BioTime Announces Clinical and Corporate Milestone Targets
ALAMEDA, Calif. BioTime, Inc., a late-stage, clinical biotechnology company developing and commercializing products addressing degenerative diseases, today announced its 2018 clinical and corporate milestone targets.
BioTime will continue to focus on the core pillars of its stated strategy of Clinical Progress, Simplification and Unlocking Value for BioTime Shareholders.
Projected 2018 OpRegen® Milestones

·       BioTime anticipates approval from the DSMB and to begin enrollment of Cohort 4.
·       The Company expects to open more U.S. sites to include the growing number of interested Retinal surgeons in the current clinical study.
·       If accepted, BioTime is planning on presenting clinical data from the first 3 Cohorts at the Association for Research in Vision and Ophthalmology (ARVO) conference in the second quarter of 2018.
·       The Company expects to present preliminary functional data from patients treated in the ongoing trial later this year.
·       If accepted, detailed data from first 3 cohorts and available data from the fourth Cohort will be presented at the American Academy of Ophthalmology (AAO) conference in the fourth quarter of 2018.
About OpRegen®

OpRegen®, which is being studied for the treatment of the dry form of AMD, consists of a suspension of Retinal Pigment Epithelial (RPE) cells that are delivered subretinally during a simple intraocular injection. RPE cells are essential components of the back lining of the retina, and function to help nourish the retina including photoreceptors. A proprietary process that drives the differentiation of human pluripotent stem cells is used to generate high purity OpRegen® RPE cells. OpRegen® RPE cells are also “xeno-free," meaning that no animal products are used at any point in the derivation and production process. The avoidance of the use of animal products eliminates some potential safety concerns. Preclinical studies in rats have shown that following a single subretinal injection of OpRegen®, the cells can rapidly organize into its natural monolayer structure in the subretinal space and survive throughout the lifetime of the animal. OpRegen® is designed to be an “off-the-shelf” allogeneic (non-patient specific) product. Unlike treatments that require multiple, frequent injections into the eye, it is expected that OpRegen® would be administered in a single procedure. OpRegen® was granted Fast Track designation from the FDA, which allows more frequent interactions with the agency, and eligibility for accelerated approval and priority review. OpRegen® is a registered trademark of Cell Cure Neurosciences Ltd., a majority-owned subsidiary of BioTime, Inc.


Overview of BioTime (source):

BioTime is leading the next revolution in medicine – regenerative medicine. Regenerative medicine utilizes advances in stem cell biology, biomaterials, lab-generated cells and tissues, and biologics to engineer and provide healthy cells, tissues and organs to patients with chronic degenerative diseases. This revolution in medical science changes the focus from treating the symptoms of chronic and degenerative diseases to providing actual cures. Together with their subsidiaries, they have a strong focus on improving patients’ lives, and we are advancing clinical trials and a robust pipeline which includes the following programs:

·       OpRegen® is in a Phase I/IIa development for the dry form of age-related macular degeneration (dry-AMD) through subsidiary Cell Cure Neurosciences Ltd.
·       Renevia®, our proprietary cell delivery matrix designed to facilitate the stable engraftment of transplanted cells, is in a pivotal clinical trial in Europe for HIV-associated lipoatrophy.
·       AST-OPC1 is in a Phase I/IIa trial for spinal cord injury rehabilitation and AST-VAC2 is advancing toward clinical development for acute myeloid leukemia (AML), and non-small cell lung cancer (NSCLC), all pluripotent stem cell-based therapies being developed by subsidiary Asterias Biotherapeutics, Inc. (NYSE MKT: AST).
·       OncoCyte (NYSE MKT: OCX) is developing a next generation of diagnostic tests that will be liquid biopsies using blood or urine samples. OncoCyte’s initial liquid biopsy products will be confirmatory diagnostics for detecting lung, bladder, and breast cancer. OncoCyte’s diagnostic tests are based on a proprietary set of genetic markers broadly expressed in numerous types of cancer.
·       Technology healthcare (mHealth) solutions are being developed and marketed by subsidiaries LifeMap Sciences, Inc. and LifeMap Solutions.
·       cGMP-compliant ES cell lines are available for research and clinical studies.

·       BioTime’s FDA-approved blood plasma expander Hextend® is marketed in collaboration with Pfizer, Inc., in the United States and under an agreement with CJ Corporation in South Korea.


Further to the below patent case BioTime/Hadasit has successfully defended their IP:


The following IP challenge by Pfizer to BioTime("BTX")/Hadasit's EPO Patent on their hESC RPE derivation method was lodged at the European Patent Registry July 2015 and marks a significant challenge by the largest Pharma company against Hadasit's granted claims. Pfizer has an hESC RPE program in development with the Pete Coffey of the University College London, called The London Project.



I provided the following summary review of the BTX/Hadasit (CellCure) project to Stem Cell Assays and include it here for reference.

BTX/CellCure's hESC RPE Cell Therapeutic Candidate Review for Alexey BersenevStem Cell Assays

Product candidate name: OpRegen®

Developer: Cell Cure Neurosciences Ltd. of Israel (a subsidiary of BioTime, Inc. with Teva Pharmaceutical Industries, Ltd. and HBL-Hadasit Bio-Holdings, Ltd. as minority shareholder partners) 

History of development: Since 2005 by Cell Cure Neurosciences Ltd. (a ES Cell International Pte Ltd) acquired by BioTime, Inc. in 2010

Type of cells: Human allogeneic embryonic stem cell-derived retinal pigment epithelium (RPE), expanded ex vivo.

Tissue source: Inner cell mass of blastocyst, derived from fertilized oocytes. Pre-embryo donated as supernumerary tissue to science rather than discarding during standard IVF treatment. hESC cell line established – HAD-C 102.

Processing steps: Laser blastocyst ZP breaching, mechanical dissection, isolated ICM plated, ES culture to embryoid body development on human foreskin fibroblasts feeder layers in KO medium, ES cells isolation, hESC master cell bank, further culturing steps w/ nicotinamide and TGF-β Growth Factors (Activin A) until RPE cells, plating, expansion, working cell bank, expansion, harvest, cryopreservation. 

Phenotypic composition: positive for MiTF-A, RPE65, Bestrophin, Mertk, Otx2, ZO-1, CD81 and CRALBP 

Stability/Safety: Genetically stable, normal karyotype, normal senescence & terminally differentiated to its RPE fate

Proposed mechanisms of action and potency: Cell replacement to restore cell cycle action to support photoreceptors (Vitamin A, phagocytosis & waste processes, nutrients & factors) 

Key publications: 
Science Summary: RPE cell replacement therapy is a potential regenerative treatment which looks to restore lost retina cells at the base of the macula to establish a new and healthy support layer to the photoreceptors which are loosing function as a result of the old RPE layer dying off. It is envisioned that by replacing the lost RPE layer the remaining photoreceptors will once again function properly thereby either arresting the decline of the age related condition or actually improve lost visual acuity. There are two companies currently pursuing hESC RPE Dry AMD suspension products in the clinic – Cell Cure and Ocata (previously Advanced Cell Technology). Each of these two programs use different hESC source processes & RPE derivation methods to produce their RPE cell therapeutic product. Cell Cure’s product is from an hESC sourced from a Blastocyst while Ocata’s product is sourced from an earlier pre-embryo state at the Blastomere stage. Both groups differentiate their hESCs to a pure terminal RPE population. Cell Cure’s product uses a more chemically directed culture method which results in a stable RPE cell while Ocata’s product is more spontaneously derived and contains a proliferative heterogeneous population in its treatment ready form while remaining RPE confined.  

Ongoing trials: Phase 1 - Dry AMD – Geographic Atrophy  NCT02286089

Administration: Vitrectomy with sub-retinal injection of cell suspension with dosing from 50,000 to 500,000 cells 

Key patents:

IP Positioning summary: Cell Cure’s underlying US Patent on Pluripotent Culture System methods (hESCs from ICM Blastocyst stage) employs a proprietary xeno-free feeder system and is therefore a valuable addition to the state-of-the-art science to maintain Pluripotent embryonic cells for further derivation into somatic cell lineages. Biotime has a leading position in hESC Blastocyst IP as a result of Geron’s IP assets in hESC science which Biotime acquired. In addition it should be noted that the process of extracting hESCs from Blastocyst ICM stage embryos results in their termination – a point that restricts the IP due to European objection to destructive methods of embryonic cell extraction.

The RPE derivation methods defined by Cell Cure have been issued Patents in various International Territories but are not, as of writing, protected in the US due to various USPTO Examination issues, including prior disclosure of the use of Nicotinamide in the above cell culture patent literature and Ocata’s lead in issued patents & prior art in RPE IP. In relation to the sector competition please see the following link for an overview: BTX Hadasit

hESC Cell Line: HAD-C 102

Web Links, Related Posts & Misc. Media Articles: 

6. Biotime Seeking Alpha Nov 2014 interview

Update from BioTime on their OpRegen deal with Teva:

"Cell Cure also announced today that the option granted to Teva Pharmaceutical Industries Ltd. (“Teva”) under a Research and Exclusive Option Agreement of October 7, 2010 to license-in rights to its OpRegen product has expired without having been exercised by Teva. Cell Cure will therefore be continuing the clinical development of OpRegen on its own and pursuing discussions with other potential strategic partners, including those that have already indicated interest in participating in development and commercialization of the product."

hESC RPE Therapeutic Program Comparison (BTX/CellCure vrs Ocata)

I've been following the developments of the BTX-CellCure/Hadasit/TEVA program for Dry AMD with interest for some time and have concluded a few observations to-date with regard to their positioning versus OCATA's hESC RPE program, namely:

- There is a fundamental difference in stem cell sourcing between the groups. OCATA derives it's ES cells from the Blastomere stage whereas Hadasit derives it's ES cell from a cell line from the later Blastocyst stage. This difference has yet to be clearly documented but there is reason to believe there exists a genetic expression profile difference between the cell origin with the Blastomeres being more "naive." Whether that has any bearing on the potency of these resulting cell population(s) is a topical question. What has been published is that the earlier the cell source the more potent & less likely there will be any issues with the committed ES cell nature of its genetic profile.

- OCATA uses a more spontaneous differentiation protocol for culturing its ES to RPE product than the directed protocol used by Hadasit's scientists. This once again speaks to the issue of potency and cell expression. By forcing the RPE cell to a final terminated non-proliferating fate, using a later stage ES cell source, Hadasit increases yield but there is reason to believe OCATA's earlier more naive source, along with their naturally derived less differentiated heterogeneous proliferating cell population, will be shown to produce comparatively superior results. The answer may be in the nature of the pigmentation maturity and ability to modulate & select the appropriate RPE phenotypes.

- CellCure doesn't have any US Patents underlying it's RPE methodology and it's recently granted European Patents have been immediately subject to a thorough challenge backed up with cited evidence negating novelty, amongst other issues. Hadasit's hESC IP grants in Europe are notable and important in so much as they were granted by the EPO in the first place. This is a favorable indication for hESC science patentability in Europe generally - including OCATA's pending hESC RPE applications. However, the reason I don't put much weight in the IP is that it is contingent upon Hadasit using an ethical process. This speaks most importantly to the issue of hESC IP in Europe. Hadasit was explicitly restricted to conform all it's work to the specific use of Non-Destructive ES lines for these European Patents to be enforceable. In this case that isn't being done as the cell line being developed and to be used for these Clinical Trials is a Blastocyst ICM derived ES line which results in the destruction of the Embryo. This is unlike OCATA's Blastomere technology which is a Non-Embryo-Destructive process, whereby a natural birth remains viable. These issues therefore significantly reduce the impact of the competitive nature of CellCure's RPE program given the IP restriction in Europe and lack of IP in the US.

- Time lag to market on the CellCure program is currently 3 years behind OCATA's program and one must consider that to be significant given the momentum behind ACTC now that peer review has been published on it's Phase 1 data. Even with accelerated progress ACTC has their Orphan status in the US & Europe on SMD which will reach the market first and establish a hard to beat first mover & off-label advantage. Teva, who hold the commercial rights to CellCure's RPE program, may well be playing catch-up and be an also ran before even reaching the market, assuming all things equal on efficacy and pricing (which is doubtful). Add in the IP road-block of unprotected markets using Blastocyst derived RPEs and there is reason to be even more circumspect commercially.

- CellCure has a xeno-free hESC Blastocyst ICM protocol and RPE product. That's a plus going in. However, OCATA also has a xeno-free RPE product awaiting use in their Clinical Trials which is covered in their RPE IP Estate. This isn't really a concern and one which an integrated bridging study or separate cell line safety study in MMD will resolve. By BioTime promoting xeno-free as a superiority issue they oversell the current difference of their cell line. More importantly at present is that Hadasit doesn't have any secured program IP in the US and are limited in Europe to IP using Non-Destructive ES cells (OCATA's ES lines for example), both of which are relevant commercial issues.

- The CellCure trial will be done at one site in Israel, the Hadassah Ein Kerem Medical Center in Jerusalem. This is versus ACTC initiating independent trial sites at the world's most important ophthalmology institutions with a who's who of principal investigators in ophthalmology. 

- I'll also note that OCATA's Generation 1 RPE product is already dated in their own lab, considering Generation 2 & 3 product improvements, in specific factor expression and gene modification technology. This is in addition to advanced programs in Photoreceptor, Ganglion, Corneal and Biologics filling out the immediate pipeline for the Eye, plus the Blood & Immune areas being developed for partnership.

- In closing I believe in BioTime, its HydroGel, Bone & other hESC activities & products and view their RPE & Blastocyst competition with OCATA as healthy & helping to drive the sector forward. However, one must be careful in defining the differences between the cell lines and programs to be clear and rely on peer reviewed data for comparative analysis. There may ultimately be similar cell type products which can survive side by side in the market for effective treatments and curative solutions - especially in an indication that is as large & global as the Dry AMD market is. Although, as with all products, category commercialization will be dependent on solidifying any first mover advantage, product comparative effectiveness, pricing power and marketing.

The race to market is on...



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