What changed in this filing

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Item 1. Business

2020-09-10 compared with 2019-09-12 · 330 added, 293 removed, 410 unchanged (60% of the section changed)

Current Business

Therapeutics Inc.

is a leading developer of placenta-based cell therapy product candidates for the treatment of multiple ischemic,

inflammatory and hematologic conditions.

Our lead indications are critical limb ischemia, or CLI, muscle recovery following surgery

for hip fracture, and acute radiation syndrome, or ARS.

Each of these indications is a severe unmet medical need.

We were incorporated

in Nevada in 2001, and have a wholly owned subsidiary in Israel called Pluristem Ltd.

We operate in one segment and our operations

are focused on the research, development, clinical trials and manufacturing of cell therapeutics and related technologies.

cells are derived from a class of placental cells that are harvested from donated placenta at the time of full term healthy delivery

PLX cell products require no tissue matching prior to administration.

They are produced using our proprietary three-dimensional

expansion technology.

Our manufacturing facility complies with the European, Japanese, Israeli, South Korean and U.S.

Drug Administration, or FDA’s, current Good Manufacturing Practice requirements and has been approved by the European and

Israeli regulators for production of PLX-PAD for late stage trials.

In December 2017, after an audit of our facilities, we were

granted manufacturer/importer authorization and Good Manufacturing Practice Certification by Israel’s Ministry of Health.

If we obtain FDA and other regulatory approvals to market PLX cells, we expect to have in-house production capacity to grow clinical-grade

PLX cells in commercial quantities.

goal is to make significant progress with our clinical pipeline and our clinical pivotal trials in order to ultimately bring innovative,

are a leading developer of placenta-based cell therapy product candidates for the treatment of multiple ischemic, inflammatory

and hematologic conditions.

Our operations are focused on the research, development, manufacturing, conducting clinical trials

and business development of cell therapeutics and related technologies.

We are currently enrolling patients in

two Phase III studies:

one for critical limb ischemia, or CLI, and another for muscle recovery following surgery for hip fracture.

In addition, we are focusing on other indications such as acute radiation syndrome, or ARS, incomplete recovery following bone

marrow transplantation, Steroid-Refractory Chronic Graft Versus Host Disease, or cGVHD, and intermittent claudication, or IC.

received clearance from the U.S.

Food and Drug Administration, or the FDA, and the German health regulatory agency, the Paul Ehrlich

Institute, or the PEI, to conduct a Phase II study evaluating PLX cells for the treatment of severe cases of the COVID-19 coronavirus,

or COVID-19, complicated by Acute Respiratory Distress Syndrome, or ARDS.

We have treated several patients in Israel and in the

United States suffering from severe ARDS associated with COVID-19 under a compassionate use program.

In addition, the FDA has cleared

our Expanded Access Program, or EAP, for the use of our PLX-PAD cells to treat up to 100 patients suffering from ARDS caused by

COVID-19 outside of our ongoing Phase II COVID-19 study in the U.S.

We believe that each of these indications is a severe unmet

medical need.

PLX cells are derived from a class of

placental cells that are harvested from donated placenta at the time of full term healthy delivery of a baby.

PLX cell products

require no tissue or blood matching prior to administration.

They are produced using our proprietary three-dimensional expansion

Our manufacturing facility complies with the European, Japanese, Israeli, South Korean and the FDA’s current

Good Manufacturing Practice, or cGMP, requirements and has been inspected and approved by the European and Israeli regulators for

production of PLX-PAD for late stage trials.

We have also granted manufacturer/importer authorization and cGMP Certification by

Israel’s Ministry of Health.

If we obtain FDA and other regulatory approvals to market PLX cells, we expect to have in-house

production capacity to grow PLX cells in commercial quantities.

Research and Development - In-House Clinical

Manufacturing”

for additional information.

goal is to make significant progress with our clinical pipeline and our clinical trials in order to ultimately bring innovative,

potent therapies to patients who need new treatment options.

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includes, but is not limited to, direct sale of our products, partnerships, licensing deals, and joint ventures with pharmaceutical

aim to shorten the time to commercialization of our product candidates by leveraging unique accelerated regulatory pathways that

exist in the United States, Europe and other territories to bring innovative products that address life-threatening diseases to

the market efficiently.

We believe that these accelerated pathways create substantial opportunities for us and for the cell therapy

industry as a whole.

have determined to invest our resources primarily on the PLX-PAD Phase III clinical trials relating to CLI and muscle recovery

following surgery for hip fracture, and focus on finalizing the clinical trials in the United States, Europe and Israel while

we prepare for the marketing phase, with the initiation of such marketing phase subject to regulatory approval, in these territories.

pivotal, Phase III multinational clinical trials are currently being conducted with our PLX-PAD product candidate:

and the other in muscle recovery following surgery for hip fracture.

In April 2019, we successfully enrolled over 50% of patients

in our Phase III study in CLI, which allows for an interim analysis of efficacy after a one-year follow-up period under the European

Medicines Agency’s, or EMA, Adaptive Pathways pilot project, or the Adaptive Pathways Project, in which PLX-PAD was selected

to participate.

Based on our current patient enrollment progress, we expect to complete the follow up of our Phase III study in

CLI in the first half of 2020 with respect to Europe, and in the first half of 2021 with respect to the United States.

based on our current patient enrollment progress, we expect to complete the efficacy follow up of our Phase III study in muscle

recovery following surgery for hip fracture in the second half of 2020.

We expect to release the clinical trial results shortly

after the conclusion of the follow ups.

PLX-PAD cell program in CLI had been selected for the EMA’s Adaptive Pathways Project, Japan’s Pharmaceuticals and

Medical Devices Agency, or PMDA, accelerated pathway, the FDA Fast Track Designation and FDA Expanded Access Program, or EAP,

in the United States.

The CLI program in the European Union was awarded a Euro 7,600,000 (approximately $8,700,000) grant as part

of the European Union’s Horizon 2020 program and to date we have received a portion of such grant.

PLX-PAD cell program in muscle recovery following surgery for hip fracture was also selected for the EMA’s Adaptive Pathways

Project and was awarded a Euro 7,400,000 (approximately $8,400,000) grant as part of the European Union’s Horizon 2020 program

and to date we have received a portion of such grant.

second product candidate, PLX-R18, is under development in the United States for ARS via the FDA Animal Rule regulatory pathway,

and, based on our assessment, is expected to advance to a pivotal trial, which may also result in approval without the prior performance

of human efficacy trials.

The National Institutes of Health’s National Institute of Allergy and Infectious Diseases has

completed a dose selection trial with our PLX-R18 product candidate in the hematologic component of ARS.

We are targeting to submit

a proposal for a contract with the U.S.

government in the second half of 2019 to fund an additional non-human primates, or NHPs

We are also targeting to receive funding from BARDA for the full cost of the ARS pivotal trial during 2020.

is also under development in the United States and Israel for the treatment of incomplete hematopoietic recovery following hematopoietic

cell transplantation, or HCT.

In March 2019, we announced that we had fully enrolled the second cohort of six patients in our

ongoing Phase I clinical trial in HCT, and received data and safety monitoring board approval to continue to the final cohort

of the trial.

In September 2018, we announced that the FDA granted orphan drug designation to our PLX cell therapy for the treatment

of graft failure and incomplete hematopoietic recovery following HCT.

were incorporated in Nevada in 2001, and we have a wholly owned subsidiary in Israel called Pluristem Ltd.

and a wholly owned

subsidiary in Germany called Pluristem GmbH.

therapy is an emerging field within the regenerative medicine area.

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allogeneic products.

develop, and intend to commercialize, cell therapy production technologies and products that are derived from the human placenta.

We develop, and intend to commercialize,

cell therapy production technologies and products that are derived from the human placenta after a full term delivery of a healthy

Our PLX cells are adherent stromal cells, or ASCs, that are expanded using a proprietary 3D process.

This system utilizes a synthetic

scaffold to create an artificial 3D environment where placental-derived stromal cells can grow.

Our 3D process enables the large-scale

monitored and controlled production of reproducible, high quality cell products and is capable of manufacturing a large number

of PLX doses originating from different placentas.

Additionally, our manufacturing process has demonstrated batch-to-batch consistency,

an important manufacturing challenge for biological products.

This system utilizes

a synthetic scaffold to create an artificial 3D environment where placental-derived stromal cells can grow.

Our automated proprietary

3D, cGMP approved, process enables the large-scale monitored and controlled production of reproducible, high quality cell products

and is capable of manufacturing a large number of PLX doses originating from different placentas.

Additionally, our current manufacturing

process, which has scaled up as compared to previous years, has demonstrated batch-to-batch consistency, an important manufacturing

challenge for biological products.

primary objective is to be the leading provider of allogeneic placenta based cell therapy products that are true off-the-shelf

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Our PLX products are in clinical stage development for multiple indications.

first product candidate, PLX-PAD, is currently in a Phase III multinational clinical trial in CLI, and in a Phase III multinational

clinical trial in recovery following surgery for hip fracture.

We have also completed Phase II multinational clinical trial in

intermittent claudication, or IC, and a Phase I/II is currently conducted with our PLX-PAD by Tel Aviv Sourasky Medical Center

(Ichilov Hospital) for the treatment of Steroid-Refractory Chronic Graft-Versus-Host-Disease.

first product candidate, PLX-PAD, is currently in a Phase III multinational clinical trial in CLI, in a Phase III multinational

clinical trial in recovery following surgery for hip fracture, and in a Phase II clinical trial in the treatment of severe COVID-19

cases complicated by ARDS.

We have also completed Phase II multinational clinical trial in IC and a Phase I/II is currently conducted

with our PLX-PAD by Tel Aviv Sourasky Medical Center (Ichilov Hospital) for the treatment of Steroid-Refractory cGVHD.

second product candidate, PLX-R18, is under development in the United States for ARS via the FDA Animal Rule regulatory pathway,

as well as in a Phase I trial in the United States and Israel for incomplete hematopoietic recovery following HCT.

third product candidate, PLX-Immune is under pre-clinical development for treatment of certain types of human cancer.

as well as in a Phase I trial in the United States and Israel for incomplete hematopoietic recovery following hematopoietic cell

transplantation, or HCT.

We developed an additional product candidate,

PLX-Immune, which is under pre-clinical development for treatment of certain types of human cancer.

In January 2018, we announced

the publication of a peer-reviewed article in a journal which examined the effect of PLX-Immune cells on the proliferation of over

50 lines of human cancerous cells.

Data showed that the PLX-Immune cells exhibited an anti-proliferative effect on a wide range

of human cancer cell types, with a strong inhibitory effect on various lines of breast, colorectal, kidney, liver, lung, muscle

and skin cancers.

We have also conducted a pre-clinical trial of female mice harboring human triple negative breast cancer.

this study, the results showed a statistically significant reduction in tumor size as well as complete tumor remission in 30% of

treated recipients.

believe that using the placenta as a unique cell source, combined with our innovative research, development and high-quality manufacturing

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Clinical Development Product Candidates

and Cardiovascular Diseases –

We are investigating the use of PLX-PAD cells for the treatment of various stages of peripheral

arterial disease, or PAD, from early stage IC to advanced CLI.

Peripheral and Cardiovascular Diseases

Peripheral and Cardiovascular Diseases –

We are investigating the use of PLX-PAD cells for the treatment of peripheral

arterial disease, or PAD, including IC and CLI.

May 2015, our CLI clinical development program was selected for the EMA’s Adaptive Pathways Project.

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treatment of CLI.

intention is to file a request for marketing authorization in the United States and in Europe following a successful completion

of this 246-patient trial.

In April 2019, we successfully enrolled over 50% of patients in our Phase III study in CLI, which allows

for an interim analysis of efficacy after a one-year follow-up period.

If the interim analysis yields positive results, it could

lead to early conditional marketing approval in Europe.

January 2018, we announced that the FDA cleared our EAP for the use of our PLX-PAD cell treatment in patients with CLI.

2018, we announced that the FDA approved cost recovery for our PLX-PAD under an EAP held by Wide Trial, Inc., or Wide Trial, a

privately-held third-party sponsor.

In April 2019, we announced the initiation of our FDA approved EAP, with several site initiations

in the United States.

Under the terms of the EAP, an initial cohort of 100 Rutherford-5 CLI patients who are ineligible for inclusion

under our ongoing Phase III study protocol can be enrolled and treated.

the FDA’s and EMA’s advice and recommendations, we implemented the following items into the study design and the interim

data readout:

primary endpoint for the interim analysis will be identical to the full study endpoint, a comparison between the PLX-PAD treated

group and the placebo treated group of the number of days from randomization to occurrence of major amputation of the index leg

full study analysis will be based on 82 events.

Each event is defined as occurrence of major amputation of the index leg or death

while the interim readout will be conducted based on a minimum of 45 events, which have already occurred.

FDA cleared our EAP for the use of our PLX-PAD cell treatment in patients with CLI and we initiated the EAP in April 2019.

the terms of the EAP, an initial cohort of 100 Rutherford-5 CLI patients who are ineligible for inclusion under our ongoing Phase

III study protocol can be enrolled and treated.

have completed two Phase I safety/dose-escalating clinical trials for CLI, one in the United States and one in Germany.

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readiness, we have not initiated clinical trial activities in Japan.

Diseases –

In April 2018, we announced that the FDA cleared our Investigational New Drug, or IND, for our Phase III

trial for recovery following surgery for hip fracture.

This multinational Phase III trial is being conducted in the United States,

Europe and Israel.

The EMA confirmed that recovery following surgery for hip fracture is eligible for the Adaptive Pathways Project

Indications –

In April 2018, we announced that the FDA cleared our IND for our Phase III trial for recovery following

surgery for hip fracture.

This multinational Phase III trial is being conducted in the United States, Europe and Israel.

confirmed that recovery following surgery for hip fracture is eligible for the Adaptive Pathways Project as well.

Phase III trial protocol and design was based on our phase I/II, randomized, double-blind, placebo-controlled study (n=20) to

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In addition, the study demonstrated that PLX-PAD was safe and well tolerated by the patients.

COVID-19 Complicated by ARDS –

In May 2020, the FDA cleared our IND application for the Phase II study of our PLX cells in the treatment of severe COVID-19 cases

complicated by ARDS and we initiated the study in June 2020.

The U.S trail is randomized, double-blind, placebo-controlled, multicenter,

parallel-group 140 patient study is evaluating the efficacy and safety of intramuscular 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 main 28-day

study period.

Safety and survival follow-up will be conducted at week 8, 26 and 52.

Secondary efficacy endpoints include all-cause

mortality, duration of mechanical ventilation, ICU free-days, and hospitalization free-days.

In addition, the FDA has cleared our

EAP for the use of our PLX-PAD cells to treat ARDS caused by COVID-19 outside of our ongoing Phase II COVID-19 study in the U.S.

The EAP will include up to 100 patients with the resulting data being collected and evaluated alongside our existing clinical trial

In August 2020, the PEI cleared our 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.

Forty patients hospitalized with severe cases of COVID-19 complicated

by ARDS will be enrolled in the study.

The primary efficacy endpoint of the study is the number of ventilator free days during

the 28 days from day 1 through day 28 of the study.

Safety and survival follow-up will be conducted at day 60, week 26 and week

Following HCT –

In March 2015, we reported positive data from three independent preclinical trials of PLX-R18.

Results from these trials, as well as those from nineteen prior studies conducted by the NIAID, Case Western University, Cleveland,

Ohio, and Hadassah Medical Center, Jerusalem, Israel, collectively suggest that PLX-R18 is safe and may improve outcomes after

bone marrow failure and/or support hematopoietic cell transplantation.

Data collected on the mechanism of action show that PLX-R18

acts by enhancing production of platelets and white and red blood cells in cases of severely damaged bone marrow, and may also

accelerate engraftment of transplanted hematopoietic cells.

In February 2018, we announced that a peer-reviewed journal published

key animal findings from a study of PLX-R18 that demonstrate the cells’

efficacy in improving human hematopoietic engraftment.

With these capabilities, PLX-R18 could potentially treat a broad range of indications related to bone marrow function which, taken

together, constitute a substantial global market.

is under development in a Phase I clinical trial in the United States and Israel for incomplete hematopoietic recovery following

HCT, which was initiated in fiscal year 2017.

PLX-R18 is also under development in the United States and Israel for the treatment of incomplete

hematopoietic recovery following HCT.

This Phase I study of PLX-R18 in HCT, as previously announced, has successfully enrolled

20 patients in the United States and Israel.

We expect to provide top line efficacy results in the first quarter of calendar 2021.

In addition, the FDA granted orphan drug designation to our PLX cell therapy for the treatment of graft failure and incomplete

hematopoietic recovery following HCT.

We have conducted several animal studies for the evaluation of PLX-R18 for the treatment of ARS, in collaboration

with the NIAID.

National Institutes of Health, or NIH, funded and conducted a pilot study in NHPs to evaluate the therapeutic

effect of PLX-R18 on hematological aspects of ARS.

In May 2017, we announced results of the NHPs pilot study for PLX-R18 as a

treatment for ARS.

Although study size was not designed to show significance, results showed a trend toward improved survival

of PLX-R18 treated animals compared to control, placebo treated animals.

The study, conducted and funded by the NIAID, was designed

to assess the safety and efficacy of PLX-R18 following intramuscular injection into irradiated and non-irradiated NHPs.

measures included survival as well as hematological parameters which are affected by exposure to high levels of radiation as may

occur in a nuclear accident or attack.

These data will help the design of a pivotal study to fulfill the requirements for a Biologics

License Application submission under the FDA’s Animal Rule regulatory pathway.

with the National Institute of Allergy and Infectious Diseases, or the NIAID.

National Institutes of Health, or NIH,

funded and conducted a pilot study in NHPs to evaluate the therapeutic effect of PLX-R18 on hematological aspects of ARS.

2017, we announced results of the NHPs pilot study for PLX-R18 as a treatment for ARS.

Although study size was not designed to

show significance, results showed a trend toward improved survival of PLX-R18 treated animals compared to control, placebo treated

The study, conducted and funded by the NIAID, was designed to assess the safety and efficacy of PLX-R18 following intramuscular

injection into irradiated and non-irradiated NHPs.

Efficacy measures included survival as well as hematological parameters which

are affected by exposure to high levels of radiation as may occur in a nuclear accident or attack.

These data will help the design

of a pivotal study to fulfill the requirements for a Biologics License Application, or BLA, submission under the FDA’s Animal

Rule regulatory pathway.

plan to continue the discussions with the different government agencies with the goal of receiving their support for pivotal studies

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in the treated group.

In addition, the data show an increase in recovery of blood lineages and a favorable safety profile.

In addition, the data shows an increase in recovery of blood lineages and a favorable safety profile.

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.

Indications –

In September 2017, we signed an agreement with Tel Aviv Sourasky Medical Center (Ichilov Hospital) to

conduct a clinical Phase I/II trial of PLX-PAD cell therapy for the treatment of Steroid-Refractory Chronic Graft-Versus-Host-Disease.

Steroid-Refractory

cGVHD –

In September 2017, we signed

an agreement with Tel Aviv Sourasky Medical Center (Ichilov Hospital) to conduct a clinical Phase I/II trial of PLX-PAD cell therapy

for the treatment of Steroid-Refractory cGVHD.

This trial is an investigator initiated study.

As such, Tel Aviv Sourasky Medical Center supports the study and is responsible

for its design and implementation.

January 2018, we announced the publication of a peer-reviewed article in a journal which examined the effect of PLX-Immune cells

on the proliferation of over 50 lines of human cancerous cells.

Data showed that the PLX-Immune cells exhibited an anti-proliferative

effect on a wide range of human cancer cell types, with a strong inhibitory effect on various lines of breast, colorectal, kidney,

liver, lung, muscle and skin cancers.

We have also conducted a pre-clinical trial of female mice harboring human triple negative

breast cancer.

In this study, the results showed a statistically significant reduction in tumor size as well as complete tumor

remission in 30% of treated recipients.

June 2018, we announced that we entered into collaboration with the U.S.

DoD and its United States Army Medical Research Institute

of Chemical Defense to study PLX-R18 in the treatment of long term lung injuries following exposure to mustard gas.

These non-clinical

trials will be funded by the NIH.

January 2019, we announced a successful one-year follow up of a compassionate use treatment in a Buerger’s disease patient

treated with our PLX-PAD cell therapy.

As such, Tel Aviv Sourasky Medical

Center supports the study and is responsible for its design and implementation.

and Clinical Affairs Strategy

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We utilize this strategy in working with the FDA, the EMA, Germany’s PEI as well

as other European national competent authorities, the Israeli Minister of Health, or MOH and Japan’s PMDA, and we are also

working with the Ministry of Food and Drug Safety, or MFDS, of South Korea authority via our collaborator, CHA.

as other European national competent authorities, the Israeli Ministry of Health, or MOH and Japan’s PMDA, and we are also

working with the Ministry of Food and Drug Safety, or MFDS, of South Korea.

Adaptive Pathways Project is part of the EMA’s efforts to improve timely access for patients to new therapies.

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The pilot is open to clinical programs in early stages of development only.

After a therapy is selected for the program, the Adaptive Pathways Project’s discussion group provides detailed guidance

to the applicant regarding the formal regulatory processes that precede a trial targeting early approval and further expansion

of the indications.

We have applied early to this program and have been selected for it.

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January 2018, we announced that the FDA cleared our EAP for the use of our PLX-PAD cell treatment in patients with CLI.

2018, we announced that the FDA approved cost recovery for our PLX-PAD under an EAP held by Wide Trial, a privately-held third-party

EAP allows the use of an investigational medical product outside of clinical trials and is usually granted in cases where

patients are unsuitable for inclusion under the study protocol and the patient’s condition is life-threatening with an unmet

medical need.

As part of the EAP, our PLX-PAD cell therapy is available to a limited number of CLI patients in the United States

who are unsuitable for revascularization and cannot take part in the our ongoing Phase III clinical trial.

the use of an investigational medical product outside of clinical trials and is usually granted in cases where patients are unsuitable

for inclusion under the study protocol and the patient’s condition is life-threatening with an unmet medical need.

of the EAP, our PLX-PAD cell therapy is available to a limited number of CLI patients in the United States who are unsuitable

for revascularization and cannot take part in our ongoing Phase III clinical trial.

August 2020, we announced that the FDA cleared our EAP for the use of our PLX-PAD cells to treat ARDS caused by COVID-19 outside

of our ongoing Phase II COVID-19 study in the U.S.

The program provides a pathway for patients that are not eligible for inclusion

in the Phase II clinical trial to be treated with PLX-PAD cells and will include up to 100 patients.

The resulting data will be

collected and evaluated alongside our existing clinical trial.

Impact of COVID-19 - In managing our ongoing global clinical

trials, as well as our daily operations, in the midst of the COVID-19 global pandemic, we are taking all necessary precautions

for the safety and well-being of patients, healthcare providers involved in our trials, and our employees.

We are continuing our

operational and manufacturing activities, subject to the directives of the Israeli Ministry of Health, with a dedicated team on

site at our facilities.

In addition, we are using remote work technologies that enable other activities to be conducted without

the need for a physical presence in our facilities.

Our allogenic, off-the-shelf approach and our advanced manufacturing capabilities

enabled us to complete the manufacturing of the entire stock of PLX cells needed to complete all of our current clinical trials

We currently hold supplies of PLX cells in inventory in Israel, and in secure storage facilities in Europe and the U.S.

In addition, we are following the FDA and EMA guidelines regarding the management of clinical trials during COVID-19

understand that our success will depend, in part, on maintaining our intellectual property, and therefore we are committed to

protecting our technology and product candidates with patents and other methods described below.

are the sole owner of 139 issued patents and 89 pending patent applications in the United States, Europe, China and Japan, as

well as in additional countries worldwide, including Israel, 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).

are the sole owner of 128 issued patents and approximately 60 pending patent applications in the United States, Europe, China

and Japan, as well as in additional countries worldwide, including Israel, 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).

April 2016, the Subsidiary entered into a licensing agreement with TES Holdings Co., Ltd., a venture company derived from the

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produced from placental tissue using these methods.

February 2017, the Subsidiary signed an agreement with founders of a certain patent for a five year option to purchase the certain

February 2017, Pluristem Ltd.

signed an agreement with founders of a certain patent for a five year option to purchase the certain

patent for an amount of 1 million Euro.

The agreement includes yearly payments of Euro 75,000, 75,000 and 100,000 in February

2017, 2018 and 2019, respectively, which have been paid.

We are entitled to terminate the agreement for convenience upon providing

the founders 30 days prior notice.

May 2019, we filed a U.S.

The agreement includes yearly payments of Euro 75,000, Euro 75,000 and Euro 100,000 in

February 2017, 2018 and 2019, respectively, which have been paid.

We are entitled to terminate the agreement for convenience upon

providing the founders 30 days prior notice.

April 2019, we filed a U.S.

provisional patent application titled “Methods and Compositions for Producing Cannabinoids,”

which covers the use of our state-of-the-art, proprietary 3-D cell culturing technology for the potential manufacturing of cannabinoid-producing

In April 2020, we filed a Patent Cooperation Treaty, or PCT, application with respect to the technology.

March 2020, we filed a U.S.

provisional patent application titled “Methods and Compositions for Treating Viral Infections

and Sequelae Thereof,”

which covers the use of placental ASC for treating coronavirus infections and sequelae thereof.

May 2020, a related Israeli patent application was filed.

on the well-established understanding that the characteristics and therapeutic potential of a cell product are largely determined

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to assign to us inventions conceived during the course of performing services for us.

following table provides a description of our key patents and patent applications and is not intended to represent an assessment

of claims, limitations or scope.

following table sets forth our key patents and patent applications and is not intended to represent an assessment of claims, limitations

In some cases, a jurisdiction is listed as both pending and granted for a single patent family.

This is due to pending continuation or divisional applications of the granted case.

This is due to pending

continuation or divisional applications of the granted case.

is a risk that our patents will be invalidated, and that our pending patent applications will not result in issued patents.

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Jurisdictions

AND APPARATUS FOR MAINTENANCE AND EXPANSION OF HAEMATOPOIETIC STEM CELLS AND/OR PROGENITOR

AND APPARATUS FOR MAINTENANCE AND EXPANSION OF HAEMATOPOIETIC STEM CELLS AND/OR PROGENITOR CELLS

PCT/US2000/02688

States, Mexico, New Zealand

6, 2020 (245 days patent term adjustment)

FOR CELL EXPANSION AND USES OF CELLS AND CONDITIONED MEDIA PRODUCED THEREBY FOR THERAPY

PCT/IL2007/000380

States, China, Hong Kong, Canada, Brazil

Europe, Israel, Singapore, Russia, South Africa, Australia, India, South Korea, Mexico, Hong Kong, China

Canada, China, Hong Kong, Europe, Israel, India, Japan, South Korea, Mexico, Russia, Singapore

CELLS FROM PLACENTA TISSUE AND USE THEREOF IN THERAPY

PCT/IL2008/001185

States, Europe, Israel, China, Hong Kong, Brazil, Russia

States, Europe, Singapore, Australia, Hong Kong, South Africa, India, Mexico, Japan, South Korea, Canada, China, Israel

States, Brazil, China, Israel

Canada, China, Europe, Hong Kong, Israel, India, Japan, Mexico, Russia, Singapore, USA, South Africa, South Korea

OF TREATING INFLAMMATORY COLON DISEASES

PCT/IL2009/000527

States, Israel, Russia, South Africa

States, Israel, Russia

OF SELECTION OF CELLS FOR TRANSPLANTATION

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PCT/IL2009/000846

States, Russia, Australia, South Africa, Mexico, Europe, Canada, Singapore, Hong Kong, Israel, India

Canada, Europe, Hong Kong, Israel, India, Mexico, Russia, Singapore, USA, South Africa

CELLS FROM PLACENTA TISSUE AND USE THEREOF IN THERAPY

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PCT/IB2011/001413

Europe, Hong Kong

April 21, 2031

March 22, 2027

CELLS FROM PLACENTA AND USE OF SAME IN DISEASE TREATMENT

PCT/IB2010/003219

States, China, Israel, India

States, Europe, China, Canada, Australia, New Zealand, South Africa, Hong-Kong, Mexico, Israel

States, China, Israel

Canada, China Hong Kong, Europe, Israel, Mexico, New Zealand, United States, South Africa

AND SYSTEMS FOR HARVESTING ADHERENT STROMAL CELLS

PCT/IB2012/000933

States, China, Europe, Hong Kong, Israel, India

States, Canada, Israel, Australia, Mexico, Singapore, South Africa, South Korea

Israel, United States

Canada, Europe, Israel, India, South Korea, Mexico, Singapore, United States

FOR TREATING RADIATION OR CHEMICAL INJURY

PCT/IB2012/000664

States, Hong Kong, Israel

Japan, South Korea, Israel, Hong Kong, Israel

Hong Kong, Israel, Japan, South Korea, United States

MUSCLE REGENERATION USING MESENCHYMAL STEM CELLS

PCT/EP2011/058730

States, Europe, Israel, Hong Kong

AND PROTEIN EXPRESSION PROPERTIES OF ADHERENT STROMAL CELLS CULTURED IN 3D PCT/IB2014/059114

AND METHODS FOR CULTURE OF CELLS PCT/IB2013/058184

States, Canada, China, Israel, Japan, Singapore, Australia, Hong Kong, South Korea, Russia, Mexico

States, Europe, Israel

AND PROTEIN EXPRESSION PROPERTIES OF ADHERENT STROMAL CELLS CULTURED IN 3D

PCT/IB2014/059114

United States

AND METHODS FOR CULTURE OF CELLS

PCT/IB2013/058184

States, Israel

FOR PREVENTION AND TREATMENT OF PREECLAMPSIA

PCT/IB2013/058186

Singapore, Hong Kong

States, Europe, China, Australia, South Africa, Japan, Korea,

Hong Kong, Europe, Israel, Japan, South Korea, United States, South Africa

AND DEVICE FOR THAWING BIOLOGICAL MATERIAL

PCT/IB2013/059808

China, South Korea, Canada, Israel, Hong Kong

States, Australia, Singapore, Japan, India, Russia

Europe, Israel, India, Japan, South Korea, Russia, Singapore, United States

AND METHODS FOR GROWING AND HARVESTING CELLS PCT/IB2015/051559

States, Europe

AND COMPOSITIONS FOR TREATING AND PREVENTING MUSCLE WASTING DISORDERS

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PCT/IB2017/050868

States, Europe, Japan, Canada, Australia, Israel

States, Japan, Canada, Australia, Israel

AND COMPOSITIONS FOR TREATING NEUROLOGICAL DISORDERS

PCT/IB2018/052806

Cooperation Treaty

United States

AND COMPOSITIONS FOR TUMOR ASSESSMENT

3 unchanged sentences

PCT/IB2018/055473

Cooperation Treaty

United States

AND COMPOSITIONS FOR DETACHING ADHERENT CELLS

10 2018 115 360.0

States, Israel, Germany

25-July 3, 2038

CONTAINING HUMAN PLACENTA-ORIGIN MESENCHYMAL CELLS AND PROCESS FOR PRODUCING VEGF USING THE CELLS JP20030579842

AND COMPOSITIONS FOR PRODUCING CANNABINOIDS

Cooperation Treaty

FOR EXPANDING ADHERENT STROMAL CELLS AND CELLS OBTAINED THEREBY

PCT/IB2019/052569

Cooperation Treaty

AND COMPOSITIONS FOR TREATING SUBJECTS EXPOSED TO VESICANTS AND OTHER CHEMICAL AGENTS

PCT/IB2019/055074

Cooperation Treaty

AND COMPOSITIONS FOR FORMULATING AND DISPENSING PHARMACEUTICAL FORMULATIONS

PCT/IB2019/053115

Cooperation Treaty;

International:

April 16, 2039

April 26, 2038

DOSAGE REGIMENS COMPRISING ADHERENT STROMAL CELLS

PCT/IB2019/054828

Cooperation Treaty

PCT/IB2019/058429

Cooperation Treaty

METHODS AND COMPOSITIONS

PCT/IB2019/059544

Cooperation Treaty

AND COMPOSITIONS FOR TREATING VIRAL INFECTIONS AND SEQUELAE THEREOF

States (provisional)

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Charité

July 2007, we entered into a five-year collaborative research agreement with the Berlin-Brandenburg Center for Regenerative Therapies

at Charité

- University Medicine Berlin, or Charité.

In August 2012, we extended our collaborative research agreement

with Charité

for a period of five years through 2017.

In June 2017, we extended our collaborative research agreement with

Charité

for a period of additional five 5 years, through June 2022.

In July 2007, we entered into a five-year

collaborative research agreement with the Berlin-Brandenburg Center for Regenerative Therapies at Charité

- University Medicine

Berlin, or Charité, which was extended from time to time through June 2022.

We and Charité

are collaborating on a variety

of indications utilizing PLX cells.

According to the agreement, we will be the exclusive owner of the technology and any products

produced as a result of the collaboration.

are collaborating on a

variety of indications utilizing PLX cells.

According to the agreement, we will be the exclusive owner of the technology and any

products produced as a result of the collaboration.

Charité

will receive between 1% to 2% royalties from new developments that have

been achieved during the joint development.

will receive between 1% to 2% royalties from net sales of new

developments that have been achieved during the joint development.

March 2020, we announced that we had signed a collaborative agreement with the BIH Center for Regenerative Therapy and the Berlin

Center for Advanced Therapies at Charité

University of Medicine Berlin to expand our existing framework and research agreement

and conduct a joint project evaluating the therapeutic effects of our patented PLX cell product candidates for potential treatment

of the respiratory and inflammatory complications associated with COVID-19.

Medical University

signed an MOU for a collaboration with Fukushima Medical University, Fukushima Global Medical Science Center.

The purpose of the

collaboration is to develop Pluristem’s PLX-R18 cells for the treatment of ARS, and for morbidities following radiotherapy in

cancer patients.

The collaboration will proceed alongside research supported by the NIH, which is studying PLX-R18 as a potential

treatment for the hematologic component of ARS.

The MOU for a collaboration with Fukushima will be renewed automatically on a

yearly basis.

Each party is entitled to terminate the agreement for convenience upon providing the other party 30 days prior notice.

June 26, 2013, we entered into an exclusive out-licensing and commercialization agreement, or the CHA Agreement, with CHA Biotech

Ltd., or CHA, for conducting clinical trials and commercialization of our PLX-PAD product in South Korea in connection with

two indications:

signed a memorandum of understanding, or MOU, for a collaboration with Fukushima Medical University, Fukushima Global Medical

Science Center.

The purpose of the collaboration is to develop Pluristem’s PLX-R18 cells for the treatment of ARS, and for morbidities

following radiotherapy in cancer patients.

The collaboration will proceed alongside research supported by the NIH, which is studying

PLX-R18 as a potential treatment for the hematologic component of ARS.

The MOU for a collaboration with Fukushima will be renewed

automatically on a yearly basis.

Each party is entitled to terminate the agreement for convenience upon providing the other party

30 days prior notice.

June 26, 2013, we entered into an exclusive out-licensing and commercialization agreement, or the CHA Agreement, with CHA for

conducting clinical trials and commercialization of our PLX-PAD product candidate in South Korea in connection with two indications:

the treatment of CLI and IC.

We will continue to retain rights to our proprietary manufacturing technology and

cell-related intellectual property.

We will continue

to retain rights to our proprietary manufacturing technology and cell-related intellectual property.

first clinical trial that was performed as part of the CHA Agreement was a Phase II trial in IC.

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commercial sale of the thawing device.

injuries joint grant

January 2019, we announced the receipt of a joint grant awarded by the Israeli Ministry of Defense and the IIA for the pre-clinical

development of our PLX cells for the treatment of burn injuries.

We have decided to suspend this current collaboration in the

near term, as we focus our attention on our on-going Phase III clinical trials.

February 2019, we entered into a collaboration with NASA’s Ames Research Center to evaluate the potential of our PLX cell

therapies in preventing and treating medical conditions caused during space missions.

Department of Defense

August 2017, we announced that a pilot study of our PLX-R18 cell therapy was initiated by the U.S.

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2019, we presented positive results from a series of studies of our PLX-R18 cell therapy product conducted by the U.S.

Duchenne Association

have performed proof of concept studies from April 2015 to December 2016 in conjunction with the Israeli Duchenne Association

to assess the utility of PLX-PAD in alleviating symptoms of Duchenne muscular dystrophy.

February 2019, we announced that the large-scale research initiative, the RESTORE project, of which we are a member, has received

funding of Euro 1,000,000 (approximately $1,100,000) from the European Union’s Horizon 2020 research and innovation program,

to submit a full grant application for the development and advancement of transformative therapeutics.

We expect the members of

the RESTORE project to collectively submit the grant application in the first quarter of the 2020 calendar year.

We plan to continue

to collaborate with universities and academic institutions and corporate partners worldwide to fully leverage our expertise and

explore the use of our cells in other indications.

are members of a large-scale research initiative, the RESTORE project which has received funding of Euro 1,000,000 (approximately

$1,100,000) from the European Union’s Horizon 2020 research and innovation program, to submit a full grant application for

the development and advancement of transformative therapeutics.

At this time, due to COVID-19, there is no open call for full

The members of the RESTORE project continue to collaborate in attempt to collectively submit the grant application once

such call is available.

June 2020, we announced that we were selected as a member of the CRISPR-IL consortium, a group funded by the IIA.

CRISPR-IL brings

together the leading experts in life science and computer science from academia, medicine, and industry, to develop AI based end-to-end

genome-editing solutions.

These next-generation, multi-species genome editing products for human, plant, and animal DNA, have

applications in the pharma, agriculture, and aquaculture industries.

CRISPR-IL is funded by the IIA with a total budget of approximately

$10,000,000 of which, an amount of approximately $480,000 is a direct grant allocated to us, for a period of 18 months, with a

potential for extension of an additional 18 months and additional budget from the IIA.

CRISPR-IL participants include leading

companies, and medical and academic institutions.

Arab Emirates-based Abu Dhabi Stem Cells Center

In August 2020, we signed a non-binding

MOU with the United Arab Emirates-based Abu Dhabi Stem Cells Center, a specialist healthcare center focused on cell therapy and

regenerative medicine.

The aim of the collaboration is to capitalize on each party’s respective areas of expertise in cell

The parties have agreed to exchange research results, share samples, join usage of equipment and testing, and other

essential activities related to advancing the treatment and research of cell therapies for a broad range of medical conditions,

including COVID-19.

plan to continue to collaborate with universities, academic institutions, and corporate partners worldwide to fully leverage our

expertise and explore the use of our cells in other indications.

Clinical Manufacturing

have the in-house capability to perform clinical cell manufacturing.

Our state-of-the-art GMP grade manufacturing facility in

Haifa has been in use since February 2013 for the main purpose of clinical grade, large-scale manufacturing.

The facility’s

new automated manufacturing process and products were approved for production of PLX-PAD for clinical use by the FDA, EMA, Korean

MFDS, PMDA and the Israeli MOH.

Our second product, PLX R18, was cleared by the FDA and the Israeli Ministry of Health for clinical

Furthermore, the site was inspected and approved by an EU qualified person (European accreditation body), approving that

the site and production processes meet the current GMP for the purpose of manufacturing clinical grade products.

site was also inspected and approved by Israel’s Ministry of Health and we received a GMP certification and manufacturer-importer

Our state-of-the-art Good Manufacturing Practice, or GMP,

grade manufacturing facility in Haifa has been in use since February 2013 for the main purpose of clinical grade, large-scale

manufacturing.

The facility’s new automated manufacturing process and products were approved for production of PLX-PAD for

clinical use by the FDA, EMA, Korean MFDS, PMDA and the Israeli MOH.

Our second product, PLX R18, was cleared by the FDA and the

Israeli Ministry of Health for clinical use.

Furthermore, the site was inspected and approved by an EU qualified person (European

accreditation body), approving that the site and production processes meet the current GMP for the purpose of manufacturing clinical

grade products.

site was also inspected and approved by Israel’s Ministry of Health and we received a cGMP Certification and manufacturer-importer

authorization.

Following the clinical approval of the facility, we are moving forward with our planned clinical trials based on

cells manufactured in the new, efficient and improved manufacturing processes.

obtain the human placentas used for our research and manufacturing activities from various hospitals in Israel after receiving

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Practice requirements to ensure their quality and reliability;

manufacture of the product according to GMP regulations and standards;

adequate and well-controlled human clinical trials in compliance with Good Clinical Practice,

or GCP, to establish the safety and efficacy of the product for its intended indication;

manufacture of the product according to GMP regulations and standards;

post-marketing clinical testing and surveillance of the product after marketing approval,

which can result in additional conditions on the approvals or suspension of clinical

of a drug for clinical trials in humans and approval of marketing are sovereign decisions of states, made by national, or, in

case of the European Union, international regulatory competent authorities.

of a drug for clinical trials in humans and approval of marketing are sovereign decisions

of states, made by national, or, in case of the European Union, international regulatory competent authorities.

Regulatory Process in the United States

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or for commercial sale:

of an Investigational New Drug Application, which must become effective before clinical

testing in humans can begin;

of an IND Application, which must become effective before clinical testing in humans

approval of Institutional Review Boards, or IRBs, of research institutions or other clinical

sites to introduce the drug candidate into humans in clinical trials;

may grant approval for EAP prior to the completion of clinical trials, in order to allow

access for the investigational drug, for patients that are excluded from the study.

may grant priority review status, in order to expedite the Biologics License Application,

or BLA, review process.

Obtaining of a Fast Track designation allows access for the request

of priority review.

may grant approval for EAP prior to the completion of clinical trials ,

in order to allow access for the investigational drug, for patients that are excluded

from the study.

may grant priority review status, in order to expedite the BLA review process.

of a Fast Track designation allows access for the request of priority review.

to the FDA of a BLA for marketing authorization of the product, which must include adequate

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This European Union regulation requires:

a Clinical Trial Application via a centralized procedure, which makes it possible to

a Clinical Trial Application for each European country involved in the clinical trial.

The application may be filed via a centralized procedure, which makes it possible to

obtain a coordinated assessment of an application for a clinical trial that is to take

place in several European countries;

approval of affiliated ethics committees of clinical sites to test the investigational

product into humans in clinical trials;

approval of affiliated ethics committees to test the investigational product into humans

in clinical trials;

and well-controlled clinical trials to establish the safety and efficacy of the investigational

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The EMA is expected to review and approve the

marketing authorization application.

April 2015, the EMA designated PLX-PAD as a tissue-engineered product.

May 2015, we were selected by EMA for development of PLX-PAD cells via the EMA Adaptive Pathways Project.

April 2019, the Pediatric Committee of the EMA granted PLX-PAD a waiver for the requirement to submit a pediatric investigational

plan for all indications falling under “treatment of peripheral atherosclerosis”, including IC and CLI.

May 2015, we were selected by EMA for development of PLX-PAD cells via the EMA Adaptive Pathways Project, with the potential to

reach the market several years faster than the traditional regulatory approval pathway.

Representatives of the Adaptive Pathways

Project at the EMA are advising us with respect to the clinical development of PLX-PAD in CLI and in recovery following surgery

for hip fracture.

plan for treatment of peripheral ischemia.

general, the approval procedure varies among countries, and may involve additional preclinical testing and clinical trials.

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An agency may, at

its discretion, re-evaluate, alter, suspend, or terminate the clinical trial based upon the data that have been accumulated to

that point and its assessment of the risk/benefit ratio to the patient.

its discretion, re-evaluate, alter, suspend, or terminate the clinical trial based

upon the data that have been accumulated to that point and its assessment of the risk/benefit ratio to the patient.

presently employ a total of 146 full-time employees and 12 part-time employees, of whom, 120 full-time employees and 12 part-time

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there are hundreds of companies in the regenerative medicine space globally, there are multiple participants in the cell therapy

field based in the United States, Europe, Japan, Korea, and Australia such as Athersys, Inc., Capricor Therapeutics, Inc., Celularity

a spin-off of Celgene Corporation, Tigenix NV (acquired by Takeda), SanBio Inc., Healios K.K., Cytori Therapeutics, Cesca.

field based in the United States, Europe, Japan, Korea, and Australia such as Athersys Inc., Celularity Inc., Tigenix NV (acquired

by Takeda), SanBio Inc.

and Mesoblast Ltd.

Among other things, we expect to compete based upon our intellectual property portfolio, our in-house manufacturing

efficiencies and capabilities, and the efficacy of our products.

Our ability to compete successfully will depend on our continued

ability to attract and retain experienced and skilled executives, scientific and clinical development personnel, to identify and

develop viable cellular therapeutic candidates, and exploit these products commercially.

Given the magnitude of the potential

opportunity for cell therapy, we expect competition in this area to intensify.

Among other things, we expect to compete based upon our intellectual property portfolio,

our in-house manufacturing efficiencies and capabilities, and the efficacy of our products.

Our ability to compete successfully

will depend on our continued ability to attract and retain experienced and skilled executives, scientific and clinical development

personnel, to identify and develop viable cellular therapeutic candidates, and exploit these products commercially.

the magnitude of the potential opportunity for cell therapy, we expect competition in this area to intensify.

information about us is contained on our Internet website at www.pluristem.com.

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on Form 10-Q, Current Reports on Form 8-K, and amendments to those reports filed or furnished pursuant to Section 13(a) of the

Securities Exchange Act of 1934, as amended (Exchange Act), as soon as reasonably practicable after we electronically file such

material with, or furnish it to, the SEC.

Our reports filed with the SEC are also made available on the SEC’s website at

Securities Exchange Act of 1934, as amended, or the Exchange Act, as soon as reasonably practicable after we electronically file

such material with, or furnish it to, the SEC.

Our reports filed with the SEC are also made available on the SEC’s website

at www.sec.gov.

The following Corporate Governance documents are also posted on our website:

Code of Business Conduct and Ethics,

and the Charters for each of the Committees of our Board of Directors.

Trading Policy and the Charters for each of the Committees of our Board of Directors, or the Board.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business