About Lineage Cell Therapeutics

Lineage Cell Therapeutics, Inc. (Lineage), a clinical-stage biotechnology company, engages in developing novel cell therapies to address unmet medical needs. The company’s programs are based on its proprietary cell-based technology platform and associated development and manufacturing capabilities. From this platform, the company designs, develops, manufactures, and tests specialized human cells with anatomical and physiological functions similar to, or identical to, cells found naturally in the human body. Cells which the company manufactures are created by specific developmental biological differentiation protocols that it applies to established, well-characterized, and self-renewing pluripotent cell lines. These cells are transplanted into patients and are designed to replace or support cells that are absent or dysfunctional due to degenerative disease, aging, or traumatic injury, and restore or augment functional activity in the affected person. The company’s strategy is to efficiently leverage the company’s technology platform and its development, formulation, delivery, and manufacturing capabilities to advance is programs internally, or in conjunction with strategic partners, to further enhance their value and probability of success. As one example, in December 2021 the company entered into a Collaboration and License Agreement (the Roche Agreement) with F. Hoffmann-La Roche Ltd and Genentech, Inc., a member of the Roche Group (collectively or individually, Roche or Genentech), wherein the company granted to Roche exclusive worldwide rights to develop and commercialize retinal pigment epithelium (RPE) cell therapies, including its proprietary cell therapy program known as OpRegen, for the treatment of ocular disorders, including geographic atrophy (GA) secondary to age-related macular degeneration (AMD). The company is in clinical development for various pluripotent cell-derived product candidates, such as RPE cells, oligodendrocyte progenitor cells, and dendritic cells and preclinical development for auditory neurons and photoreceptor cells. In addition, the company is considering the differentiation of pluripotent cells into additional cell types that may have therapeutic benefits in other areas of unmet medical need. Data were presented at the Association for Research in Vision and Ophthalmology annual meeting (ARVO), suggesting that OpRegen continues to be well tolerated with an acceptable safety profile, coupled with visual function and outer retinal structure improvements in patients with geographic atrophy (GA) and impaired vision. As of December 31, 2022, the company had five allogeneic, or ‘off-the-shelf’, cell therapy programs in development, of which three have reached clinical testing: Product Candidates OpRegen, an allogeneic retinal pigment epithelium cell replacement therapy in a Phase 2a multicenter clinical trial, being conducted by Genentech, for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD), also known as atrophic or dry AMD. A previous Phase 1/2a trial conducted by Lineage enrolled twenty-four (24) individuals with dry AMD with GA. In December 2021, this program was partnered with Roche for further clinical development and commercialization. OPC1, an allogeneic oligodendrocyte progenitor cell therapy in long-term follow-up from a Phase 1/2a multicenter clinical trial for cervical spinal cord injuries (SCI). As of December 31, 2022, five (5) patients with thoracic spinal cord injuries and twenty-five (25) patients with cervical spinal cord injuries had been enrolled in clinical trials of OPC1. VAC, an allogeneic cancer immunotherapy consisted of antigen-presenting dendritic cells. One of the VAC product candidates, VAC2, is in a Phase 1 clinical trial in non-small cell lung cancer (NSCLC). This clinical trial is being funded and conducted by Cancer Research UK, one of the world’s largest independent cancer research charities. An additional VAC-based product candidate is in preclinical development with the company’s partner, Immunomic Therapeutics, Inc. (ITI), for the treatment of glioblastoma multiforme (GBM). ANP1, an allogeneic auditory neuron progenitor cell transplant in preclinical development for the treatment of debilitating hearing loss (DHL). PNC1, an allogeneic photoreceptor cell transplant in preclinical development for the treatment of vision loss due to photoreceptor dysfunction or damage. Other Programs The company has additional undisclosed product candidates being considered for development, which cover a range of therapeutic areas and unmet medical needs. Generally, these product candidates are based on the same platform technology and employ a similar guided cell differentiation and transplant approach as the product candidates detailed above, but in some cases may also include genetic modifications designed to enhance efficacy and/or safety profiles. Business Strategy One area of focus is the company’s continued effort to support its partner, Genentech, with the production and testing of its lead product candidate, OpRegen (RG6501), which is being evaluated in a 30-60 patient Phase 2a multicenter, open-label, single arm clinical study, as well as in the follow-up portion of a 24-patient Phase 1/2a multicenter, open-label, clinical study, in patients with dry age-related macular degeneration (dry AMD). The company has identified, and it may seek to develop, additional product candidates based on its cell replacement approach. The company may elect to conduct these activities on its own or through various collaborative arrangements. Such additional product candidates could include gene edits, which may provide enhanced functionality or offer more attractive safety or commercial profiles. The company may utilize various types of pluripotent cell lines as starting material for its product candidates. Presently, the company’s process development and manufacturing activities, including its cGMP production of clinical trial material, are predominantly conducted at its facility located in Jerusalem Israel, but such work may be supplemented or complemented by its additional facility located in Carlsbad, California. Cell Therapy Technology Platform The company is in clinical development for various pluripotent cell-derived product candidates, such as RPE cells, oligodendrocyte progenitor cells, and dendritic cells and preclinical development for auditory neurons and photoreceptor cells. In addition, the company is considering the differentiation of pluripotent cells into additional cell types that may have therapeutic benefits in other areas of unmet medical need. Novel Clinical Cell Therapy Pipeline OpRegen OpRegen is a retinal pigment epithelial cell therapy in Phase 2a development for the treatment of geographic atrophy secondary to age-related macular degeneration. Following subretinal delivery, OpRegen has the potential to counteract RPE cell loss in areas of GA lesions by supporting retinal structure and function. OpRegen is being developed under a worldwide collaboration between Lineage, Roche and Genentech, a member of the Roche Group. OpRegen has been granted Fast Track Designation from the U.S. FDA, which includes an expedited regulatory path with the ability for increased interfacing with the FDA during the clinical development process. OpRegen is a cell replacement therapy derived from the company’s pluripotent cell technology in which its proprietary directed-differentiation methods convert pluripotent stem cells into nearly pure populations of RPE cells. Using this method, OpRegen is grown free of any animal products and consists of human RPE cells with high yield and purity that can be transplanted directly into the patient’s eye, where the patient’s own RPE cells are missing or dysfunctional. The OpRegen therapeutic approach is designed to replace damaged or lost RPE cells with the goal of slowing disease progression to preserve and/or restore visual function. In December 2021, the company entered into the Roche Agreement for the development and commercialization of OpRegen. In a Phase 1/2a clinical trial, OpRegen has demonstrated the potential to slow, stop or reverse disease progression in geographic atrophy secondary to AMD. This is an open-label, single-arm, multi-center, dose-escalation trial evaluating a single administration of OpRegen delivered subretinally in patients with bilateral GA. In November 2022, the company announced its partner Genentech, a member of the Roche group has launched a Phase 2a, multicenter, open-label, single arm clinical study of RG6501 (OpRegen), a retinal pigment epithelial cell therapy. The study is intended to optimize subretinal surgical delivery and evaluate the safety and activity of OpRegen in approximately 30, and up to 60, patients with geographic atrophy (GA) secondary to age-related macular degeneration. OPC1 OPC1 is an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute SCI. OPC1 is derived from the company’s pluripotent cell technology under current good manufacturing practice (cGMP) conditions using a directed differentiation method. The development of OPC1 has been supported by a clinical development grant from California Institute for Regenerative Medicine (CIRM). The company intends to apply for additional grants from CIRM for the program’s continued development. The FDA designated OPC1 as a Regenerative Medicine Advanced Therapy (RMAT), for the treatment of subacute SCI. RMAT is an accelerated development pathway and includes the ability for increased interfacing with the FDA during clinical development. The FDA has also granted OPC1 Orphan Drug Designation, providing a pathway to possible market exclusivity. In 2019, the company transferred all cGMP manufacturing processes, including the establishment of cell banks and the OPC1 process development and manufacturing for clinical studies, to its cell therapy manufacturing facility in Jerusalem, Israel. Improvements to the manufacturing process were performed to create enhancements to the production process and scale and to achieve greater purity of OPC1. The company also developed a thaw and inject formulation of OPC1 to facilitate logistics and handling at the point of care with the elimination of the dose preparation at the clinical site. In 2021, the company manufactured clinical batches based on the improved process in a thaw and inject formulation in preparation for a larger-scale, late-stage clinical trial. In February 2021, the company announced an exclusive agreement with Neurgain Technologies, Inc. (Neurgain), to evaluate a novel delivery system for OPC1. Preliminary assessment of prototypes revealed promising compatibility with OPC1 product while simplifying the surgical procedure by providing surgeons with an instrument that is small, simple to use, and would not require stopping the patient’s ventilator to perform the injection, allowing for flexibility with accurate delivery to the injury site. The company continued to evaluate the Neurgain device throughout 2022. The company has submitted an RMAT package to the FDA to support the use of a new delivery device, along with a protocol synopsis for a small safety study in both subacute and chronic patients. The company intends to submit an IND amendment during 2023 for a human safety clinical study to validate the device (DOSED – Delivery of Oligodendrocyte Progenitor Cells for Spinal Cord Injury: Evaluation of a Novel Device) and an additional submission to support the use of the device in a late-stage clinical study to follow. The company is actively working both on expanding its existing and establishing new collaborative partnerships with SCI patient engagement and advocacy organizations, with the overarching goals of enhancing awareness of SCI and elevating the patient’s voice in the treatment development process. VAC Platform VAC is the company’s immuno-oncology platform using dendritic cells loaded with antigens for the treatment of cancer. Cancer afflicts millions worldwide and represents one of the largest unmet clinical needs with treatment options providing limited efficacy and a wide range of potentially debilitating side effects. As the most potent type of antigen-presenting cell in the body, dendritic cells instruct the human body’s immune system to attack and eliminate harmful pathogens and unwanted cells, including cancer cells. To provide a more targeted treatment for non-small cell lung cancer (NSCLC), the company is developing VAC2 as an allogeneic, or non-patient specific, cancer vaccine designed to stimulate patient immune responses to an antigen, human telomerase reverse transcriptase (hTERT), which is commonly expressed in cancerous cells but is not usually found in normal adult cells. VAC2 is produced by the company’s pluripotent cell technology using a directed differentiation method and consisted of a population of mature dendritic cells to which the hTERT antigen was introduced via an mRNA construct which is loaded into the dendritic cell via electroporation. The VAC1 autologous program, which preceded VAC2 but relied on the same antigen, served as proof of concept behind the company’s approach to utilize dendritic cell vaccines targeting telomerase to treat cancer. In September 2014, Asterias initiated clinical development of VAC2 by entering into a Clinical Trial and Option Agreement (the CRUK Agreement) with Cancer Research UK (CRUK) and Cancer Research Technology Limited (CRT), a wholly owned subsidiary of CRUK, under which CRUK agreed to fund Phase 1 clinical development of VAC2 in NSCLC. CRUK was responsible, at its own cost, for manufacturing clinical grade VAC2 and for carrying out the Phase 1 clinical trial of VAC2. In April 2022, the company announced that CRUK had completed patient enrollment in the ongoing Phase 1 clinical trial of VAC2 for the treatment of NSCLC. All eight patients completed dosing in the initial aspect of the trial and CRUK is conducting analyses of various samples collected per protocol. As previously reported, VAC2 demonstrated potent and specific induction of immune response in all patients dosed and analyzed as of December 31, 2022, with high levels of peripheral antigen-specific immunogenicity observed at multiple time points. Importantly, VAC2 appeared to be well tolerated with no unexpected adverse events (AEs) and no dose-limiting toxicity, serious adverse events (SAEs) or AEs. The company completed the transfer of all cGMP manufacturing processes, including the establishment of cell banks and the VAC2 process development and manufacturing for clinical studies, to its cell therapy manufacturing facility in Jerusalem, Israel. In April 2021, Lineage entered into a worldwide license and development collaboration agreement with ITI. In 2022, the company focused on improving the manufacturing process for VAC to provide a reliable supply for potential future clinical studies and commercial development. The company submitted a pre-IND package to the FDA in the third quarter of 2022 and have received important feedback that will help guide any future full IND submission(s). The company also continues to evaluate additional opportunities for the introduction of new VAC candidates based on internally identified or partnered tumor antigens to expand the VAC platform. Auditory Neurons The Auditory Neurons program was established in 2022 with the intention of advancing auditory neuron transplant therapy as a treatment option for hearing loss conditions. The initial focus of this program is on the treatment of auditory neuropathy spectrum disorders (ANSD), a group of conditions characterized by the loss of auditory neuron function where the sound is not transmitted properly from the cochlea (inner ear) to the brain. Based on the company’s proprietary technology platform, it has developed a unique differentiation process for generating auditory neurons (ANP1), which are planned to undergo preclinical testing this year to assess their safety and delivery system. In February 2023, the company reported that preclinical testing of ANP1 had begun through a collaboration with the University of Michigan. Photoreceptors The Photoreceptor program is developing the process of directing the differentiation of human pluripotent cells into clinical-grade transplantable photoreceptor precursors/cells (PRCs) and to show their further differentiation, integration, and function after transplantation into the subretinal space of animal models of photoreceptor degeneration. Photoreceptor degeneration is the hallmark of a variety of retinal diseases, such as retinitis pigmentosa (RP).The only approved treatments are gene therapies which treat specific genetic defects that lead to RP. The company’s PNC1 program is aimed to replace damaged photoreceptors regardless of the origin of degeneration. Collaborations Roche Collaboration Agreement On December 17, 2021, Lineage entered into the Roche Agreement, pursuant to which Lineage granted to Roche exclusive worldwide rights to develop and commercialize retinal pigment epithelium cell therapies, including its proprietary cell therapy known as OpRegen, for the treatment of ocular disorders, including advanced dry AMD with GA. Under the terms of the Roche Agreement, Roche will assume responsibility for further clinical development and commercialization of OpRegen, Lineage will be responsible for completing activities related to the ongoing clinical study Phase 1/2a open-label, dose-escalation clinical safety and efficacy study in patients with advanced dry AMD with GA, for which enrollment is complete, and performing certain manufacturing and process development activities. On April 16, 2021, Lineage entered a worldwide license and development collaboration with ITI (the ITI Agreement). Lineage is the sole and exclusive owner of the rights to the VAC platform and has licensed to ITI patents and materials for the development and commercialization of a novel cancer immunotherapy agent derived from this platform utilizing an antigen provided by ITI. Patents and Trade Secrets OpRegen The company has rights to issued U.S. and international patents and pending patent applications covering OpRegen. The issued patents have expiration dates ranging from 2028 to 2036. The pending applications, if issued, will have estimated expiration dates ranging from 2028 to 2042. These U.S. and international issued patents and pending applications also include those in-licensed from Hadasit, a wholly owned subsidiary of Hadassah Medical Organization. The company also solely owns pending U.S. and international patent applications relating to a cryopreserved thaw-and-inject formulation. The U.S. patent applications, and any filed international patent applications based on the PCT applications, if issued, will have estimated expiration dates in 2038. Pursuant to the Roche Agreement, the company has licensed these patent rights to Roche to further develop and commercialize RPE cell therapies, including OpRegen. OPC1 The company has numerous U.S. and international issued patents and pending patent applications that are relevant to neural cells, such as oligodendrocyte progenitor cells, including patent families acquired from Geron Corporation (Geron) that are directed to the differentiation of pluripotent stem cells, including human embryonic stem (hES) cells, into various neural cell types, as well as various culture and purification methods. Additionally, there are four patent families with pending patent applications owned by the company directed to improved methods of producing oligodendrocyte progenitor cells, oligodendrocyte progenitor cell compositions, and methods of treatment of spinal cord injury using oligodendrocyte progenitor cells. The estimated expiration dates of the four patent families with pending applications owned by the company ranges from 2036 to 2043. The commercial success of OPC1 depends, in part, upon the company’s ability to exclude competition for this product with the existing patent portfolio, regulatory exclusivity, undisclosed know-how and/or trade secrets, or a combination of these barriers to entry. VAC Platform The company has numerous U.S. and international issued patents and pending patent applications that are relevant to dendritic cells, including patent families acquired from Geron or in-licensed from third parties that are directed to the differentiation of pluripotent stem cells, including hES cells, into hematopoietic progenitor cells and immature and mature dendritic cells. In addition, these patent rights include a patent family with claims directed to immunogenic compositions comprising antigen-presenting dendritic cells and methods of eliciting an anti-telomerase immune response in a subject by administering to the subject such compositions. The expiration dates of the patents, and the estimated expiration dates of the pending applications, acquired from Geron or in-licensed to the company ranges from 2022 to 2029. The company also solely owns pending U.S. and international patent applications relating to VAC and VAC processes with estimated expiration dates, if issued, from 2041 to 2043. The commercial success of VAC products depends, in part, upon the company’s ability to exclude competition in these products with this patent portfolio, regulatory exclusivity, undisclosed know-how and/or trade secrets, or a combination of these barriers to entry. Auditory Neurons The company has a pending U.S. provisional patent application for its ANP1 program. It is anticipated that this provisional patent application will be converted to a U.S. utility patent application and one or more international patent applications in 2023 and, if issued, would have estimated patent expiration dates of 2043. Photoreceptors The company has pending U.S. and international patent applications for its photoreceptor neural cell (PNC1) program. These pending patent applications include a patent family licensed from Hadasit and a patent family solely owned by Lineage. The pending patent applications licensed from Hadasit, if issued, would have estimated patent expiration dates of 2038. The pending patent applications owned by Lineage, if issued, would have estimated patent expiration dates of 2036. The company also has a pending U.S. provisional patent application jointly owned with Hadasit. It is anticipated that this provisional patent application will be converted to a U.S. utility patent application and one or more international applications in 2023 and, if issued, would have estimated patent expiration dates of 2043. Licensed Technology and Product Development Agreements In March 2020, Lineage and its wholly owned subsidiary Asterias entered into a Second Amendment to Clinical Trial and Option Agreement (the CTOA Amendment) with CRUK and CRT, which amends the Clinical Trial and Option Agreement entered into between Asterias, CRUK and CRT dated September 8, 2014, as amended September 8, 2014. Pursuant to the CTOA Amendment, Lineage assumed all obligations of Asterias and exercised early its option to acquire data generated in the Phase 1 clinical trial of VAC2 in non-small cell lung cancer being conducted by CRUK. Under the WARF Agreements, the company has a worldwide non-exclusive license under certain WARF patents and WARF-owned primate (including human) stem cell lines covered by such patents for use in internal research, and to make, use and sell products that are used as research tools and products that are discovered or developed through its internal research using such patents and stem cells. WARF Agreements The company has rights to certain U.S and international issued patents, pending patent applications, and stem cell lines with the Wisconsin Alumni Research Foundation (WARF) under a Commercial License and Option Agreement entered into between Lineage and WARF in January 2008 and a Non-Exclusive License Agreement entered into between Asterias and WARF in October 2013 (collectively, the WARF Agreements). Under the WARF Agreements, the company has a worldwide non-exclusive license under certain WARF patents and WARF-owned primate (including human) stem cell lines covered by such patents for use in internal research, and to make, use and sell products that are used as research tools and products that are discovered or developed through its internal research using such patents and stem cells. Research and Development The company’s research and development expenses were $14.0 million for the year ended December 31, 2022. Government Regulation The company’s domestic human drug and biologic products will be subject to rigorous FDA review and approval procedures. Competition The company is aware that some of its competitors, including Bristol-Myers Squibb Company; Novo Nordisk A/S; Novartis AG; Johnson & Johnson; Merck & Co Inc.; Gilead Sciences Inc.; Astellas Pharma Inc.; Bayer AG; BioNTech SE; Moderna Inc.; Sana Biotechnology Inc.; Senti Biosciences Inc.; Iveric Bio Inc.; Apellis Pharmaceuticals Inc.; Century Therapeutics Inc.; and Allogene Therapeutics Inc. History The company was founded in 1990. It was incorporated in 1990 in the state of California. The company was formerly known as BioTime, Inc. and changed its name to Lineage Cell Therapeutics, Inc. in 2019.