Pluri Stock

Pluri Inc., a biotechnology company, focuses on the field of regenerative medicine.

The company develops placenta-based cell therapy product candidates for the treatment of multiple inflammatory, muscle injuries and hematologic conditions. Its operations focus on the research, development, manufacturing, conducting clinical trials and business development of cell therapeutics and related technologies.

Technology

The company develops, and intends to commercialize, cell therapy production technologies and products that are derived from the human placenta after a full-term delivery of a healthy baby. Its PLX cells are adherent stromal cells that are expanded using a proprietary three-dimensional (3D) process. This system utilizes a synthetic scaffold to create an artificial 3D environment where placental-derived stromal cells could grow. Its automated proprietary 3D, current Good Manufacturing Practice approved, process enables the large-scale monitored and controlled production of reproducible, cell products and could manufacture various placental expanded (PLX) doses.

Product Candidates

The company’s primary focus is to be a major provider of allogeneic placenta-based cell therapy products that are off-the-shelf products that does not require any matching or additional manipulation prior to administration.

PLX-PAD

The company’s first product candidate, PLX-PAD (peripheral arterial disease), includes maternal cells originating from the placenta. PLX-PAD is being used in a Phase III multinational clinical study in recovery following surgery for hip fracture, and in two Phase II clinical studies in acute respiratory distress syndrome (ARDS) associated with COVID-19 in the United States, Europe and Israel.

The company has also conducted a pivotal Phase III multinational clinical study in the use of PLX-PAD for the treatment of Critical Limb Ischemia (CLI), which it terminated in December 2020, and in a Phase II multinational clinical study in Intermittent Claudication (IC).

PLX-PAD is also under clinical development in collaboration with Tel Aviv Sourasky Medical Center (Ichilov Hospital) through an investigator initiated study, and used in a Phase I/II for the treatment of Steroid-Refractory Chronic Graft versus Host Disease (cGVHD).

PLX-R18

The company’s second product candidate, PLX-R18, includes fetal cells originated from the placenta.

The company has completed enrollment in its first in human Phase I clinical study in incomplete hematopoietic recovery following hematopoietic cell transplantation (HCT) in the United States and Israel.

Through the company’s collaboration in the United States with the National Institutes of Health (NIH) and the U.S. Department of Defense (DoD), it is also developing a solution for acute radiation syndrome (ARS) following or before exposure to massive radiation via the U.S. Food and Drug Administration (FDA) Animal Rule regulatory pathway.

Modified PLX cells

As a platform technology company, the company is developing additional product candidates, which are modified or induced PLX cells:

Induced PLX Cells: The company is using cells from the placenta, induced with inflammatory cytokines, to transiently alter their secretion profile.

Modified PLX Cells Using CRISPR Technology: CRISPR is a technology that opens the door for precise gene editing of cells. Using such technology could initiate the next evolution in cell therapy by allowing the reprograming of cells for specific needs. The company’s focus is to incorporate the genetic engineering techniques into its cell manufacturing platform to develop large scale allogenic engineered PLX products designed for specific indications.

Clinical Development Product Candidates

Orthopedic Indications: Following FDA and European Medicine Agency clearance, a multinational Phase III study is being conducted in the United States, Europe and Israel. The primary endpoint of this study is the Short Physical Performance Battery, a test for lower leg performance and functional status. The study is planned to include various patients and would assess efficacy at six months and a year, as well as safety for approximately two years. Approximately 95% of the study patients have been enrolled in this study.

The company’s Phase III study protocol and design was based on its phase I/II, randomized, double-blind, placebo-controlled study (n=20) to assess the safety and efficacy of intramuscular (IM) injections of allogeneic PLX-PAD cells for the regeneration of injured gluteal musculature after total hip replacement had been conducted in Germany under the approval of PEI. In this study, PLX-PAD cells or placebo were administered into the traumatized gluteal muscle during total hip replacement surgery. The study results met its primary efficacy endpoint, change in maximal voluntary isometric contraction force of the gluteal muscle at six months after total hip replacement. In addition, the study demonstrated that PLX-PAD was tolerated by patients.

COVID-19 Complicated by ARDS: In May 2020, the FDA cleared the company’s Investigational New Drug Application (IND) for a Phase II study of its PLX-PAD cells for treatment of severe COVID-19 cases complicated by ARDS and it initiated the study in June 2020. The U.S. study is a randomized, double-blind, placebo-controlled, multicenter, parallel-group intended to evaluate the efficacy and safety of IM injections of PLX-PAD for the treatment of severe COVID-19 cases complicated by ARDS. The primary endpoint is the number of ventilator free days during the 28-days following dosing. Secondary efficacy endpoints include all-cause mortality, duration of mechanical ventilation, ICU free-days, and hospitalization free-days. Safety and survival follow-up would be conducted until week 52. In addition, the FDA has cleared the company’s Expanded Access Program (EAP) for the use of its PLX-PAD cells to treat ARDS caused by COVID-19 outside of the Phase II COVID-19 complicated by ARDS study in the United States. The EAP approval was for approximately 100 patients.

In August 2020, the PEI cleared the company’s Phase II study in Germany titled, ‘A Randomized, Controlled, Multicenter, Parallel-Group Phase II Study to Evaluate the Efficacy and Safety of Intramuscular Injections of PLX PAD for the Treatment of severe COVID-19’, relating to the treatment of patients hospitalized with severe cases of COVID-19 complicated by ARDS. The primary efficacy endpoint of the study is the number of ventilator free days during the 28-days from day one through day 28 of the study. Secondary efficacy endpoints include all-cause mortality, duration of mechanical ventilation, ICU free-days, and hospitalization free-days. Safety and survival follow-up would be conducted until week 52. The company enrolled patients in Europe and Israel under this protocol.

In July 2021, the company announced that it is bringing its COVID-19 complicated by ARDS Phase II studies in the United States, Europe and Israel to clinical readout. It focuses to announce the topline results of the readout during the fourth quarter of 2021. The company also announced that it would not pursue the previously announced plans in December 2020 to expand its COVID-19 program in Mexico in collaboration with Innovare R&D SA de CV.

Recovery Following HCT: This Phase I study of PLX-R18 in HCT, has completed enrollment of patients in the United States and Israel. The study is designed to assess the safety of PLX-R18 by assessing adverse events, safety labs and vital signs in patients receiving different doses of PLX-R18. The company focuses to complete one year follow up for various patients in September 2021. In April 2021, the company announced topline results of this study.

Peripheral and Cardiovascular Diseases: The company investigated the use of PLX-PAD cells for the treatment of peripheral arterial disease (PAD), including IC and CLI.

The company completed two Phase I safety/dose-escalating clinical studies for CLI, one in the United States and one in Germany. These CLI studies demonstrated that no blood type or human leukocyte antigen matching is required, and that the administration of PLX-PAD cells is safe, even if two doses are administered to a patient on two different occasions.

The company conducted a pivotal Phase III study of PLX-PAD cells in the treatment of CLI for patients with minor tissue loss (Rutherford Category 5) who are unsuitable for revascularization. This multinational Phase III study was conducted in the United States, Europe and Israel.

In December 2020, the independent Data Monitoring Committee (DMC) issued its recommendation letter following an interim analysis relating to the CLI Phase III study. A clinical dataset was reviewed by the independent DMC for safety and analysis of the primary endpoint of amputation-free survival, defined as time to occurrence of major amputation of the index leg or death. Based on the review, the DMC concluded that the CLI study was unlikely to meet the primary endpoint by the time of the final analysis. Following the DMC’s recommendation, the company decided to terminate the CLI study.

ARS: The company has conducted various animal studies for the evaluation of PLX-R18 for the treatment of ARS, in collaboration with the National Institute of Allergy and Infectious Diseases (the NIAID). The NIH, funded and conducted a pilot study in non-human primates (NHPs) to evaluate the therapeutic effect of PLX-R18 on hematological aspects of ARS. In 2017, the company announced results of the NHPs pilot study for PLX-R18 as a treatment for ARS.

The company plans to continue the discussions with the various government agencies with the focus of receiving their support for pivotal studies in NHPs, as well as conducting the safety studies required to file Biologics License Application for this indication.

In 2017, the company announced that the FDA granted it an orphan drug designation for its PLX-R18 cell therapy for the prevention and treatment of ARS.

In 2018, the company announced that the FDA approved its IND application for PLX-R18 cell therapy in the treatment of ARS. The IND allows the company to treat victims who might have been acutely exposed to high dose radiation due to nuclear attack or accident.

In July 2019, the company presented positive results from a series of studies of its PLX-R18 cell therapy product conducted by the DoD, Armed Forces Radiobiology Research Institute, part of the Uniformed Services University of Health Sciences. The studies were designed to evaluate PLX-R18 as a potential prophylactic countermeasure against ARS administered prior to radiation exposure. These animal studies demonstrate that PLX-R18, administered 24 hours before radiation exposure, and again 72 hours after exposure, resulted in a significant increase in survival rates, from 4% survival rate in the placebo group to 74% in the treated group. In addition, the data shows an increase in recovery of blood lineages and a favorable safety profile. Furthermore, histopathological analysis and hematopoietic progenitor clonogenic assay of tissues collected show a significant increase in bone marrow cell numbers and improved regenerative capability into all blood lineages.

Steroid-Refractory cGVHD: In 2017, the company signed an agreement with Tel Aviv Sourasky Medical Center (Ichilov Hospital) to conduct a Phase I/II clinical study of PLX-PAD cell therapy for the treatment of Steroid-Refractory cGVHD. This study is an investigator-initiated study. As such, Tel Aviv Sourasky Medical Center supports the study and is responsible for its design and implementation.

Intellectual Property

The company is the owner of 133 issued patents and approximately 70 pending patent applications in the United States, Europe, China, Japan and Israel, as well as in additional countries worldwide, including countries in the Far East and South America (in calculating the number of issued patents, each European patent validated in multiple jurisdictions was counted as a single patent).

In April 2016, the Israeli subsidiary entered into a licensing agreement with TES Holdings Co., Ltd., a venture company derived from the University of Tokyo, to obtain a key patent in Japan to cover the treatment of ischemic diseases with placental cell therapy. This license is subject to future single low-digit royalties from sales of the company’s product for treatment in the field of ischemic diseases in Japan, until expiry of the patent in 2023. This license is in addition to the grant of 13 patents to the company by the Japanese Patent Office, which address three dimensional methods for expanding placental and adipose cells, and specified cell therapies produced from placental tissue using these methods and bedside thawing devices.

In April 2019, the company filed a U.S. provisional patent application titled ‘Methods and Compositions for Producing Cannabinoids’, which covers the use of its proprietary 3D cell culturing technology for the potential manufacturing of cannabinoid-producing cells. In April 2020, it filed a Patent Cooperation Treaty (PCT) application with respect to the technology. In June 2021, national or regional phase applications of the PCT were filed in the United States, Europe, Japan, Canada, and Israel.

In March 2020, the company filed a U.S. provisional patent application titled ‘Methods and Compositions for Treating Viral Infections and Sequelae Thereof’, which covers the use of placental adherent stromal cells for treating coronavirus infections and sequelae thereof. In May 2020, a related Israeli patent application was filed, which was allowed in March 2021. In March 2021, a PCT application, as well as national applications were filed in the United States and Israel. In June 2021, national or regional phase applications of the PCT were filed in Europe and Mexico.

The company’s multi-national portfolio of patent and patent applications includes various claims, such as its proprietary expansion methods for 3D stromal cells; composition of matter claims covering the cells; the therapeutic use of PLX cells for the treatment of various medical conditions; and cell-culture, harvest, and thawing devices.

The expiration dates of these patents, based on filing dates, range from 2027 to 2041. Actual expiration dates would be determined according to extensions received based on the Drug Price Competition and Patent Term Restoration Act of 1984 (P.L. 98-417), commonly known as the ‘Hatch-Waxman’ Act, which permits extensions of pharmaceutical patents to reflect regulatory delays encountered in obtaining FDA market approval. The Hatch-Waxman Act is based on a U.S. federal law and therefore only relevant to the U.S. patents.

Collaborations and Ongoing Research and Development Plans

Charité Agreement: In 2007, the company entered into a five-year collaborative research agreement with the Berlin-Brandenburg Center for Regenerative Therapies at Charité – University Medicine Berlin (Charité), which was extended from time to time through June 2022. The company and Charité are collaborating on various indications utilizing PLX cells. According to the agreement, it would be the exclusive owner of the technology and any products produced as a result of the collaboration. Charité would receive between 1% to 2% royalties from net sales of new developments that have been achieved during the joint development.

CHA Agreement: In 2013, the company entered into an exclusive out-licensing and commercialization agreement, or the CHA Agreement, with CHA for conducting clinical studies and commercialization of its PLX-PAD product candidate in South Korea in connection with two indications, such as the treatment of CLI and IC. The company would continue to retain rights to its proprietary manufacturing technology and cell-related intellectual property.

The first clinical study that was performed as part of the CHA Agreement was a Phase II study in IC. Upon the first regulatory approval for a PLX product in South Korea, if granted, for the specified indications, the company and CHA would establish an equally owned joint venture with the purpose of commercializing PLX cell products in South Korea. Additionally, it would be able to use the data generated by CHA to pursue the development of PLX product candidates outside of South Korea. The term of the CHA Agreement extends from June 24, 2013 until the later of the expiration, lapse, cancellation, abandonment or invalidation of the last valid patent claim covering the development of the product indications.

Horizon 2020: The Phase III study of PLX-PAD in CLI was conducted as a collaborative project carried out by an international consortium led by the Berlin-Brandenburg Center for Regenerative Therapies, together with the company and with the participation of additional third parties.

The company’s Phase III study of PLX-PAD cell therapy in the treatment of muscle recovery following surgery for hip fracture is a collaborative project carried out by an international consortium led by Charité, together with it and with the participation of additional third parties.

In October 2017, the company entered into a collaborative project, the nTRACK, carried out by an international consortium led by Leitat. The focus of this project is to examine gold nano particles labeling of stem cells to enable assessment of cells’ in vivo persistence and distribution in correlation to biological efficacy. Under the project, PLX cells, labeled and non-labeled would be characterized and examined in animal models for muscle injury.

Indiana University: In 2018, NIAID awarded a grant to Indiana University to conduct, together with the company, studies of its PLX-R18 cell therapy in the treatment of ARS. The focus of this project is to extend the PLX-R18 ARS studies to include examination of survival in pediatric and geriatric populations, as well as the ability of PLX-R18 to alleviate delayed effects of radiation in survivors.

Thermo Fisher: In 2018, the company entered into a strategic collaboration agreement with Thermo Fisher Scientific Inc. (Thermo Fisher) with the focus of advancing the fundamental knowledge of cell therapy industrialization and to improve quality control of the supply chain. The collaboration enables the company to combine Thermo Fisher’s experience in cell therapy development and bioproduction scaleup with its focus in cell therapy manufacturing, clinical development, and quality control.

Chart Industries: In 2018, the company entered into a license agreement with a subsidiary of Chart Industries, Inc. (Chart) regarding its thawing device for cell-based therapies. Pursuant to the terms of the agreement, Chart obtained the exclusive rights to manufacture and market the thawing device in all territories worldwide, excluding Greater China, and the company is to receive royalties from sales of the product and supply of an agreed upon number of thawing devices. Royalties shall commence on the date of Chart’s first commercial sale of the thawing device.

NASA: In 2019, the company entered a collaboration with NASA’s Ames Research Center to evaluate the potential of its PLX cell therapies in preventing and treating medical conditions caused during space missions.

The U.S. Department of Defense: In 2017, the company announced that a pilot study of its PLX-R18 cell therapy was initiated by the DoD. The study examined the effectiveness of PLX-R18 as a treatment for ARS prior to, and within the first 24 hours of exposure to radiation. In 2019, the company presented positive results from a series of studies of its PLX-R18 cell therapy product conducted by the DoD.

CRISPR-IL: In June 2020, the company announced that it was selected as a member of the CRISPR-IL consortium, a group funded by the IIA. In August 2021, the company submitted an additional budget for the Second Period. The CRISPR-IL consortium program does not require the company to pay royalties to the IIA.

Research and Development

The company’s research and development net costs were $30,066,000 for the year ended June 30, 2021.

Government Regulation

In the United States, the company’s product candidates are subject to regulation as a biological product under the Public Health Service Act and the Federal Food, Drug and Cosmetic Act.

In the European Union, the company’s investigational cellular products are regulated under the Advanced Therapy Medicinal Product regulation, a regulation specific to cell and tissue products.

In Japan, the company has completed the required regulatory interactions with the Japan’s Pharmaceuticals and Medical Devices Agency, prior to the submission of clinical study notification, in the framework of the new regulations for regenerative therapy effective in November 2014, which promote expedited approval for regenerative therapies that are being developed for seriously debilitating/life-threatening indications.

History

The company was founded in 2001. It was incorporated as a Nevada corporation in 2001. The company was formerly known as Pluristem Therapeutics Inc. and changed its name to Pluri Inc. in July 2022.