for very high FVIII activity and would aim for activity levels above 12% but within the normal range (i.e. 50-150%).
· Evolution of HemoA gene therapy landscape: Management believes differences in treatment protocols (e.g., steroid usage), vector doses (likely important for COGS calculations), and associated minor asymptomatic rises in transaminase levels would not be differentiators between products as long as clinically meaningful FVIII levels were maintained with no additional risks. Instead, management considers access and reimbursement as more important factors for commercial success of gene therapies and in this regard highlighted partner Pfizer’s experience in commercialization of therapeutics.
· Management’s perspective on path forward for SGMO’s HemoB program: Management noted a smaller patient population (~1/5th of HemoA market per management), lack of familiarity with gene editing, and competitive trials as key reasons behind recruitment challenges faced by SB-FIX. In this regard, good data from ONCE’s SPK-9001 (using the Padua gene for higher expression) has played a role in locking in patients for their upcoming trials, per management. Management also reiterated that patients not qualifying in competitors’ trials are not necessarily prime candidates for recruitment in SGMO’s trial since many of these patients also showed antibodies against AAV6. To circumvent these issues, management highlighted SGMO’s focus on European sites (with one CTA recently approved) and their ultimate goal to move to the pediatric population. However, management noted that any decision on moving HemoB forward would be made after careful consideration and SGMO would not deter from making difficult decisions.
Some additional color on MPS II:
· Management appears to be satisfied with SB-913’s (utilizing SGMO’s ZFN-based genome editing approach) safety profile so far. Management discussed four potential sources of safety risks: 1) Allergic response to AAV6: No such reactions have been observed so far. 2) Liver enzyme elevation: SGMO has not disclosed any data regarding patients’ transaminase levels and management intends to provide an update once data from more patients are available. 3) Toxicity due to on-target insertion of target gene: Management noted that, given the progression of the trial, it could be fair to assume that SGMO has not observed any such events so far and also noted that the possibility of acute toxicity resulting from on-target insertion would likely be very low. 4) Off target editing by ZFNs: Management believes that, based on rodent and NHP data so far, off-target risks appear minimal. Management noted that editing of ≤1% should be sufficient to incorporate the transgene, which should not lead to significant off-target effects. However the company would continue to follow these patients for a long term and envisions a collaborative effort (amongst gene editing companies) to share data/reassure patients regarding off-target effects.
· Expectations from efficacy data update. Initial update (still expected in mid-18) would likely include biomarker data such as enzyme levels (both in tissues and serum) and GAG levels, as well as clinical measurements. Management reiterated that adult patients may not show substantial changes in the phenotype (due to significant disease progression). However these data would be important to understand efficiency of delivering gene editing machinery by AAV6 which would form the basis for formulating dosage for children (i.e. patients with higher potential to benefit from the treatment based on SGMO’s conversation with EU KOLs/regulators).
· Translatability of mice data to humans: Recall that recent publication (Laoharawee et al, Mol Ther 2018, 26:1) reported data from MPS II mice treated with ZFNs delivered by AAV8 vectors (vs. AAV6 used in SB913 and SGMO’s other clinical programs). Management noted that AAV8 works better in mice while AAV6 is more effective in NHPs/humans and hence the choice of two different vectors in these studies. Management appears confident regarding the preclinical data and also highlighted that, although AAV8 (or AAV6) is not expected to cross the blood brain barrier, results from the Barnes maze experiment with MPS II mice treated with ZFNs potentially suggest some level of cognitive benefit.
Ph1/2 in beta-thalassemia (BT, with Sanofi) on-track to enroll patients this year; clinical data likely in 1H19. Management noted that partner Sanofi (which acquired Bioverativ) has reiterated its commitment in the BT and sickle cell disease programs. For the clinical trial, a typical treatment process would include apheresis, hematopoietic stem cells gene editing and manufacturing, and infusion of the edited cells, which could take about 2 months after a patient has provided consent. After treatment, it could take ~2-3 months for the cells to engraft and produce red blood cells with elevated expression of fetal hemoglobin. Initial clinical data are expected in 1H19. Management believe that SGMO’s prior experience in IND filing, clinical study and manufacturing of gene editing therapeutics would enable reliable progression of the clinical development in BT, despite increasing competition in the field.
Other early-stage pipeline programs
· ST-920 in Fabry disease, a cDNA gene therapy program. Although preclinical studies were conducted in Fabry disease using both gene editing and gene therapy approaches, the selection of gene therapy was mainly a prudent portfolio decision. Management would wait for clinical data from the MPS I/II programs to validate the in vivo delivery of the ZFN gene editing machineries. If shown very effective in MPS I/II programs, then SGMO might apply the gene-editing strategy in Fabry and other diseases. In addition, Fabry disease has substantial adult component, which could be readily addressed by the gene therapy approach.
· CNS programs. Since tau reduction could potentially address many indications, SGMO would pursue rarer diseases such as frontotemporal dementia, while it might be more reasonable to seek a partner for common diseases like Alzheimer's. Additional preclinical from the tau program would be presented in the coming months. The capability of gene regulation using zinc finger protein and transcriptional repressor fusion proteins represents a platform technology that could be applied in additional CNS indications.
Barclays - SGMO: 1Q18: Clinical programs progressing; eyes on data updates by late summer (Overweight PT 30)
Key takeaways: SGMO 1Q18 update reported continued progress in multiple clinical programs including the Ph1/2 studies of SB-525 in hemoA and SB-913 in MPS II with more patients enrolled in higher dose cohorts. Based on the safety data at the first dose cohort in the SB-913 Ph1/2 in MPS II, SGMO amended the protocol for SB-318 in MPS I to start directly from the 2nd dose cohort. Initial clinical data from both hemoA and MPS II programs are expected by late summer this year, and we would look for initial signs of efficacy and note that better activity likely would be achieved with dose escalation provided good safety profile.
SB-525 Ph1/2 data in hemoA expected by late summer; 4 patients treated so far in 2 dose cohorts. Management noted that the 5th subject will be treated soon, likely at a 3rd dose as planned. The company plans to issue a PR and report the topline results ahead of a medical conference by late summer. SB-525 target profile is to achieve factor VIII level higher than 12% but lower than 150% to prevent thrombosis risk.
Updates on the MPS I/II programs: Four patients in 2 dose cohorts have been enrolled Ph1/2 study in MPS II and initial data are expected by late summer, which would include safety, IDS enzyme level and urinary GAG levels. IDS enzyme level of 2% of normal was quoted as therapeutically meaningful. Ph1/2 study in MPS I would move directly to the 2nd dose cohort based on safety data from MPS II study. Management commented that while the activity of ZFNs has been evaluated extensively, the MPS I/II studies would provide a benchmark for AAV delivery capacities of the ZFNs.
Other ongoing programs: 1) ST-400 Ph1/2 study in beta-thalassemia is expected to enroll first patient in 1H18; 2) UK study for SB-FIX in hemoB to start by YE18, which would allow enrollment of adolescent patients after initial safety data in adults; 3) IND filing for Fabry disease is expected in 2018; 4) BIVV-003 (with Sanofi) IND filing in 2018
SGMO – multiple presentations/posters highlight broad application of the zinc finger nuclease (ZFN) and zinc finger protein transcription factor (ZFP-TF). ZFP-TF targeting tau was designed and multiple candidates were shown to have high efficiency/specificity in reducing tau expression (#949). To deliver the tau ZFP-TF in vivo, AAV9 and AAV.PHP.B were used for local brain injection and IV infusion respectively, which led to robust and sustained reduction in tau mRNA and protein (IV delivery: ~50% mRNA reduction, ~60-80% tau protein reduction in brain and ~80% CSF tau protein reduction). IV delivery of tau ZFP-TF in a mouse disease model showed that tau reduction was neuroprotective against amyloid toxicity after pathology onset. SGMO also reported preclinical data on LNP-mediated delivery of ZFNs (#952). Upon one or two doses of LNP-encapsulated ZFNs targeting TTR or PCSK9, >90% reduction of target proteins was observed in mice. Repeat dosing of ZFN mRNA in LNPs along with a donor DNA AAV (hIDS in this case) resulted in increasing levels of target trasngene insertion and protein expression (~2 to 3 fold improvement per dose). Initial data of ZFN mRNA delivery to the lung via LNPs showed >10% gene editing in lung epithelial cells following IV delivery in mice. Additional presentations/posters (e.g. #968) shared progresses in mutiplexed gene editing to enable allogeneic T cell therapy and technological improvements.
Barclays SGMO says hemoA data would be better mature than early, MPS1 starting JUNE
ZFN-based technology platform and strategic directions. Management highlighted that zinc finger nuclease (ZFN) based gene editing is different from other technologies, with high efficiency (>90% target cleavage), capability of multiplexing, and good specificity (off-target much lower with improvement in ZFN framework). With broad capability in gene editing, management noted the importance to prioritize different programs and make the decision to keep in-house or out-license the programs involving in vivo gene editing, ex vivo gene editing or transcriptional control. In general, the companies aim to keep assets with breakthrough potential and operationally/financially feasible for SGMO, while externalize programs in therapeutic areas with heavy competition, requiring significant investment or special disease expertise. At the comment, delivery remains a key bottleneck for developing gene editing therapeutics, and most initial indications focused on organs with readily available delivery methods (ex vivo, liver). Increasing evidence also supports delivery to the brain while it remains difficult to reach lung or muscle, per management.
Updates on clinical programs:
· SB-525 (gene therapy in hemoA) ideal profile – reliable and predictable with 12-80% FVIII levels. Management reiterated the philosophy of reporting data when “meaningful and reliable” and noted it would be better mature than early. From physician feedback, a predicable profile would be highly desirable while transient liver transaminase elevation would not be considered as a significant safety concern. It is expected that ~20-30% patients would carry neutralizing antibodies against the AAV6 vector used in SB-525, which would preclude the patients from being treated with SB-525. As for future pricing of the gene therapy in hemoA, management quoted life time cost of $6.5M each patient and speculated that payers likely could calculate the value of gene therapy for 3-5 years. To explore potential retreatment, approaches like LNP delivery or plasma apheresis to reduce neutralizing antibodies might be explored. Initial hemoA data continue to be expected by late summer 2018.
· MPS I/II programs progressing well with patient enrollment for MPS I expected in June. Recall that the Ph1/2 study in MPS I would go directly to the 2nd dose given the good safety data from the MPS II program. For the Ph1/2 study in MPS II (≥4 adult patients treated and initial data by late summer 2018), patients still are receiving enzyme replacement therapy (ERT) and more accurate measure of GAG and enzyme levels would be available after patients discontinue ERT treatment. When patients are on ERT, the benefits of gene therapy could be reflected via the GAG level at ERT trough stage. Based on KOL feedback, only 1-2% enzyme activity of normal level would be therapeutically meaningful for MPS II. For the MPS I/II programs, management commented that it is more about validating the delivery methods for ZFN.
· Ex vivo programs in BT/SCD and immuno-oncology. Initial data for the ST-400 in beta-thalassemia (BT) are expected in 1Q19, which would include data from the first 3 patients. Partner Sanofi (covered by European Pharma analyst Emmanuel Papadakis) has reported FDA acceptance of the IND for BIVV003 in sickle cell disease (SCD) on May 16, 2018 and planned to open clinical sites in the US this year. Partner GILD (covered by US Biopharma analyst Geoff Meacham) would develop ZFN-based T cell and NK cell therapies in oncology and SGMO would retain any areas outside oncology, including regulatory T cells in autoimmunity
Barclays - SGMO: Proposed TxCell acquisition to accelerate development of regulatory T cell therapies
Key takeaways: SGMO announced this morning the proposal to acquire TxCell (not covered) at about €72M (i.e. $84M, ~177% premium to last close) to add access to the expertise in regulatory T cells (Tregs). TxCell’s lead program Tx200, Tregs genetically transduced with a chimeric antigen receptor (or CAR-Treg), is set for CTA filing in 2019 for prevention of solid organ transplantation. SGMO plans to combine its ex vivo gene editing capacities and TxCell’s Treg for development of next-generation products for a broad array of autoimmune diseases such as Crohn’s disease and multiple sclerosis. Although the Treg technology remains at the nascent stage, we see the proposed transaction would expand and accelerate SGMO’s capability in immunology and autoimmune diseases.
Proposed transaction terms: SGMO would complete the majority of ordinary shares (at €2.58 per share in cash) following its stock purchase agreement with shareholders holding ~53% of total shares, subject to conditions precedent, including those relating to regulations governing foreign investments in France and the delivery of a favorable report from HAF Audit & Conseil. The filing of the cash simplified tender offer (at €2.58/share) would ensue and the transaction is expected to close in 4Q18.
TxCell’s Treg capability and programs. TxCell has the experience and capacity to isolate and expand Tregs ex vivo and design CAR constructs for antigen-specific activation of Tregs. Key conceptual advantage of CAR-Tregs includes localized activation of Tregs against the specific targets to induce immune tolerance, while other immune suppressive drugs result in systematic effects. TxCell lead program Tx200 targets HLA-A2, which would be initially evaluated in rental transplants (~20,000 renal transplants in the US in 2017) with HLA-A2 positive donor and HLA-A2 negative recipient. CTA filing is expected in 2019 and initial clinical data would validate the therapeutic hypothesis and enable future expansion into additional transplant types such as lung and skin. SGMO also plans to apply its ZFN-mediated gene editing to improve the potency and safety of CAR-Tregs and potentially develop off-the-shelf allogeneic CAR-Tregs. Future programs would target a broad range of autoimmune indications such as multiple sclerosis and Crohn’s disease.
Under: Been on the sidelines for a bit holding (building) cash. Now that "BIGLEY" has rolled out the tax plan its time to jump in.
Dec 21, 2017 19:06:02 GMT -6
martyc: Looks like you are buying Msft again!
Dec 15, 2017 11:23:29 GMT -6
martyc: The news that Trump called Rupert to congratulate him sure seems to indicate that this is heading to approval
Dec 15, 2017 11:22:23 GMT -6
Under: DIS finally getting some traction.?
Dec 14, 2017 17:08:45 GMT -6
martyc: I took an entry level position in DIS. Will add eventually to overweight when it becomes clearer that the deal will go thru. Can't believe how well positioned they will be. 60% Hulu. 20% of content watched on NFLX they can pull. More in thread
Dec 14, 2017 11:05:16 GMT -6
Under: Great posts on $DIS
Dec 13, 2017 17:50:49 GMT -6
Under: $ROKU Citron on a war path.
Nov 28, 2017 15:11:20 GMT -6
Under: $HAS takeover bid for $MAT?
Nov 10, 2017 16:16:07 GMT -6
martyc: Not looking like the market will provide any discounted opp for SGMO. Call was just too professional and all signs indicate they are on a great path for commercialization. Happy with core but wish I had some trading shs
Nov 10, 2017 9:04:05 GMT -6
martyc: For anyone looking to find an entry point into SGMO, I'm almost hoping is sells off in next few days so I can add more. They are really clicking but the fact they haven't signed new deals might cause some to exit. Watching as I have room for trading shs
Nov 9, 2017 18:28:09 GMT -6
martyc: Been an interesting ride so far. I figured the Bears would be about this good but hoped the O wouldn't look so lame. Another building yr but still possible to get to 8-8 IMO
Nov 9, 2017 18:26:08 GMT -6
Under: whats up with your Bears this year Marty?
Nov 9, 2017 17:35:25 GMT -6
martyc: Hope you were long ROKU. I wanted to see Q first so missed out
Nov 9, 2017 7:08:53 GMT -6