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Item 1. Business

2021-03-01 compared with 2020-03-02 · 340 added, 326 removed, 500 unchanged (57% of the section changed)

We are a biopharmaceutical company dedicated to developing and delivering medicines for patients with B-cell mediated diseases, including Chronic Lymphocytic Leukemia (CLL), non-Hodgkin Lymphoma (NHL) and Multiple Sclerosis (MS).

We have developed a robust B-cell directed research and development (R&D) platform for identification of key B-cell pathways of interest and rapid clinical testing.

Currently, we have five B-cell targeted drug candidates in clinical development, with the lead two therapies, ublituximab (TG-1101) and umbralisib (TGR-1202), in pivotal trials for CLL, NHL and MS.

Ublituximab is a novel anti-CD20 monoclonal antibody (mAb) that has been glycoengineered for enhanced potency over first generation antibodies.

Umbralisib is an oral, once daily, dual inhibitor of PI3K-delta and CK1-epsilon, which may lead to a differentiated safety profile.

When used together in combination therapy, ublituximab and umbralisib are referred to as "U2".

Additionally, in early clinical development we have an anti-PD-L1 monoclonal antibody referred to as cosibelimab (TG-1501), an oral Bruton’s Tyrosine Kinase (“BTK”) inhibitor referred to as TG-1701, and an anti-CD47/CD19 bispecific antibody referred to as TG-1801.

TG Therapeutics is a fully-integrated, commercial stage biopharmaceutical company focused on the acquisition, development and commercialization of novel treatments for B-cell malignancies and autoimmune diseases.

In addition to an active research pipeline including five investigational medicines across these therapeutic areas, we have received accelerated approval from the U.S.

Food and Drug Administration (FDA) for UKONIQ (umbralisib), for the treatment of adult patients with relapsed or refractory marginal zone lymphoma who have received at least one prior anti-CD20-based regimen and relapsed or refractory follicular lymphoma who have received at least three prior lines of systemic therapies.

Currently, we have two programs in Phase 3 development for the treatment of patients with relapsing forms of multiple sclerosis (RMS) and patients with chronic lymphocytic leukemia (CLL) and several investigational medicines in Phase 1 clinical development.

We also actively evaluate complementary products, technologies and companies for in-licensing, partnership, acquisition and/or investment opportunities.

To date, we have not received approval for the sale of any of our drug candidates in any market and, therefore, have not generated any product sales from our drug candidates.

FDA Accelerated Approval of UKONIQ

On February 5, 2021, we announced that the FDA granted accelerated approval of umbralisib, now referred to as UKONIQ, for the treatment of adult patients with relapsed or refractory Marginal Zone Lymphoma (MZL) who have received at least one prior anti-CD20 based regimen and adult patients with relapsed or refractory Follicular Lymphoma (FL) who have received at least three prior lines of systemic therapy.

UKONIQ is the first and only, oral, once daily, inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon.

Accelerated approval was granted for these indications based on overall response rate (ORR) data from the Phase 2b UNITY-NHL Trial (NCT02793583).

Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

This application was granted priority review for the MZL indication.

In addition, UKONIQ was granted Breakthrough Therapy Designation (BTD) for the treatment of MZL and orphan drug designation (ODD) for the treatment of MZL and FL.

Current Phase 3 or Registration Directed Clinical Trial Highlights:

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● UNITY-NHL Phase 2b Trial:

UNITY-NHL is a broad Phase 2b registration-directed clinical trial designed to evaluate the efficacy and safety of umbralisib monotherapy and U2 combinations in patients with previously treated NHL.

The marginal zone lymphoma (MZL) and the follicular lymphoma (FL)/small lymphocytic lymphoma (SLL) single agent umbralisib cohorts of this trial are fully enrolled.

The primary objective of these cohorts is to assess the efficacy of single agent umbralisib as measured by Overall Response Rate (ORR).

In February 2019, we announced that the MZL cohort met the primary endpoint of ORR as determined by Independent Review Committee (IRC) for all treated patients (n=69).

The results met our target guidance of 40-50% ORR.

Interim safety and efficacy data from the MZL cohort were presented in an oral presentation at three medical meetings, the American Association for Cancer Research (AACR) annual meeting in April 2019, the American Society of Clinical Oncology (ASCO) annual meeting in June 2019 and the International Conference on Malignant Lymphoma (ICML) also in June 2019.

In October 2019, we announced that the FL patients within the FL/SLL cohort met the primary endpoint of ORR as determined by Independent Review Committee (IRC) for all treated patients (n=118).

The results also met our target guidance of 40-50% ORR.

Most recently, in January of 2020, we received guidance from the FDA allowing submission of a single New Drug Application (NDA) for MZL and FL indications and initiated a rolling submission of an NDA to the FDA for umbralisib in MZL/FL.

We anticipate completion of the rolling submission in the first half of 2020.

UNITY-NHL is a broad Phase 2b registration-directed clinical trial designed to evaluate the efficacy and safety of umbralisib monotherapy and ublituximab and umbralisib (U2) combinations in patients with previously treated non-Hodgkin’s lymphoma (NHL).

The trial is currently enrolling patients with relapsed/refractory marginal zone lymphoma (MZL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL) to receive umbralisib either alone or in combination.

o UMBRALISIB MONOTHERAPY MZL/FL COHORTS:

The MZL and the FL single agent umbralisib cohorts of the UNITY-NHL trial met their primary endpoint of ORR.

Data from these cohorts were presented in December 2020 at the 62 nd American Society of Hematology annual meeting.

In addition, data from the MZL and FL monotherapy cohorts were used to support a New Drug Application (NDA) for umbralisib to treat adult patients with relapsed or refractory MZL and FL, which was approved by the FDA on February 5, 2021.

● UNITY-CLL Phase 3 Trial Evaluating Umbralisib plus Ublituximab (U2):

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Two additional arms evaluating single agent ublituximab and single agent umbralisib were also enrolled for purposes of evaluating contribution in the U2 combination regimen.

The primary endpoint for this study is progression free survival (PFS) which we intend to use to support a submission for approval of the U2 combination in CLL.

The study completed enrollment in October 2017 with over 600 patients enrolled across the four treatment arms, with approximately 420 patients in the U2 and the active control arm combined.

endpoint for this study is progression free survival (PFS).

This trial is conducted under Special Protocol Assessment (SPA) with the FDA.

In early December 2020, we initiated a rolling submission of a Biologics License Application (BLA) for ublituximab in combination with umbralisib as a treatment for patients with CLL, with the completion of the rolling submission targeted for the first half of 2021.

On December 7, 2020, we presented safety and efficacy results from the UNITY- CLL trial at the American Society of Hematology (ASH) annual meeting, demonstrating that U2 significantly improved PFS over obinutuzumab plus chlorambucil (HR=0.54, p<0.0001) as well as ORR (p<0.001) in patients with CLL;

with consistent PFS improvement across subgroups, including treatment naïve CLL (HR=0.48) and relapsed/refractory CLL (HR=0.60).

● ULTIMATE I & II Trials Evaluating Single Agent Ublituximab in RMS:

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These trials are conducted under a SPA with the FDA.

Full enrollment for the ULTIMATE studies was completed in second half of 2018, with approximately 1,100 subjects enrolled in both studies combined.

● ULTRA-V Phase 2b Trial Evaluating U2 plus Venetoclax in CLL:

ULTRA-V is a Phase 2b open-label, multicenter, registration-directed clinical trial designed to investigate the efficacy and safety of ublituximab and umbralisib (U2) combined with venetoclax in subjects with Chronic Lymphocytic Leukemia.

The primary endpoint for this study is ORR and Complete Response (CR) rate.

This trial is currently enrolling.

In December 2020, we announced positive topline results from the ULTIMATE I & II Phase 3 trials.

Both studies met their primary endpoint of significantly reducing ARR (p<0.005 in each study) with ublituximab demonstrating an ARR of <0.10 in each of the studies with relative reductions of approximately 60% and 50% in ARR over teriflunomide observed in ULTIMATE I & II, respectively.

Further analyses of the ULTIMATE I & II studies including safety and secondary endpoints are being conducted and detailed data is targeted to be presented in first half of 2021.

Additionally, data from these studies are intended to support a BLA submission for ublituximab in RMS targeted in mid-year 2021.

● ULTRA-V Phase 2 Trial Evaluating U2 plus Venetoclax in CLL:

ULTRA-V is a Phase 2 open-label, multicenter, registration-directed clinical trial designed to investigate the efficacy and safety of U2 combined with venetoclax in subjects with treatment-naïve and relapsed or refractory CLL.

The primary endpoint for the Phase 2 component of this study is ORR and Complete Response (CR) rate.

The primary endpoints for this study are ORR and Complete Response (CR) rate.

CORPORATE INFORMATION

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Our executive offices are located at 2 Gansevoort Street, 9th Floor, New York, New York 10014.

Our telephone number is 1-212-554-4484, and our e-mail address is info@tgtxinc.com.

Our telephone number is 1-877-575-TGTX(8489), and our e-mail address is info@tgtxinc.com.

We maintain a website with the address www.tgtherapeutics.com and maintain various social media accounts, including but not limited to Twitter and LinkedIn.

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social media channels listed on our website.

● Completing our current Phase 3 and registration-directed trials for umbralisib and ublituximab, including, UNITY-CLL, UNITY-NHL, and the ULTIMATE Phase 3 Program in MS;

● Gaining regulatory approval for umbralisib in NHL, umbralisib plus ublituximab (“U2”) in CLL, and ublituximab in MS;

● Preparing for commercial launch and building commercial capability to ensure, when approved, broad access to patients for the approved indications for umbralisib and ublituximab;

● Developing U2 in NHL;

● Advancing cosibelimab (TG-1501), TG-1701, and TG-1801 through clinical development and defining potential regulatory paths for these drug candidates both as single agents and in combination with umbralisib, ublituximab, and/or U2;

● Building upon the MS program to expand ublituximab into additional MS indications and other autoimmune diseases;

As a fully-integrated, commercial stage biopharmaceutical company focused on the acquisition, development and commercialization of novel treatments for B-cell malignancies and autoimmune diseases, our key corporate objectives include:

● Successfully commercializing UKONIQ in the U.S.

for relapsed or refractory MZL and FL;

● Completing U.S.

regulatory submissions for U2 in CLL and ublituximab in MS;

● Obtaining FDA approval for U2 in CLL, and ublituximab in MS;

● Preparing for additional commercial launches and scaling commercialization capabilities to ensure, if approved, broad access to patients for the approved indications for umbralisib and ublituximab;

● Developing U2 in NHL as well as in combination with other novel agents for CLL;

● Advancing cosibelimab (TG-1501), TG-1701, and TG-1801 through clinical development and defining potential regulatory paths for these drug candidates either as single agents and in combination with umbralisib, ublituximab, and/or U2;

● Building upon the MS clinical program to develop ublituximab in additional MS indications and other autoimmune diseases;

● Continuing to expand our pipeline with mechanisms of importance to B-cell mediated diseases;

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Our approach to drug development is centered on developing solutions for patients rather than developing single therapies for a disease.

Our process begins by identifying validated targets against B-cell diseases, and then searching for and, ideally, acquiring what we believe to be “best-in-class” compounds with complementary mechanisms against these targets, with the goal of developing multi-drug proprietary targeted combinations, which can potentially offer better outcomes for patients.

Our preference is to identify targets for which there is human clinical proof of concept that the mechanism is active in B-cell diseases and then to identify drug candidates that effectively modulate the desired molecular target.

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By focusing on B-cell diseases and targets with a known activity profile, we believe that we can quickly identify the patients most likely to respond, resulting in a more efficient development path with the potential for a greater likelihood of success.

Importantly, since all our drug candidates are focused in one disease area, we can rapidly explore combination therapies, which we believe is essential to improving outcomes for patients and holds the key to identifying cures for patients with B-cell diseases.

Importantly, since our drug candidates have complementary mechanisms of action, we can rapidly explore combination therapies, which we believe is essential to improving outcomes for patients and may hold the key to potentially identifying cures for patients with B-cell diseases.

Our approach is enabled by our clinical development platform which includes:

● An internal team with a deep understanding of B-cell diseases and the treatment of patients;

● An external network of more than 350 community and academic clinical trial sites globally.

● An internal team with a deep understanding of B-cell diseases and significant experience successfully pioneering innovative treatments for these complex diseases;

● A vast external network of more than 350 community and academic clinical trial sites with significant experience researching B-cell diseases.

B-CELL DISEASES OVERVIEW

B-cell mediated diseases comprise a constellation of disorders that result from cancerous B-cells or aberrant B-cells.

In the case of cancerous B-cells, the most common forms of B-cell cancers or B-cell malignancies are non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).

In the case of aberrant B-cells, many autoimmune diseases are believed to result from aberrant B-cell activity, including, Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), and Lupus.

The Company’s current clinical programs are focused on CLL, MZL, FL and MS.

Chronic Lymphocytic Leukemia Overview

CLL is the most common type of adult leukemia, and in 2019, it is estimated there will be more than 20,000 new cases of CLL diagnosed in the United States 1 .

Although signs of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of malignant cells.

The constellation of diseases that arise from abnormally growing or behaving B-cells is substantial.

One group of diseases related to abnormal B-cell growth is malignant lymphomas, including NHL and CLL.

There are over 80 types of NHL, approximately 40 to 50 of which are due to malignant B-cells.

These diseases can include some of the slowest and fastest growing cancers known to medicine.

Some of the more common B-cell malignancies include MZL, FL, SLL and CLL.

The other major group of diseases caused by abnormally functioning B-cells is autoimmune disorders.

These diseases may result from inappropriate production of antibodies from the B-cells.

These antibodies cannot discriminate “self” from “non-self,” and inadvertently mount a disabling immune response against normal organs.

Examples of common and very debilitating autoimmune disorders for which abnormally functioning B-cells have been implicated include MS and rheumatoid arthritis (RA).

The Company’s current clinical programs are focused on MZL, FL, CLL and MS.

Marginal Zone Lymphoma Overview

MZL comprises a group of indolent (slow growing) B-cell non-Hodgkin lymphomas (NHLs) that begin forming in the marginal zone of lymphoid tissue.

With an annual incidence of approximately 7,500 newly diagnosed patients in the United States 2 , MZL is the third most common B-cell NHL, accounting for approximately eight percent of all NHL cases.

MZL comprises a group of indolent (slow growing) mature B-cell non-Hodgkin lymphomas (NHLs).

MZL is generally considered a chronic and incurable disease.

With an annual incidence of approximately 8,200 newly diagnosed patients in the United States MZL is the third most common B-cell NHL, accounting for approximately ten percent of all NHL cases.

MZL consists of three different subtypes:

extranodal MZL of the mucosal-associated lymphoid tissue (MALT), nodal marginal zone lymphoma (NMZL), and splenic marginal zone lymphoma (SMZL).

1 Cancer Stat Facts:

Leukemia – Chronic Lymphocytic Leukemia https://seer.cancer.gov/statfacts/html/clyl.html

2 2016 Lymphoid Malignancy Statistics by World Health Organization Subtypes VOLUME 66 _ NUMBER 6 _ NOVEMBER/DECEMBER 2016 https://onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21357

3 Lymphoma Research Foundation:

Marginal Zone Lymphoma https://lymphoma.org/aboutlymphoma/nhl/mzl/

Follicular Lymphoma Overview

FL is typically a slow-growing or indolent form of NHL which accounts for 20 to 30 percent of all NHL cases 4 , with a prevalence of approximately 245,000 5 and an incidence of approximately 31,000 6 in the US, Japan, and 5 major EU markets.

Advanced stage FL is usually not considered to be curable, but more of a chronic disease, with patients living for many years.

FL is typically an indolent form of NHL that arises from B-lymphocytes.

It is the second most common form of NHL.

FL is generally not curable and is considered a chronic disease, as patients can live for many years with this form of lymphoma.

With an annual incidence in the United States of approximately 13,200 newly diagnosed patients FL is the most common indolent lymphoma accounting for approximately 17 percent of all NHL cases.

Chronic Lymphocytic Leukemia Overview

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia.

It is estimated there will be more than 20,000 new cases of CLL diagnosed in the United States in 2020 and approximately 45,000 new cases globally in 2020.

Although signs and symptoms of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of malignant cells.

Multiple Sclerosis Overview

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RRMS is the most common form of multiple sclerosis (MS) and is characterized by episodes of new or worsening signs or symptoms (relapses) followed by periods of recovery.

It is estimated that nearly 1,000,000 people are living with MS in the United States 7 and approximately 85 percent are initially diagnosed with RRMS 8 .

It is estimated that nearly 1 million people are living with MS in the United States and approximately 85% are initially diagnosed with RRMS.

The majority of people who are diagnosed with RRMS will eventually transition to SPMS, in which they experience steadily worsening disability over time.

Worldwide, more than 2.3 million people have a diagnosis of MS.

OUR PRODUCTS UNDER DEVELOPMENT

We have leveraged our B-cell platform to develop a robust drug pipeline of both targeted orally available, potent and selective small molecule kinase inhibitors and intravenously delivered “off-the-shelf” immunotherapies that leverage the patient’s own immune system to fight cancer.

We currently own worldwide development and commercial rights, subject to certain limited geographical restrictions, to all of our pre-clinical and clinical programs.

We currently license worldwide development and commercial rights, subject to certain limited geographical restrictions, to all of our pre-clinical and clinical programs.

The following table summarizes our most advanced drug candidates as of February 2021.

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Phase 3 trials (ULTIMATE I and II)

Umbralisib (Dual PI3K delta and CK1 epsilon inhibitor)

Umbralisib (PI3K delta and CK1 epsilon inhibitor)

Chronic Lymphocytic Leukemia

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Phase 1 trial

4 Lymphoma Research Foundation:

Follicular Lymphoma https://lymphoma.org/aboutlymphoma/nhl/fl/

5 Decision Resources via Pharmacyclics Investor Presentation, December 2014

6 Global Data 2016 NHL Model

7 National MS Society https://www.nationalmssociety.org/About-the-Society/MS-Prevalence

8 Multiple Sclerosis International Federation, 2013 via Datamonitor p.

Ublituximab Overview

Ublituximab (also referred to as TG-1101) is a glycoengineered anti-CD20 monoclonal antibody that targets a unique epitope on the CD20 antigen found on the surface of B-lymphocytes.

We hold exclusive worldwide rights to develop and commercialize ublituximab for all indications, except for the territories of France and Belgium for which an option to commercialize has been retained by LFB Biotechnologies, South Korea and Southeast Asia which we licensed to Ildong Pharmaceutical Ltd in November 2012.

Generally, anti-CD20 antibodies are believed to exert their B-cell depleting effects through three primary mechanisms:

antibody dependent cell-mediated cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and direct or programmed cell death (DCD or PCD).

Ublituximab has been specifically glycoengineered to enhance ADCC activity, which should enhance its ability to deplete B-cells and may improve its anti-cancer effects when compared to rituximab the leading anti-CD20 monoclonal antibody, which had worldwide sales in 2018 of approximately $7 billion.

ADCC is a mechanism that is dependent on interactions between the Fc region of the antibody and the FcγR receptors on immune system effector cells, most notably the Fc−gammaRIIIA (CD16) receptor found on NK cells.

These interactions trigger effector cells to release cytotoxic molecules and proteases resulting in B-cell death.

Ublituximab is a next generation, type I chimeric IgG1 monoclonal antibody with a glycoengineered Fc region designed specifically to induce higher ADCC activity in comparison to rituximab.

In pre-clinical (non-human) experiments, ublituximab has demonstrated an ability to enhance ADCC by >50x over rituximab, resulting in enhanced potency.

Umbralisib Overview

Umbralisib (also referred to as TGR-1202) is an oral, once daily dual inhibitor of PI3K-delta and CK1-epsilon, with nanomolar potency to the delta isoform and high selectivity over the alpha, beta, and gamma isoforms.

Umbralisib also uniquely inhibits CK1-epsilon, which may lead to a differentiated safety profile.

The phosphoinositide-3-kinases (“PI3Ks”) are a family of enzymes involved in various cellular functions, including cell proliferation and survival, cell differentiation, intracellular trafficking, and immunity.

There are four isoforms of PI3K (alpha, beta, delta, and gamma), of which the delta isoform is strongly expressed in cells of hematopoietic origin, and often implicated in B-cell related lymphomas.

In October 2016, a manuscript titled, "Silencing c-Myc Translation as a Therapeutic Strategy through Targeting PI3K Delta and CK1 Epsilon in Hematological Malignancies,"

was published online in the First Edition section of Blood, the Journal of the American Society of Hematology.

The publication presents preclinical data describing the synergy of umbralisib with the proteasome inhibitor carfilzomib and the unique effects of the combination to silence c-Myc in various preclinical lymphoma and myeloma models.

Ublituximab is an investigational glycoengineered monoclonal antibody that targets a unique epitope on CD20-expressing B-cells.

When ublituximab binds to the B-cell it triggers a series of immunological reactions (including antibody-dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), leading to destruction of the cell.

Additionally, ublituximab is uniquely designed to lack certain sugar molecules normally expressed on the antibody.

Removal of these sugar molecules, a process called glycoengineering, has been shown to enhance the potency of ublituximab, especially the ADCC activity.

Targeting CD20 using monoclonal antibodies has proven to be an important therapeutic approach for the management of B-cell malignancies and autoimmune disorders, both diseases driven by the abnormal growth or function of B-cells.

Ublituximab is being evaluated in pivotal and early phase clinical trials for patients with NHL, CLL, and RMS.

In December 2020, we announced initiation of a rolling BLA submission of ublituximab in combination with umbralisib for the treatment of CLL based on the results of the UNITY-CLL Phase 3 trial.

Umbralisib - UKONIQ Overview

Umbralisib is an oral inhibitor of PI3K-delta and CK1-epsilon administered once daily.

The phosphoinositide-3-kinases (PI3Ks) are a family of enzymes involved in many important cellular functions, including cell proliferation and survival, cell differentiation, intracellular trafficking, and immunity.

There are 4 isoforms of PI3K (alpha, beta, delta, and gamma), of which the delta isoform is highly expressed in hematopoietic cells and malignant lymphoid diseases.

Dysregulation of the PI3K pathway is among one of the most commonly mutated pathways across all of cancer biology.

Umbralisib is highly selective for the delta isoform of PI3K and has limited to no impact on the other PI3K isoforms.

Umbralisib also inhibits casein kinase 1 epsilon (CK1-epsilon).

CK1-epsilon is a major regulator of oncoprotein translation, which drives growth and survival of lymphoma cells, including c-Myc.

A manuscript titled, "Silencing c-Myc Translation as a Therapeutic Strategy through Targeting PI3K Delta and CK1 Epsilon in Hematological Malignancies,"

was published in the First Edition section of Blood, the Journal of the American Society of Hematology.

Importantly, the manuscript for the first time reported on umbralisib’s unique complimentary mechanism of inhibiting the protein kinase casein kinase-1 epsilon (CK1e), which may lead to a differentiated safety profile by supporting T regulatory cells, a part of the immune system necessary to protect against autoimmune mediated toxicities.

We are commercializing umbralisib in the U.S.

for the treatment of relapsed or refractory MZL and FL under the brand name UKONIQ.

In February 2021, we obtained accelerated approval of UKONIQ by the FDA for the treatment of adult patients with relapsed or refractory MZL who have received at least 1 prior anti-CD20-based regimen and adult patients with relapsed or refractory FL who have received at least 3 prior lines of systemic therapy.

Both indications were approved based on overall response rate observed in the UNITY-NHL trial.

Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

In December 2020, we announced initiation of a rolling BLA submission of umbralisib in combination with ublituximab for the treatment of CLL based on the results of the UNITY-CLL trial.

In addition, we are studying umbralisib in combination regimens with ublituximab and other treatments, including venetoclax and TG-1701, our investigational Bruton's tyrosine kinase (BTK) inhibitor.

Early Clinical Development of Ublituximab and Umbralisib

Single Agent Ublituximab (TG-1101) in Relapsed/Refractory NHL & CLL

Two single-agent, dose-escalation, Phase I studies were undertaken with ublituximab to establish an optimal dose in patients with NHL and CLL.

The first was a two part first-in-human Phase I clinical trial completed in France in which ublituximab was evaluated in relapsed or refractory CLL.

In 2012 a second single-agent Phase I study was undertaken in the US entitled "An Open Label Phase I/II Trial of the Efficacy and Safety of TG-1101 in Patients with B-cell Non-Hodgkin Lymphoma who have Relapsed or are Refractory After CD20 Directed Antibody Therapy."

In July 2014, this trial completed enrollment of 35 patients, of which 12 patients were included in the dose escalation component and 23 patients in various expansion cohorts.

All enrolled patients were relapsed or refractory to rituximab or a rituximab containing regimen, and in most cases multiple other lines of therapy.

Owen O'Connor, Professor of Medicine and Director, Center for Lymphoid Malignancies at New York Presbyterian Columbia Medical Center was the Principal Investigator for the multi-center study.

Data from this study were published in the British Journal of Haematology in February 2017.

In both Phase 1 studies, single agent ublituximab was deemed well tolerated by treating investigators and displayed promising clinical activity in relapsed and refractory patients.

In February 2017, data from the Phase 1/2 trial of ublituximab (TG-1101) were published in the British Journal of Haematology in a manuscript titled “A phase 1/2 trial of ublituximab, a novel, glycoengineered anti-CD20 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma or chronic lymphocytic leukemia previously exposed to rituximab”.

Single Agent Ublituximab (TG-1101) in Relapsing Forms of Multiple Sclerosis

In May 2016, we commenced our first study of ublituximab in patients with relapsing forms of multiple sclerosis (RMS), a chronic demyelinating disease of the central nervous system (CNS).

In May 2016, we commenced our first study of ublituximab in patients with RMS, a chronic demyelinating disease of the CNS.

The study, entitled "A Placebo-Controlled Multi-Center Phase 2 Dose Finding Study of Ublituximab, a Third-Generation Anti-CD20 Monoclonal Antibody, in Patients with Relapsing Forms of Multiple Sclerosis,"

was led by Edward Fox, MD, PhD, Director of the Multiple Sclerosis Clinic of Central Texas and Clinical Associate Professor at the University of Texas Dell Medical School in Austin, TX.

The primary objective of the study was to determine the optimal dosing regimen for ublituximab with a focus on accelerating infusion times.

primary objective of the study was to determine the optimal dosing regimen for ublituximab with a focus on accelerating infusion times.

In addition to monitoring for safety and tolerability at each dosing cohort, B-cell depletion and established MS efficacy endpoints were also evaluated.

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Median B cell depletion was >99% at the primary analysis point of Week 4 (n=48) and maintained at Week 24 and Week 48.

Ublituximab also completely eliminated all (100%) T1 Gd-enhancing lesions at Week 24 and maintained complete elimination at Week 48 (n=46) and an Annualized Relapse Rate (ARR) of 0.07 was observed with 93% of subjects relapse free at Week 48.

In October of 2019, at the 35 th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Stockholm, Sweden, we re-presented the final 48-week data from the Phase 2 trial, and also presented long-term follow-up data for 45 patients from the Phase 2 trial that enrolled into the Open Label Extension (OLE) trial.

Ublituximab also completely eliminated all (100%) T1 Gd-enhancing lesions at Week 24 and maintained complete elimination at Week 48 (n=46) and an ARR of 0.07 was observed with 93% of subjects relapse free at Week 48.

In October of 2019, at the 35 th Congress of the ECTRIMS meeting in Stockholm, Sweden, we re-presented the final 48-week data from the Phase 2 trial, and also presented long-term follow-up data for 45 patients from the Phase 2 trial that enrolled into the Open Label Extension (OLE) trial.

With a median duration of follow-up of 124.7 weeks, ublituximab continued to be well tolerated, no subjects discontinued due to an adverse event (AE) related to ublituximab, and AEs deemed at least possibly related to ublituximab were infrequent with all patients dosed at 450mg administered in a one-hour infusion.

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Single Agent Umbralisib (TGR-1202) in Patients with Relapsed/Refractory Hematologic Malignancies

In January 2013, we initiated a Phase I, open label, multi-center, first-in-human clinical trial of umbralisib in patients with hematologic malignancies.

The study entitled "A Phase I Dose Escalation Study Evaluating the Safety and Efficacy of TGR-1202 in Patients with Relapsed or Refractory Hematologic Malignancies,"

is being run in collaboration with the Sarah Cannon Research Institute in Nashville, TN with Howard “Skip” Burris, MD, Executive Director, Drug Development as the acting Study Chair.

Enrollment was open to patients with relapsed or refractory NHL, CLL, and other select hematologic malignancies.

As of February 2016, this study closed to enrollment.

In February 2018, data from this first-in-human Phase 1 clinical trial of umbralisib was published in The Lancet Oncology.

The manuscript was titled, “Umbralisib, a novel PI3K and casein kinase-1 epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukemia and lymphoma:

an open-label, phase 1, dose-escalation, first-in-human study.” The paper includes safety and efficacy information from 90 patients with relapsed or refractory hematologic malignancies, including patients with CLL and various forms of lymphoma treated with single agent umbralisib.

In this study, the data showed that umbralisib was well tolerated with a favorable safety profile.

Additional Early Studies with Ublituximab (TG-1101) and/or Umbralisib (TGR-1202)

In addition to the above Phase 1 trials for ublituximab and umbralisib, the following Phase 1 and Phase 2 studies, as well as an integrated analysis were conducted:

● Phase 1/2 Study of Umbralisib, Ublituximab and Venetoclax in patients with relapsed or refractory CLL – In December 2019, we presented triple therapy data from patients with relapsed/refractory CLL treated with the triple therapy combination of ublituximab, umbralisib and venetoclax during an oral session at the 61st American Society of Hematology (ASH) annual meeting and exposition.

At the time of presentation, twenty-seven patients were evaluable for safety and 23 were evaluable for efficacy.

The triple therapy regimen was administered with 3 cycles of U2 induction/debulking to reduce the risk of tumor lysis syndrome (TLS), followed by the combination of umbralisib and venetoclax starting in cycle 4.

Patients who were bone marrow MRD negative after cycle 12 stopped all therapy.

Overall response rate (ORR) of 87% (20/23) after U2 induction period at cycle 3, prior to introduction of venetoclax, in relapsed/refractory CLL patients, including patients refractory to ibrutinib.

U2 induction appeared to reduce venetoclax TLS risk, with no patients remaining as TLS high-risk following 3 cycles of U2.

13 patients were treated for >7 cycles and 9 patients for > 12 cycles, with the following response rates observed:

100% ORR (13/13) after cycle 7 for the triple combination;

100% ORR (9/9) including 44% Complete Response (CR) after cycle 12 for the combination;

100% (9/9) of patients had undetectable minimal residual disease (MRD) (<0.01%) in peripheral blood after 12 cycles of therapy;

and 78% (7/9) of patients who completed 12 cycles of therapy had undetectable MRD in bone marrow and have stopped therapy.

At the time of the presentation, no patients (n=27) had progressed with a median follow-up of 6.4 months.

Overall the triplet regimen was generally well tolerated with no events of TLS observed.

● Phase 1 Study of TG-1701, a Once-Daily BTK inhibitor, as a Single Agent and in Triple Combination with Umbralisib and Ublituximab in patients with relapsed or refractory NHL and CLL – In December 2019, we presented data from patients with relapsed/refractory NHL and CLL treated with the triple therapy combination of TG-1701, umbralisib and ublituximab during a poster session at the 61st American Society of Hematology (ASH) annual meeting and exposition.

The proprietary triplet of U2 plus TG-1701 induced 86% ORR (6 of 7) in patients with relapsed/refractory NHL and CLL at the lowest dose of TG-1701 tested.

Of the 7 patients treated with the triple, 4 patients had follicular lymphoma (FL), of which 2 achieved a complete response (CR), 1 patient achieved partial response (PR) and 1 patient had stable disease SD).

The remaining three patients treated with the combination included the following:

1 patient with marginal zone lymphoma (MZL) achieved a PR, 1 patient with Waldenström's macroglobulinemia (WM) achieved a PR;

and 1 patient with diffuse large B-cell lymphoma (DLBCL) achieved a PR.

As of the time of the presentation, all patients treated with the triple combination of TG-1701 plus U2 remained on study.

● Ublituximab in Combination with Umbralisib with/without ibrutinib or bendamustine for Relapsed/Refractory NHL & CLL— In November 2013, we initiated a multi-center, Phase I study to evaluate the safety and efficacy of the combination of ublituximab and umbralisib, (U2), for patients with relapsed and/or refractory CLL and NHL.

an open-label, phase 1, dose-escalation, first-in-human study.”

In addition to the above Phase 1 trials for ublituximab and umbralisib, the following Phase 1 and Phase 2 studies were conducted:

● Phase 1/2 Study of Umbralisib, Ublituximab and Venetoclax in patients with relapsed or refractory CLL – In December 2020, we presented data from patients with relapsed/refractory CLL treated with the triple therapy combination of ublituximab, umbralisib and venetoclax during the 62nd ASH annual meeting and exposition.

At the time of presentation, 43 patients were evaluable for safety and 29 were evaluable for efficacy.

The triple therapy regimen was administered with 3 cycles of U2 as induction in cycles 1 through 3, U2 plus venetoclax in cycles 4,5 and 6, followed by umbralisib plus venetoclax in cycles 7 through 12 in patients with R/R CLL.

Patients with centrally confirmed undetectable minimal residual disease (uMRD) in the bone marrow after cycle 12 were permitted to stop all therapy, while MRD detectable patients continued on single agent umbralisib.

Among evaluable patients, ORR was 77% (30/39) after cycle 3 (U2 only), 100% (31/31) after cycle 7, and 100% (27/27) after cycle 12.

Among the 27 patients who finished 12 cycles of therapy, 41% achieved a complete response (CR) by iwCLL criteria, 96% achieved undetectable MRD in the peripheral blood and 77% achieved undetectable MRD in the bone marrow.

At a median follow up of 15.6 months (n=43), only 1 patient has progressed, occurring 10 months after stopping treatment in cycle 12.

Grade 3/4 adverse events occurring in > 5% of patients were neutropenia (21%), leukopenia (12%), infusion related reactions (7%), anemia (5%), and diarrhea (5%).

No TLS events were observed during venetoclax administration, with one TLS event occurring prior to venetoclax administration.

● Phase 1 Study of TG-1701, a Once-Daily BTK inhibitor, as a Single Agent and in Triple Combination with Umbralisib and Ublituximab in patients with relapsed or refractory NHL and CLL – In December 2020, we presented data from patients with relapsed/refractory NHL and CLL treated with TG-1701 monotherapy and the triple therapy combination of TG-1701, umbralisib and ublituximab during the 62nd ASH annual meeting and exposition.

A total of 102 patients with R/R CLL or b-cell lymphoma have been treated with TG-1701, with patients receiving monotherapy in the dose-escalation cohort (n=25) or in the 200 mg dose-expansion cohort (n=61), or TG-1701 in combination with U2 in the dose escalation cohort (n=16).

TG-1701 monotherapy was well tolerated and the maximum tolerated dose was not reached up through 400 mg QD.

Grade 3/4 adverse events (AE) occurring in >10% of patients treated with TG-1701 monotherapy were limited and included ALT increase (12%), all of which were patients treated with 400 mg QD.

At the target single-agent Phase 2 dose of 200mg (QD) (n=61), AEs of special interest included Grade 3 hypertension (1.6%), atrial fibrillation (1.6%), and no instances of major bleeding observed.

Grade 3/4 AEs occurring in >10% of patients treated with U2+1701 were ALT increase (25%), AST increase (19%) and neutropenia (12%).

At a median follow up of 7 months in the 200 mg QD monotherapy expansion cohorts, preliminary

overall response rates (ORR) were:

95% (19/20) in CLL, 50% (6/12) in mantle cell lymphoma (MCL), and 95% (18/19) in Waldenstrom macroglobulinemia (WM).

At a median follow up of 12 months, the 1701+U2 dose escalation (using doses of 100mg to 300 mg QD of TG-1701) resulted in 79% ORR, with 22% CR rate across patients with WM, CLL, MZL, diffuse large B-cell lymphoma (DLBCL) and FL (n=14).

● Ublituximab in Combination with Umbralisib with/without ibrutinib or bendamustine for Relapsed/Refractory NHL & CLL— In November 2013, we initiated a multi-center, Phase I study to evaluate the safety and efficacy of the combination of U2, for patients with relapsed and/or refractory CLL and NHL.

The MD Anderson Cancer Center was the lead center for this clinical trial.

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Both U2 and the triplet combinations demonstrated acceptable levels of tolerability with promising activity.

Enrollment in all cohorts is now closed and patients continued to be followed for safety and efficacy.

Data highlights from each cohort include the following:

Data highlights include the following:

o Ublituximab plus Umbralisib (U2):

◾ In December 2015 we presented the results from the U2 portion of this trial at the 57th American Society of Hematology (ASH) annual meeting, Abstract Number 1538.

The presentation included data from patients with relapsed and refractory NHL and CLL treated with U2.

The combination was well tolerated in the 71 patients evaluable for safety at all dose levels up through 1200mg.

This was a heavily pretreated population with high-risk features, including 58% refractory to last treatment with multiple previous lines of rituximab-based therapy.

Notably, the only Grade 3/4 adverse event occurring in > 5% of patients was neutropenia and of the 71 patients available for safety, only 6 patients (8%) discontinued due to an umbralisib related event.

Additionally, 26 patients had been on U2 for 6+ months, with no events of colitis reported as of the date of publication.

Efficacy data was presented on patients treated at the higher doses of umbralisib (1200mg of the original formulation and 600mg or greater of the micronized formulation).

80% (8 of 10) ORR was observed in patients with CLL/SLL, including 1 complete response (CR) and 7 partial responses (PRs).

Notably, 75% of CLL patients had high-risk cytogenetics (17p and/or 11q del).

71% (12 of 17) ORR was observed in heavily pretreated patients with indolent NHL (FL & MZL), including 4 CRs (24%) and 8 PRs, with 4 of the remaining 5 patients achieving stable disease.

◾ In September of 2019, results from the Phase I/IB combination trial of U2 were published in Blood, the Journal of the American Society of Hematology.

The paper includes safety and efficacy information from 22 patients with CLL or small lymphocytic lymphoma (SLL) and 53 patients with NHL treated with the combination of ublituximab and umbralisib, referred to as “U2”.

◾ In September of 2019, results from the Phase I/IB combination trial of U2 were published in Blood, the Journal of the American Society of Hematology in a manuscript titled, “Ublituximab and Umbralisib in Relapsed/ Refractory B-cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia”.

The paper includes safety and efficacy information from 22 patients with CLL or SLL and 53 patients with NHL treated with the combination of U2.

Safety data was available from all 75 patients and demonstrated that the U2 combination was well tolerated with the majority of adverse events (AEs) being grade 1 or 2 in severity and no maximum tolerated dose achieved in either CLL or NHL.

◾ Efficacy data was available from 69 patients and showed the combination to be highly active with a 72.5% clinical benefit rate (defined as patients obtaining a Complete Response, Partial Response, or Stable Disease) across all subtypes of B-cell cancers enrolled in the study.

Of note, a median PFS of 27.57 months was observed in patients with relapsed/refractory CLL (n=15) treated at therapeutic dose levels of umbralisib and a 65% overall response rate (ORR) was observed in patients relapsed/refractory indolent NHL (n=20), including a 100% ORR amongst MZL patients (n=5).

◾ These data are described further in the manuscript entitled, “Ublituximab and Umbralisib in Relapsed/ Refractory B-cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia,” which was published online in the First Edition section of Blood, the Journal of the American Society of Hematology.

Importantly, U2 exhibited low rates of immune-mediated toxicities, typically associated with other PI3K-delta inhibitors including colitis, pneumonia/pneumonitis, or hepatic toxicity, and discontinuations due to AEs were limited (13%).Efficacy data was available from 69 patients and showed the combination to be highly active with a 72.5% clinical benefit rate (defined as patients obtaining a Complete Response, Partial Response, or Stable Disease) across all subtypes of B-cell cancers enrolled in the study.

Of note, a median PFS of 27.57 months was observed in patients with relapsed/refractory CLL (n=15) treated at therapeutic dose levels of umbralisib and a 65% ORR was observed in patients relapsed/refractory indolent NHL (n=20), including a 100% ORR amongst MZL patients (n=5).

o U2 plus Bendamustine:

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o U2 plus Ibrutinib:

In January 2019, we announced the publication of results from the U2 plus ibrutinib cohort in The Lancet Haematology.

In January 2019, we announced the publication of results from the U2 plus ibrutinib cohort in The Lancet Haematology in a manuscript titled, “Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma:

a phase 1 dose escalation and expansion trial”.

Safety data was available from 46 patients and the triple combination of ublituximab, umbralisib, and ibrutinib was well tolerated with a manageable adverse event profile and no maximum tolerated dose achieved for the combination.

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Among patients with NHL, 68% (15 of 22) achieved a response, including a 71% ORR in FL (n=7), a 100% ORR in MZL (n=3), and a 100% ORR in MCL (n=6).

● Umbralisib as a single agent in CLL patients who are intolerant to prior BTK inhibitor or PI3K delta inhibitor therapy— In September 2019, at the XVIII iwCLL meeting in Edinburgh, Scotland, data was presented from 51 patients with CLL who were intolerant to prior BTK or PI3K delta inhibitor therapy who were then treated with single agent umbralisib.

Umbralisib demonstrated a favorable safety profile with only 12% of patients discontinuing due to an umbralisib related adverse event, of which only one patient discontinued due to a recurrent adverse event (AE) also experienced with prior kinase inhibitor therapy.

● Umbralisib as a single agent in CLL patients who are intolerant to prior BTK inhibitor or PI3K delta inhibitor therapy— In December 2020, we announced the publication of results from 51 patients with CLL who were intolerant to prior BTK or PI3K delta inhibitor therapy who were then treated with single agent umbralisib in Blood, the Journal of the American Society of Hematology.

Umbralisib demonstrated a favorable safety profile with only 12% of patients discontinuing due to an umbralisib related adverse event, of which only one patient discontinued due to a recurrent AE also experienced with prior kinase inhibitor therapy.

Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%).

As of the data presentation, over half of the patients enrolled had been on umbralisib for a duration longer than their prior kinase inhibitor.

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Enrollment is now closed with patients continuing to be followed.

● Umbralisib Long-term Follow-up Integrated Analysis in Patients with Relapsed/Refractory Hematologic Malignancies— In December 2017, at the 59th ASH Annual Meeting, the Company presented integrated long-term follow-up data from 347 patients exposed to umbralisib across 5 studies, which continued to demonstrate high response rates in CLL, and FL coupled with a favorable safety profile.

In June 2018, an update on the data was presented at the 23rd Congress of the European Hematology Association (EHA).

The presentation included data pooled from 4 completed or ongoing Phase 1 or 2 studies containing umbralisib, focusing on 177 patients who have been on daily umbralisib for a minimum of 6 months.

Patients were heavily pretreated, with 45% of patients having seen 3 or more prior lines of therapy.

Umbralisib continued to exhibit a tolerable safety profile with serious adverse events occurring in >1% of patients after 6 months on therapy limited to pneumonia (3%), diarrhea (2%), and cellulitis (2%) with only 2% of patients discontinuing umbralisib as a result of diarrhea/colitis after being on umbralisib for more than 6 months.

● Phase 2 trial of Umbralisib plus Ibrutinib in patients with relapsed or refractory CLL and MCL — In December 2018, we announced the publication of results from the multicenter Phase 1/1b trial of umbralisib in combination with ibrutinib, the oral Bruton's tyrosine kinase (BTK) inhibitor, in Lancet Haematology.

In December 2020, data from this trial was described further in the manuscript entitled, “Phase 2 Study of the Safety and Efficacy of Umbralisib in Patients with CLL Who Are Intolerant to BTK or PI3Kδ Inhibitor Therapy,” which was published online in the First Edition section of Blood, the Journal of the American Society of Haematology.

This investigator-initiated trial was conducted at Dana-Farber Cancer Institute and four additional centers across the USA in collaboration with the Leukemia and Lymphoma Society, Blood Cancer Research Partnership with funding by TG Therapeutics.

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Of the 21 patients treated with MCL, 67% (n=14) achieved an overall response, of which 48% (n=10) achieved a partial response and 19% (n=4) achieved a complete response.

In June 2020, updated long term data from this trial were presented at the 25th European Hematology Association (EHA) Annual Congress.

As of the updated data cutoff, 42 patients were evaluable for safety and efficacy (21 CLL patients and 21 MCL patients).

With long term follow up (median follow-up of 43.5 months (range 8.4-61), there were no cumulative or recurrent late onset toxicities observed.

In relapsed/refractory CLL, the overall response rate was 95% including a 29% complete response (CR) rate, and the 4-year Progression-free Survival (PFS) and Overall Survival (OS) were 78% and 90%, respectively.

In relapsed/refractory MCL, the ORR was 71% with a 24% CR rate, and median PFS and OS were 10.8 and 30.7 months, respectively.

● Phase 2 trial of Ublituximab plus Ibrutinib in patients with relapsed or refractory CLL and Mantle Cell Lymphoma (MCL)— In December 2013, we initiated a multi-center Phase 2 clinical trial to evaluate the safety and efficacy of the combination of ublituximab and ibrutinib for patients with CLL and MCL.

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The combination displayed marked clinical activity, reporting an 88% (35/41) response rate in patients with CLL, a 95% (19/21) response rate in those CLL patients with high-risk cytogenetics, and an 87% (13/15) response rate in patients with MCL.

The data from the CLL cohort of this study supported the Phase 3 GENUINE study evaluating ublituximab plus ibrutinib in CLL patients with high-risk cytogenetics.

● Additional early combination studies utilizing umbralisib with approved agents— Umbralisib has been evaluated in combination with the anti-CD30 antibody drug conjugate, brentuximab vedotin, in patients with relapsed or refractory Hodgkin lymphoma and in combination with the JAK inhibitor, ruxolitinib, in patients with Myelofibrosis or Polycythemia Vera.

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This cohort was designed to evaluate the safety and efficacy of single agent umbralisib and the primary endpoint is ORR as determined by Independent Review Committee (IRC) assessment.

The primary analysis of ORR will be conducted once all treated patients have had at least 9 cycles (Cycle = 28 days) of follow-up.

Secondary endpoints include safety, duration of response, and progression-free survival (PFS).

In February 2019, we announced that the MZL cohort met the primary endpoint of ORR as determined by IRC for all treated patients (n=69).

The results met our target guidance of 40-50% ORR.

Interim safety and efficacy data from the MZL cohort were presented in an oral presentation at the American Association for Cancer Research (AACR) annual meeting on April 1, 2019.

The data presented included safety and tolerability data on all 69 treated patients (safety population) and efficacy data on 42 patients who were enrolled at least 9 cycles (28 day cycles) prior to the data cut-off date (interim efficacy population).

The safety population had a median duration of exposure of 6.9 months and no unexpected toxicities were observed.

Analysis of the interim efficacy population showed an ORR by IRC of 52%, including 19% CR rate, an 88% clinical benefit rate by IRC (defined as patients obtaining Complete Response + Partial Response + Stable Disease) and a median duration of exposure of 10.1 months.

These results were also presented in oral presentations during the 2019 American Society of Clinical Oncology (ASCO) annual meeting and the 2019 International Conference on Malignant Lymphoma (ICML) both held in June of 2019.

Previously, in January 2019, the U.S.

In January 2019, the U.S.

Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) to umbralisib for the treatment of adult patients with MZL who have received at least one prior anti-CD20 regimen.

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nodal, extranodal, and splenic MZL.

Most recently, in January of 2020, we initiated a rolling submission of an NDA to the FDA for umbralisib as a treatment for previously treated MZL or FL.

We anticipate completion of this rolling submission in the first half of 2020.

In December 2020, at the American Society of Hematology Annual meeting results from the MZL and FL/SLL umbralisib monotherapy cohorts of the UNITY-NHL were presented.

● UNITY-NHL FL/SLL Single Agent Umbralisib Cohort :

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In October 2019, we announced that the FL patients within this cohort met the primary endpoint of ORR as determined by Independent Review Committee (IRC) for all treated follicular lymphoma patients (n=118).

The results met our target guidance of 40-50% ORR.

Importantly, umbralisib monotherapy appeared to be well tolerated with a safety profile consistent with previous reports.

Most recently, in January of 2020, we received guidance from the FDA allowing submission of a single NDA for MZL and FL indications.

As noted earlier, we initiated a rolling submission of an NDA to the FDA for umbralisib in MZL/FL and anticipate completion of the rolling submission in the first half of 2020.

We plan to present the data at a future medical conference as well as discuss the data with the FDA.

In March 2020, the US FDA granted orphan drug designation to umbralisib, for the treatment of patients with FL.

As noted above, in December 2020, at the ASH meeting results from the MZL and FL/SLL umbralisib monotherapy cohorts of the UNITY-NHL were presented.

● UKONIQ Approval:

On February 5, 2021, we announced the US FDA granted accelerated approval of umbralisib, now referred to as UKONIQ, for the treatment of adult patients with relapsed or refractory MZL who have received at least one prior anti-CD20 based regimen and adult patients with relapsed or refractory FL who have received at least three prior lines of systemic therapy.

Accelerated approval was granted for these indications based on overall response rate (ORR) data from the Phase 2 UNITY-NHL Trial (NCT02793583).

Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

● UNITY-NHL Additional Cohorts :

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The study completed enrollment in October 2017 with over 600 patients across the four treatment arms, with approximately 420 patients in the U2 arm and the active control arm combined.

In September 2015, we reached an agreement with the FDA regarding a Special Protocol Assessment (SPA) on the design, endpoints, and statistical analysis approach of the UNITY-CLL Phase 3 trial.

In September 2015, we reached an agreement with the FDA regarding a SPA on the design, endpoints, and statistical analysis approach of the UNITY-CLL Phase 3 trial.

The SPA provides agreement that the Phase 3 trial design adequately addresses objectives that, if met, would support the regulatory submission for drug approval of both ublituximab and umbralisib in combination.

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In September 2018, we announced that the independent Data Safety Monitoring Board (DSMB) reviewed ongoing data from the trial and advised us that the second interim analysis of ORR could not be conducted at that time as the data were not sufficiently mature to conduct the analysis.

Given the uncertainty surrounding the timing and outcome of the ORR analysis, as well as the significant regulatory hurdles associated with accelerated approval in CLL, we are no longer planning to seek accelerated approval for U2 in CLL based on ORR.

The Company remains blinded to all efficacy data and the trial continues to be conducted under SPA agreement with the FDA.

We await the results for the primary endpoint for the study, PFS, to seek full approval for U2 in patients with CLL, if the study is positive.

Importantly, an application based on PFS is expected to support full approval versus accelerated approval, which is a conditional approval.

Additionally, in September 2018, the DSMB reviewed safety data from over 600 patients, including over 300 patients treated with umbralisib either alone or in combination with ublituximab, of which approximately 60% were treatment naïve.

After review of the data, the DSMB identified no safety concerns and recommended the trial continue without modification.

In March 2019, the UNITY-CLL Data and Safety Monitoring Board (DSMB) conducted a pre-planned futility analysis of PFS.

The DSMB determined that the trial was not futile and recommended the UNITY-CLL trial continue as planned.

The pre-specified futility analysis of the UNITY-CLL trial did not allow for early stopping due to positive efficacy but only for lack of efficacy.

The DSMB also again reviewed safety information from all 600+ CLL patients on the UNITY-CLL trial, including over 300 treatment naive and previously treated patients on umbralisib alone or in combination with ublituximab.

Based on its review, no safety concerns were identified and the DSMB recommended the UNITY-CLL trial continue without modification.

Given the uncertainty surrounding the timing and outcome of the ORR analysis, as well as the significant regulatory hurdles associated with accelerated approval in CLL, we decided to continue to conduct the trial under the SPA and seek full approval for U2 in patients with CLL based on the PFS endpoint, if positive.

In May 2020, we announced the UNITY-CLL trial met the primary endpoint of improved PFS (p<.0001) and the trial would be stopped early for superior efficacy observed at the interim analysis.

In October 2020, we announced the US FDA granted Fast Track designation to the combination of ublituximab and umbralisib for the treatment of adult patients with CLL.

The US FDA previously granted Orphan Drug Designation (ODD) covering ublituximab in combination with umbralisib for the treatment of CLL.

On December 1, 2020, we initiated a rolling submission of a BLA to the US FDA requesting approval of ublituximab, in combination with umbralisib, as a treatment for patients with CLL, with completion of the rolling submission for the BLA expected in the first half of 2021.

On December 7, 2020, we presented safety and efficacy results from the UNITY- CLL trial at the ASH annual meeting, demonstrating that U2 significantly improved PFS over obinutuzumab plus chlorambucil (HR=0.54, p<0.0001) as well as ORR (p<0.001) in patients with CLL;

with consistent PFS improvement across treatment naïve CLL (HR=0.48) and relapsed/refractory CLL (HR=0.60).

Grade 3/4 Adverse Events (AEs) of clinical interest (U2 vs O+Chl) included elevated ALT (8.3% vs 1.0%), elevated AST (5.3% vs 2.0%), non-infectious colitis (1.9% vs 0%), infectious colitis (0.5% vs 0.5%), pneumonitis (0.5% vs 0%), rash (2.4% vs 0.5%), and opportunistic infections (5.8% vs.

GENUINE Phase 3 Trial Evaluating Ublituximab plus Ibrutinib:

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Patients in this trial were randomized to receive either ublituximab plus ibrutinib or ibrutinib alone.

Due to enrollment challenges associated with this study, in October 2016, we announced revisions to the design of the GENUINE study to accelerate its completion.

Initially the study was being conducted pursuant to an SPA with the FDA, and was designed to enroll approximately 330 patients, with a two-part analysis of both ORR and PFS.

The trial as amended in October 2016, and PFS was removed as a co-primary endpoint leaving ORR as the sole primary endpoint.

The target number of patients was also reduced to 120 patients.

The SPA was terminated at the time the changes were implemented.

In March 2017, we reported positive top-line data from the GENUINE study.

The study met its primary endpoint demonstrating a statistically significant improvement in ORR, as determined by an Independent Review Committee (IRC) using the iwCLL (Hallek 2008) criteria, compared to ibrutinib alone in both the Intent to Treat (ITT) population (p=0.001) and Treated population (p < 0.001).

In June 2017, the results were presented by Dr.

Sharman, Medical Director, Hematology Research, US Oncology in an oral session during the 53rd American Society of Clinical Oncology ("ASCO") Annual Meeting in Chicago, IL.

We had hoped to use the ORR results from the GENUINE trial to file for accelerated approval for the combination of ublituximab plus ibrutinib.

In October of 2017, we announced the results of a meeting with the FDA related to the potential accelerated approval application.

The FDA had expressed concern that an intervening approval for the treatment of relapsed or refractory CLL could, as available therapy, have the effect of blocking our accelerated approval application.

In June 2018, venetoclax received full approval for the treatment of relapsed or refractory CLL, the same indication for which we planned to file for accelerated approval.

While we do believe under the FDA guidance related to accelerated approval that there are benefits of ublituximab plus ibrutinib over presently available therapies that could support approval, we have decided at this time to not pursue the filing of the results from the GENUINE trial to support accelerated approval.

In October 2019, we announced that final long-term results from the Phase 3 GENUINE study demonstrated that ublituximab in combination with ibrutinib improved progression-free survival (PFS), as determined by Independent Review Committee (IRC).

Additionally, the combination of ublituximab and ibrutinib was well tolerated with no new safety signals identified at a median follow-up of >4 years.

We plan to present these final data at a future medical conference, as well as share the results with the U.S.

Food and Drug Administration (FDA).

In February 2021, final results from this trial were published in The Lancet Haematology, in a manuscript titled, “A Phase 3, Randomized Trial of Ublituximab Plus Ibrutinib for Patients With Relapsed/Refractory High-Risk Chronic Lymphocytic Leukemia”.

ULTIMATE I & II Trials Evaluating Single Agent Ublituximab in RMS:

ULTIMATE I and ULTIMATE II are two independent Phase 3 trials.

Each trial is a global, randomized, multi-center, double-blinded, double-dummy, active-controlled study comparing ublituximab to teriflunomide in subjects with relapsing forms of Multiple Sclerosis (RMS).

The primary endpoint for each study is Annualized Relapse Rate (ARR) following 96 weeks of treatment which we intend to use to support a submission for approval of ublituximab in RMS.

Each trial is a global, randomized, multi-center, double-blinded, double-dummy, active-controlled study comparing ublituximab to teriflunomide in subjects with RMS.

The primary endpoint for each study is ARR following 96 weeks of treatment which we intend to use to support a submission for approval of ublituximab in RMS.

Each trial was designed to enroll approximately 440 subjects, randomized in a 1:1 ratio.

This trial is being led by Lawrence Steinman, MD, George A.

This program is being led by Lawrence Steinman, MD, George A.

Zimmermann Professor and Professor of Pediatrics, Neurology and Neurological Sciences at Stanford University.

In August 2017, we reached an agreement with the FDA regarding an SPA on the design of two Phase 3 clinical trials for ublituximab, referred to as the ULTIMATE I and ULTIMATE II trials, for the treatment of relapsing forms of Multiple Sclerosis (RMS).

In August 2017, we reached an agreement with the FDA regarding an SPA on the design of the ULTIMATE I and ULTIMATE II trials, for the treatment of RMS.

The SPA provides agreement that the two Phase 3 trial designs adequately address objectives that, if met, would support the regulatory submission for approval of ublituximab in RMS.

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In October 2019, at the 35th Congress of ECTRIMS, we presented the ULTIMATE I & II Phase 3 program trial design and demographic data.

The presentation concluded that patient baseline characteristics were consistent with a typical RMS population, and topline results from the ULTIMATE I & II trials are expected in the second half of 2020.

ULTRA-V Phase 2b Trial Evaluating U2 plus Venetoclax in CLL:

The primary endpoint for this study is ORR and CR rate.

This trial is currently enrolling.

The presentation concluded that patient baseline characteristics were consistent with a typical RMS population.

In December 2020, we announced positive topline results from the ULTIMATE I & II trials.

Both studies met their primary endpoint of significantly reducing ARR (p<0.005 in each study) with ublituximab demonstrating an ARR of <0.10 in each of the studies.

reductions of approximately 60% and 50% in ARR over teriflunomide were observed in ULTIMATE I & II, respectively.

Further analyses of the ULTIMATE I & II studies including safety and secondary endpoints are being conducted and detailed data is targeted to be presented in first half of 2021.

Additionally, data from these studies are intended to support a BLA submission for ublituximab in RMS targeted in mid-year 2021.

ULTRA-V Phase 2 Trial Evaluating U2 plus Venetoclax in CLL:

The primary endpoints for this trial are ORR and CR rate.

Early Pipeline Overview and Clinical Development

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We are currently evaluating TG-1701 in a Phase 1, multi-center, dose-escalation clinical trial in patients with B-cell malignancies.

This trial is designed to evaluate the safety and tolerability of TG-1701 alone and in combination with ublituximab and umbralisib (U2) in adults with B-cell malignancies and determine the recommended Phase 2 dose.

This trial is designed to evaluate the safety and tolerability of TG-1701 alone and in combination with U2 in adults with B-cell malignancies and determine the recommended Phase 2 dose.

Key secondary objectives include evaluation of pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity.

Preliminary data from this Phase 1 study was presented at ASH 2019.

Preliminary data from this Phase 1 study was presented at ASH 2020 (described above).

TG-1801 (anti-CD47/anti-CD19 bispecific monoclonal antibody) Overview

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By co-targeting both CD47 and CD19, TG-1801 has the potential to overcome the limitations of existing CD47 targeted therapies by avoiding the side effects caused by indiscriminate blockade of CD47 on healthy cells.

In addition to potentially enhancing tolerability, the co-targeting of CD19 by TG-1801 may provide a secondary mechanism of direct anti-tumor activity through the engagement of effector cells and induction of antibody dependent cellular cytotoxicity (ADCC).

TG-1801 binds to human CD19 with significantly higher affinity than towards CD47.

This difference between its affinity to CD19 and CD47 allows TG-1801 to bind and selectively block CD47 on CD19 + B-cells but not on CD19 - red blood cells or platelets in human peripheral blood.

In in vitro assays, TG-1801 induces antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) of malignant tumor B-cell lines and primary tumor B-cells from patients with B-cell acute lymphoblastic leukemia (B-ALL), B-cell chronic lymphocytic leukemia (B-CLL) and numerous subtypes of NHL.

In in vitro assays, TG-1801 induces antibody-dependent cellular phagocytosis (ADCP) and ADCC of malignant tumor B-cell lines and primary tumor B-cells from patients with B-cell acute lymphoblastic leukemia (B-ALL), B-cell chronic lymphocytic leukemia (B-CLL) and numerous subtypes of NHL.

In in vivo mouse tumor models, treatment with TG-1801 inhibited tumor growth in Raji cell subcutaneous xenograft model, NALM-6 cell disseminated tumor model, and patient-derived xenograft models, including primary tumor cells from patients with diffuse large B-cell lymphoma (DLBCL) and B-ALL.

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In addition to our clinical programs, we currently have licensed preclinical programs for BET (TG-1601), IRAK4, and GITR.

COSTS AND TIME TO COMPLETE PRODUCT DEVELOPMENT

The information below provides estimates regarding the costs associated with the completion of the current development phase and our current estimated range of the time that will be necessary to complete that development phase for our key pipeline products.

We also direct your attention to the risk factors which could significantly affect our ability to meet these cost and time estimates found in this report in Item 1A under the heading “Risks Related to the Company’s Business and Industry.”

Product Candidate

Target Indication

Development Status

Estimated Completion of Phase

Estimated Cost to Complete Phase

Ublituximab & Umbralisib

Approximately $2 million

In Relapsing forms of Multiple Sclerosis (RMS)

Approximately $15 million

Umbralisib + Ublituximab

Relapsed/refractory NHL patients

Approximately $3 million

*Completion of phase for this study indicates completion of portion of study, which, if successful, would support an accelerated approval.

Completion dates and costs in the above table are estimates due to the uncertainties associated with clinical trials and the related requirements of development.

In the cases where the requirements for clinical trials and development programs have not been fully defined, or are dependent on the success of other trials, we cannot estimate trial completion or cost with any certainty.

The actual spending on each trial during the year is also dependent on funding.

We therefore direct your attention to Item 7 under the heading “Liquidity and Capital Resources.”

INTELLECTUAL PROPERTY AND PATENTS

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We also depend upon the skills, knowledge and experience of our scientific and technical personnel, as well as that of our advisors, consultants and other contractors.

This knowledge, trade secrets, proprietary information and experience we call “know-how.” To help protect our proprietary know-how which is not patentable, and for inventions for which patents may be difficult to enforce, we rely on trade secret protection and confidentiality agreements to protect our interests.

secret protection and confidentiality agreements to protect our interests.

To this end, we seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our collaborators, scientific advisors, employees and consultants, and invention assignment agreements with our employees and consultants.

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The intellectual property portfolios for our most advanced drug candidates as of February 2021 are summarized below.

Each of these portfolios contains pending patent applications covering our drug candidates and uses and combinations of the drug candidates, prosecution has just begun or is in progress.

Each of these portfolios contains one or more pending patent applications covering our products and product candidates and uses and combinations thereof.

For those patents, prosecution is in progress.

Prosecution is a lengthy process, during which the scope of the claims initially submitted for examination by the USPTO is often significantly narrowed by the time they issue, if they issue at all.

We expect this to be the case with respect to our pending patent applications referred to below.

Additionally, because the date for any potential regulatory approval is currently unknown we cannot predict the expected expiration date, and it is possible that the life of these patents following regulatory approval could be minimal.

This may be the case with respect to our pending patent applications referred to below.

UKONIQ (umbralisib)

Pursuant to our license for UKONIQ with Rhizen, we have the exclusive commercial rights to a series of patents and patent applications in the U.S.

and multiple countries around the world.

The patent applications include composition of matter patents relating to the structure, mechanism of action, and formulation for UKONIQ as well as method of use patents which cover use of UKONIQ in combination with various agents and for various therapeutic indications.

The composition of matter patent for UKONIQ has been issued in the U.S., Europe, and other jurisdictions, including Canada, China, Korea, Japan, and Australia.

The expected expiration of the composition of matter patent is 2033, exclusive of patent term extensions, which could result in later expiration dates.

Applications are pending in other jurisdictions.

We also have a method of use patent on the combination of UKONIQ and ublituximab, which has been issued in the U.S., Europe, and other jurisdictions, including Australia, China, Korea, and Japan, and is pending in other territories.

The expected expiration of the method of use patent for the combination of UKONIQ and ublituximab is 2033.

Pursuant to our license for ublituximab with LFB Biotechnologies, GTC Biotherapeutics, and LFB/GTC LLC, we have the exclusive commercial rights to a series of patents and patent applications in the U.S.

and in multiple countries around the world, as well as a non-exclusive license to additional background patent rights.

These patents and patent protections include composition of matter patents relating to the structure and mechanism of action for ublituximab as well as method of use patents which cover use of ublituximab in combination with various agents and for various therapeutic indications.

The composition of matter patent for ublituximab has been issued in the U.S.

and Europe, which affords patent protection until 2029 in the U.S.

and 2025 in Europe, exclusive of patent term extensions.

We also have a method of use patent on the combination of umbralisib and ublituximab which has been issued in the U.S., Europe, and Japan, and is pending in other territories globally.

Additionally, we have numerous granted patents and pending patent applications outside the U.S.

which include claims directed to the composition of matter and methods of treatment with ublituximab in various settings.

Pursuant to our license for umbralisib with Rhizen, we have the exclusive commercial rights to a series of patent applications in the U.S.

and multiple countries around the world.

The patent applications include composition of matter patents relating to the structure, mechanism of action, and formulation for umbralisib as well as method of use patents which cover use of umbralisib in combination with various agents and for various therapeutic indications.

The composition of matter patent for umbralisib has been issued in the U.S.

and Europe, which affords patent protection until 2033, exclusive of patent term extensions.

We also have a method of use patent on the combination of umbralisib and ublituximab which has been issued in the U.S., EU, and Japan, and is pending in other territories globally.

All other patent applications currently filed for umbralisib are currently pending.

Because the dates for any potential regulatory approval are currently unknown we cannot predict the expected expiration date, and it is possible that the life of these patents following regulatory approval could be minimal.

Cosibelimab (anti-PDL1 monoclonal antibody)

Pursuant to our Global Collaboration with Checkpoint Therapeutics, we have the exclusive commercial rights in the treatment of hematological cancers and autoimmune diseases to a series of patent applications pending in the United States, Australia, Canada, Europe, Israel and Korea.

Any patents maturing from these pending applications will expire no sooner than October 2033.

These patents and patent applications include composition of matter patents relating to the structure and mechanism of action for ublituximab, as well as method of use patents which cover use of ublituximab in combination with various agents and for various therapeutic indications.

The composition of matter patent for ublituximab has been issued in the U.S., Europe and other jurisdictions, including Australia, Canada, China, Japan, Korea, and India.

The expected expiration for the composition of matter patent is 2029 in the U.S.

and 2025 in Europe and other non-US jurisdictions, exclusive of patent term extensions, which could result in later expiration dates.

The expected expiration of the method of use patent for the combination of UKONIQ and ublituximab is 2033.

Cosibelimab (anti-PD-L1 monoclonal antibody)

Patents to the anti-PD-L1 antibody and methods of use have issued in the U.S., Australia, Japan, Israel, Korea, and Mexico, and are pending in other jurisdictions.

Any patents maturing from these pending applications are expected to expire no sooner than October 2033.

A patent directed to the composition of matter of cosibelimab has issued in the United States and is expected to expire in 2037, exclusive of patent term extensions, which could result in later expiration dates.

Applications are pending in many other jurisdictions.

TG-1701 (BTK inhibitor)

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and certain other countries.

All patent applications currently filed for the BTK program are currently pending.

Any patents maturing from these pending applications will expire no sooner than October 2034.

Patents directed to the compound have granted in the U.S., Europe, and other jurisdictions, including Australia, Canada, Japan, China, and Korea and are expected to expire no sooner than October 2034.

Applications are pending in other jurisdictions.

TG-1801 (anti-CD47/anti-CD19 bispecific antibody)

Pursuant to our joint venture and license option agreement with Novimmune, we maintain an exclusive option, exercisable at specific times during development, to license the commercial rights to a series of global patent applications, and the non-exclusive right to certain technology patent applications.

Any patents maturing from these pending applications will expire no sooner than December 2032.

Pursuant to our joint venture and license option agreement with NovImmune, we maintain an exclusive option, exercisable at specific times during development, to license the commercial rights to a series of global patent applications and patents, and the non-exclusive right to certain technology patent applications.

Patents directed to a bispecific antibody have issued in Australia, China, Europe, Japan, and Russia and are pending in other jurisdictions including the U.S.

Any patents maturing from these pending applications are expected to expire no sooner than December 2033.

Limitations on Patent Rights and Trade Secrets

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See “Item 1A – Risk Factors -- Risks Related to the Company’s Intellectual Property.

” In addition, the limited patent protection may adversely affect the value of our product candidates and may inhibit our ability to obtain a corporate partner at terms acceptable to us, if at all.

” In addition, the limited patent protection may adversely affect the value of our products or product candidates and may inhibit our ability to obtain a corporate partner at terms acceptable to us, if at all.

Proof of direct infringement by a competitor for method of use patents can prove difficult because the competitors making and marketing a product typically do not engage in the patented use.

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Pursuant to these regulations, ublituximab received Orphan Drug Designation from the FDA for the treatment of MZL (Nodal and Extranodal) in September 2013, for the treatment of CLL in August of 2010, and Orphan Drug Designation by the European Medicines Agency (“EMA”) for the treatment of CLL in November of 2009.

We also obtained Orphan Drug Designation for umbralisib as monotherapy for the treatment of CLL in August 2016, and for the treatment of nodal, extranodal, and splenic MZL in April 2019.

We also obtained Orphan Drug Designation for umbralisib as monotherapy for the treatment of CLL in August 2016, for the treatment of nodal, extranodal, and splenic MZL in April 2019, and for the treatment of FL in March 2020.

In addition, in January 2017, we announced that the FDA granted Orphan Drug Designation covering the combination of ublituximab and umbralisib for the treatment of patients with CLL and DLBCL.

We believe that ublituximab and umbralisib, as well as our other pipeline products may be eligible for additional Orphan Drug Designations;

however, we cannot assure you that ublituximab, umbralisib, or any other drug candidates we may acquire or in-license, will obtain such Orphan Drug Designations or that we will be the first to receive FDA approval for any drug candidates that do obtain Orphan Drug Designation so as to be eligible for market exclusivity protection.

Patent Term Restoration and Marketing Exclusivity

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This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request” for such a trial.

Upon FDA approval, we believe umbralisib would qualify for five years of data exclusivity as a NCE and ublituximab would qualify for twelve years of data exclusivity as an innovator biologic.

LICENSING AGREEMENTS AND COLLABORATIONS

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The license will terminate on a country by country basis upon the expiration of the last licensed patent right or 15 years after the first commercial sale of a product in such country, unless the agreement is earlier terminated (i) by Ildong if the Company challenges any of the licensed patent rights, (ii) by either party due to a breach of the agreement, or (iii) by either party in the event of the insolvency of the other party.

UKONIQ (umbralisib)

In September 2014, we exercised our option to license the global rights to umbralisib, thereby entering into an exclusive licensing agreement (the “Umbralisib License”) with Rhizen Pharmaceuticals, S A (“Rhizen”) for the development and commercialization of umbralisib.

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Under the terms of the Umbralisib License, Rhizen received a $4.0 million cash payment and 371,530 shares of our common stock as an upfront license fee.

With respect to umbralisib, Rhizen will be eligible to receive regulatory filing, approval and sales-based milestone payments in the aggregate of approximately $175 million, a small portion of which will be payable on the first New Drug Application (NDA) filing and the remainder on approval in multiple jurisdictions for up to two oncology indications and one non-oncology indication and attaining certain sales milestones.

In addition, if umbralisib is co-formulated with another drug to create a new product (a "New Product"),

Rhizen will be eligible to receive similar regulatory approval and sales-based milestone payments for such New Product.

With respect to umbralisib, Rhizen will be eligible to receive regulatory filing, approval and sales-based milestone payments in the aggregate of approximately $175 million, a small portion of which will be payable on the first NDA filing and the remainder on approval in multiple jurisdictions for up to two oncology indications and one non-oncology indication and attaining certain sales milestones.

In addition, if umbralisib is co-formulated with another drug to create a new product (a "New Product"), Rhizen will be eligible to receive similar regulatory approval and sales-based milestone payments for such New Product.

Additionally, Rhizen will be entitled to tiered royalties that escalate from high single digits to low double digits on our future net sales of umbralisib and any New Product.

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Pursuant to the agreement, in June 2018 we paid Novimmune an upfront payment of $3.0 million in our common stock.

Further milestone payments will be paid based on early clinical development, and the Company will be responsible for the costs of clinical development of the product through the end of the Phase 2 clinical trials, after which the Company and Novimmune will be jointly responsible for all development and commercialization costs.

Further milestone payments will be paid based on early clinical development, and the Company will be responsible for the costs of clinical

development of the product through the end of the Phase 2 clinical trials, after which the Company and Novimmune will be jointly responsible for all development and commercialization costs.

The Company and Novimmune will each maintain an exclusive option, exercisable at specific times during development, for the Company to license the rights to TG-1801, in which case Novimmune is eligible to receive additional milestone payments totaling approximately $185 million as well as tiered royalties on net sales in the high single to low double digits upon and subject to the achievement of certain milestones.

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For the cancer indications for which we are developing our products there are a number of established therapies with which we will compete:

● For the treatment of Chronic Lymphocytic Leukemia, if U2 is approved, we expect U2 to compete with approved drugs such as ibrutinib (AbbVie and Janssen), venetoclax (AbbVie and Roche), obinutuzumab (Roche), idelalisib (Gilead) and duvelisib (Verastem), and established treatments such as rituximab (Roche), and several generically available chemotherapies.

Additionally, there are two second generation BTK inhibitors similar to ibrutinib in late-stage clinical testing for CLL that could enter the market in the next 12-36 months.

● For the treatment of Chronic Lymphocytic Leukemia, if U2 is approved, we expect U2 to compete with approved drugs such as ibrutinib (AbbVie and Janssen), acalabrutinib (AstraZeneca), venetoclax (AbbVie and Roche), obinutuzumab (Roche), idelalisib (Gilead), duvelisib (Verastem), and established treatments such as rituximab (Roche), and several generically available chemotherapies.

Additionally, there are second generation BTK inhibitors similar to ibrutinib in late-stage clinical testing for CLL that could enter the market in the next 12-36 months.

Each of these agents can be used as monotherapy or in combination with one or more of the other agents.

● For the treatment of Marginal Zone Lymphoma, if approved, we expect umbralisib to compete with ibrutinib (AbbVie and Janssen), lenalidomide (Bristol-Myers) and established treatments such as rituximab and several generically available chemotherapies.

● For the treatment of Follicular Lymphoma, if approved, we expect umbralisib to compete with approved drugs such as obinutuzumab (Roche), idelalisib (Gilead), copanlisib (Bayer), and duvelisib (Verastem), lenalidomide (Bristol-Myers) and established treatments such as rituximab (Roche), and several generically available chemotherapies.

● For the treatment of Marginal Zone Lymphoma, we expect UKONIQ (umbralisib) to compete with ibrutinib (AbbVie and Janssen), lenalidomide (Bristol-Myers), and established treatments such as rituximab, and several generically available chemotherapies.

There are several kinase inhibitors in earlier stages of development.

● For the treatment of Follicular Lymphoma, we expect umbralisib to compete with approved drugs such as obinutuzumab (Roche), idelalisib (Gilead), copanlisib (Bayer), duvelisib (Verastem), lenalidomide (Bristol-Myers), tazemetostat (Epizyme), and established treatments such as rituximab (Roche), and several generically available chemotherapies.

Each of these agents can be used as monotherapy or in combination with one or more of the other agents.

There are also several PI3K delta inhibitors in earlier stages of development.

● In addition, a number of pharmaceutical companies are developing antibodies and bispecific antibodies targeting CD20, CD19, CD47 and other B-cell associated targets, chimeric antigen receptor T-cell (“CAR-T”) immunotherapy, and other B-cell ablative therapy which, if approved, would potentially compete with U2 and umbralisib.

There are several kinase inhibitors in earlier stages of development.

In addition, a number of pharmaceutical companies are developing antibodies and bispecific antibodies targeting CD20, CD19, CD47 and other B-cell associated targets, chimeric antigen receptor T-cell (“CAR-T”) immunotherapy, and other B-cell ablative therapy which, if approved, would potentially compete with U2 and UKONIQ.

For Multiple Sclerosis for which we are developing ublituximab there are a number of established therapies with which we will compete:

● If ublituximab is approved, we expect ublituximab will primarily compete against other CD20 targeted agents, while the group of CD20 targeted agents will also compete broadly against a number of already approved MS therapies.

Currently, there is one anti-CD20 monoclonal antibody approved, ocrelizumab (Roche), and another having recently completed Phase 3 development, ofatumumab (Novartis), which is expected to enter the market in the next 12 months.

Currently, there are two anti-CD20 monoclonal antibodies approved, ocrelizumab (Roche) and ofatumumab (Novartis).

Cosibelimab, TG-1701 and TG-1801 if approved will also face competition from drugs on the market and under development that are in the same therapeutic class as each of those drugs.

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As with any supply program, obtaining pre-clinical and clinical materials of sufficient quality and quantity to meet the requirements of our development programs cannot be guaranteed and we cannot ensure that we will be successful in this endeavor.

In addition, as we move closer to commercialization for ublituximab and umbralisib we will need to scale-up production to ensure adequate commercial supply, complete validation batches and complete pre-approval inspection batches.

We are currently in the process of scaling up ublituximab and completing validation and pre-approval inspection batches for both ublituximab and umbralisib.

In addition, as we move closer to commercialization for ublituximab we will need to scale-up production to ensure adequate commercial supply, complete validation batches and complete pre-approval inspection batches.

We have completed validation batches and are currently in the process of scaling up ublituximab production, including completing pre-approval inspection batches for ublituximab.

This is an expensive process which will require significant investment on our part over the next 24 months and there can be no assurance given that such scale-up and process validation will be successful in providing pharmaceutical product that is of sufficient quantity, or of a quality that is consistent with our previously established specifications, or that meets the requirements set by regulatory agencies under which we may seek approval of our product candidates.

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However, there can be no assurance that we will be able to successfully contract with such manufacturers on terms acceptable to us, or at all.

Contract manufacturers are subject to ongoing periodic and unannounced inspections by the FDA, the Drug Enforcement Administration and corresponding state agencies to ensure strict compliance with cGMP and other state and federal regulations.

Contract manufacturers in the U.S.

are subject to ongoing periodic and unannounced inspections by the FDA, the Drug Enforcement Administration if applicable, and corresponding state agencies to ensure strict compliance with cGMP and other state and federal regulations.

Contract manufacturers outside of the United States face similar challenges from the numerous local and regional agencies and authorized bodies.

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If they are deemed out of compliance with cGMPs, product recalls could result, inventory could be destroyed, production could be stopped and supplies could be delayed or otherwise disrupted.

If we need to change manufacturers after commercialization, the FDA and corresponding foreign regulatory agencies must approve these new manufacturers in advance, which will involve testing and additional inspections to ensure compliance with FDA regulations and standards and may require significant lead times and delay.

If we need to change manufacturers after commercialization, the FDA and corresponding foreign regulatory agencies must approve these new manufacturers in advance, which will involve testing, regulatory submissions, and additional inspections to ensure compliance with FDA regulations and standards and may require significant lead times and delay.

Furthermore, switching manufacturers may be difficult because the number of potential manufacturers is limited.

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GOVERNMENT AND INDUSTRY REGULATION

Numerous governmental authorities, principally the FDA and corresponding state and foreign regulatory agencies, impose substantial regulations upon the clinical development, manufacture and marketing of our drug candidates, as well as our ongoing research and development activities.

None of our drug candidates have been approved for sale in any market in which we have marketing rights.

Before marketing in the U.S., any drug that we develop must undergo rigorous pre-clinical testing and clinical trials and an extensive regulatory approval process implemented by the FDA under the FDCA.

The FDA regulates, among other things, the pre-clinical and clinical testing, safety, efficacy, approval, manufacturing, record keeping, adverse event reporting, packaging, labeling, storage, advertising, promotion, export, sale and distribution of biopharmaceutical products.

Numerous governmental authorities, principally the FDA and corresponding state and foreign regulatory agencies, impose substantial regulations upon the clinical development, manufacture and marketing of our product candidates, as well as our ongoing research and development activities.

We, along with our third-party contractors, will be required to navigate the various pre- and post-approval requirements of the governing regulatory agencies of the jurisdictions in which we wish to conduct clinical studies or market our product candidates.

None of our product candidates, except UKONIQ, have been approved for sale in any market in which we have marketing rights.

Before marketing in the U.S., any drug that we develop must undergo rigorous pre-clinical testing and clinical trials and an extensive regulatory review and approval process implemented by the FDA under the FDCA and, in the case of biologics, the Public Health Service Act (PHS Act).

The FDA regulates, among other things, the pre-clinical and clinical testing, safety, efficacy, approval, manufacturing, quality control and assurance, record keeping, pharmacovigilance and adverse event reporting, packaging, labeling, storage, advertising, promotion, import and export, sale and distribution of biopharmaceutical products.

The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

Product Development and Applications for Marketing Authorization

The regulatory review and approval process is lengthy, expensive and uncertain.

We are required to submit extensive pre-clinical and clinical data and supporting information to the FDA for each indication or use to establish a drug candidate’s safety and efficacy before we can secure FDA approval to market or sell a product in the U.S.

We are required to submit extensive pre-clinical and clinical data and supporting information to the FDA for each indication or use to establish a drug candidate’s safety and efficacy before

we can secure FDA approval to market or sell a product in the U.S.

The approval process takes many years, requires the expenditure of substantial resources and may involve ongoing requirements for post-marketing studies or surveillance.

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The appearance of any unacceptable toxicity or side effect could cause us or regulatory authorities to interrupt, limit, delay or abort the development of any of our drug candidates and could ultimately prevent approval by the FDA or foreign regulatory authorities for any or all targeted indications.

For purposes of NDA approval, clinical trials are typically conducted in the following sequential phases:

For purposes of clinical development and to pursue NDA or BLA approval, clinical trials are typically conducted in the following sequential phases:

The drug is administered to a small group of humans, either healthy volunteers or patients, to test for safety, dosage tolerance, absorption, metabolism, excretion, and clinical pharmacology.

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Additionally, in August 2017, we reached an agreement with the FDA regarding an SPA on the design of two Phase 3 clinical trials for ublituximab, referred to as the ULTIMATE I and ULTIMATE II Phase 3 clinical trials, for the treatment of relapsing forms of Multiple Sclerosis (RMS).

Additionally, in August 2017, we reached

an agreement with the FDA regarding an SPA on the design of two Phase 3 clinical trials for ublituximab, referred to as the ULTIMATE I and ULTIMATE II Phase 3 clinical trials, for the treatment of relapsing forms of Multiple Sclerosis (RMS).

The SPA provides agreement that the two Phase 3 trial designs adequately address objectives that, if met, would support the regulatory submission for approval of ublituximab.

Despite obtaining an SPA the trials may not be positive and even if positive may not support FDA approval.

The FDA may permit expedited development, evaluation, and marketing of new therapies intended to treat persons with serious or life-threatening conditions for which there is an unmet medical need under its fast track drug development programs.

A sponsor can apply for Fast Track designation at the time of submission of an IND, or at any time prior to receiving marketing approval of the new drug application, or NDA.

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Sponsors of products in Fast Track drug development programs must be in regular contact with the reviewing division of the FDA to ensure that the evidence necessary to support marketing approval will be developed and presented in a format conducive to an efficient review.

Sponsors of products in fast track drug development programs ordinarily are eligible for priority review of a completed application in six months or less and also may be permitted to submit portions of an NDA to the FDA for review before the complete application is submitted.

Sponsors of products in Fast Track drug development programs are also permitted to submit portions of an NDA or BLA to the FDA on a rolling basis where the FDA may consider reviewing portions of a marketing application before the sponsor submits the complete application.

In addition, sponsors may also apply to the FDA for Breakthrough Therapy Designation (“BTD”).

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In January 2019, we announced that the FDA granted Breakthrough Therapy Designation for umbralisib for the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one prior anti-CD20 regimen based on interim results from a subset of patients from the MZL cohort of the UNITY-NHL clinical trial.

Sponsors of drugs designated as fast track and as breakthrough therapy also may seek approval under the FDA’s accelerated approval regulations.

Sponsors of drugs granted Fast Track or breakthrough therapy designation also may seek approval under the FDA’s accelerated approval regulations.

Under this authority, the FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity.

To obtain accelerated approval you have to be the first company to have a treatment that successfully addresses a certain unmet medical need or you need to clearly be better than all other treatments for that medical need, subject to certain qualifications.

Many companies have filed for accelerated approval and have subsequently failed to obtain such approval for a variety of reasons, including not being first or not being best.

To the extent a product does obtain an accelerated approval, such approval will be subject to the requirement that the applicant study the drug further in a post-marketing confirmation clinical trial to verify and describe its clinical benefit where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit or uncertainty as to the relation of the observed clinical benefit to ultimate outcome.

Accelerated approval is sometimes referred to as conditional approval because if the results of these confirmation clinical trials are not successful, the FDA has the right to remove the drug from the market and has done so in the past.

To obtain accelerated approval a sponsor must be able to demonstrate the drug candidate treats a serious condition, provides a meaningful advantage over other available therapies, and demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

Many companies have filed for accelerated approval and have subsequently failed to obtain such approval for a variety of reasons.

To the extent a product does obtain an accelerated approval, such approval will be subject to the requirement that the applicant study the drug further in a post-marketing confirmatory clinical trial to verify and describe its clinical benefit where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit or uncertainty as to the relation of the observed clinical benefit to ultimate outcome.

Accelerated approval is sometimes referred to as conditional approval because if the results of these confirmatory clinical trials fail to verify clinical benefit, the FDA has the right to remove the drug from the market and has done so in the recent past.

Post-marketing confirmation studies are usually underway at the time an applicant files the NDA.

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The applicant must carry out any such post-marketing confirmation studies with due diligence.

It is also becoming more common for the FDA to request a Risk Evaluation and Mitigation Strategy, or REMS, as part of a NDA/BLA.

In February 2021, we obtained accelerated approval of UKONIQ for relapsed or refractory MZL who have received at least one prior anti-CD20-based regimen and for relapsed or refractory FL who have received at least three prior lines of systemic therapy.

The FDA approved these indications based on overall response rate.

Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

It is also becoming more common for the FDA to request a Risk Evaluation and Mitigation Strategy, or REMS, as part of an NDA/BLA.

The REMS plan contains post-market obligations of the sponsor to train prescribing physicians, monitor off-label drug use, and conduct Phase 4 follow-up studies and registries to ensure the continued safe use of the drug.

As part of the approval process, the FDA must inspect and approve each manufacturing facility.

Among the conditions of approval is the requirement that a manufacturer’s quality control and manufacturing procedures conform to cGMP.

Manufacturers must expend significant time, money and effort to ensure continued compliance, and the FDA conducts periodic inspections to certify compliance.

The NDA and BLA review process also generally includes a pre-approval inspection, or PAI, to assess the manufacturing facilities and relevant processes and data for compliance, and readiness for commercial manufacture in accordance with cGMPs.

Among the conditions of approval is the requirement that a manufacturer’s quality systems and manufacturing procedures conform to cGMP.

Even when product approval is received, manufacturers must expend significant time, money and effort to ensure continued compliance, and the FDA conducts periodic surveillance inspections to monitor the manufacturing process and drug quality and evaluate whether the manufacturers are in compliance.

It may be difficult for our manufacturers or us to comply with the applicable cGMP, as interpreted by the FDA, and other FDA regulatory requirements.

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If we were to experience any such delay that would negatively impact our business and timeline to commercialization of any of our drug candidates affected by such manufacturing issue.

If the FDA grants approval, the approval will be limited to those disease states, conditions and patient populations for which the product is safe and effective, as demonstrated through clinical studies.

Further, a product may be marketed only in those dosage forms and for those indications approved in the NDA/BLA.

Certain changes to an approved NDA/BLA, including, with certain exceptions, any significant changes to labeling, require approval of a supplemental application before the drug may be marketed as changed.

Any products that we manufacture or distribute pursuant to FDA approvals are subject to continued monitoring and regulation by the FDA, including compliance with cGMP and the reporting of adverse experiences with the drugs.

The nature of marketing claims that the FDA will permit us to make in the labeling and advertising of our products will generally be limited to those specified in FDA approved labeling, and the advertising of our products will be subject to comprehensive monitoring and regulation by the FDA.

Drugs whose review was accelerated may carry additional requirements on marketing activities, including the requirement that all promotional materials are pre-submitted to the FDA.

Claims exceeding those contained in approved labeling will constitute a violation of the FDCA.

Violations of the FDCA or regulatory requirements at any time during the product development process, approval process, or marketing and sale following approval may result in agency enforcement actions, including withdrawal of approval, recall, seizure of products, warning letters, injunctions, fines and/or civil or criminal penalties.

Post-Approval Requirements

Any products for which we receive FDA approval are subject to continuing regulation by the FDA and other federal and state regulators on a wide range of matters, including, among other things cGMPs and product quality, pharmacovigilance and reporting of adverse events, product distribution requirements, fulfilling post-marketing or confirmatory study or REMS commitments, and complying with FDA promotion and advertising requirements.

Violations of the FDCA or other post-approval regulatory requirements may result in agency enforcement actions, including withdrawal of approval, recall, seizure of products, warning letters, injunctions, fines and/or civil or criminal penalties.

Any agency enforcement action could have a material adverse effect on our business.

The FDA promotion and advertising requirements applicable to marketed products include, among other things, standards for direct-to-consumer advertising, restrictions against promoting products for uses or in patient populations that are not either described in the product’s approved indications and uses or otherwise consistent with the FDA-approved product labeling, limitations on industry-sponsored scientific and educational activities, rules regarding communication of health care economic information regarding biopharmaceutical products to payors and formularies, and requirements for promotional activities involving the internet.

Drugs whose review was accelerated may carry additional requirements on marketing activities, including the requirement that all promotional materials are pre-submitted to the FDA.

Although a healthcare provider may prescribe a product for a use that has not been approved by the FDA when the healthcare provider deems such use to be appropriate in his or her professional medical judgment, manufacturers may not market or promote unapproved uses.

Although court decisions have to some degree impacted FDA’s enforcement activity regarding alleged off-label promotion in light of First Amendment considerations, there are still significant risks in this area, in part because there is the potential for False Claims Act exposure in addition to the potential for enforcement under the FDCA.

After product approval, quality control and manufacturing procedures must continue to conform to applicable manufacturing requirements.

FDA regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMPs.

Manufacturers and other entities involved in the manufacture and distribution of approved products are required to register their establishments and list their products with the FDA and certain state agencies.

Manufacturers and their third-party contractors may be subject to periodic unannounced inspections by the FDA and certain state agencies for assessment of compliance with cGMPs and other applicable laws.

Accordingly, manufacturers must continue to expend time, money, and effort in the areas of production and quality control to maintain quality control and manufacturing compliance.

Discovery of problems with a product after approval may result in restrictions on a product, including, among other things, withdrawal of approval, recall or withdrawal of the product from the market.

In addition, changes to the manufacturing process are strictly regulated, and depending on the significance of the change, may require prior FDA approval or notification before being implemented.

Other types of changes to the approved product, such as adding new indications and claims to the product labeling, are also subject to further FDA review and approval.

Marketed products must meet the requirements of the Drug Supply Chain Security Act, or DSCSA, which regulates the commercial distribution of prescription drug products at the federal level.

The DSCSA sets certain standards for federal or state registration, requires tracing of products through the pharmaceutical distribution supply chain, and imposes other requirements on entities in the supply chain, including manufacturers and repackagers, wholesale distributors, third-party logistics providers, and dispensers.

The DSCSA requirements, development of standards, and the system for product tracing have been and will continue to be phased in over a period of years, with FDA indicating enforcement discretion on certain aspects due to the COVID-19 pandemic.

In addition, the postmarketing discovery of previously unknown problems with a product or the failure to comply with applicable FDA requirements can have negative consequences, including adverse publicity, judicial or administrative enforcement, warning letters from the FDA, mandated corrective advertising or communications with doctors, and civil or criminal penalties, among others.

Newly discovered or developed safety or effectiveness data may require changes to a product’s approved labeling, including the addition of new warnings and contraindications, and may require the implementation of other risk management measures.

From time to time, legislation is drafted, introduced and passed in Congress that could significantly change the statutory provisions governing the approval, manufacturing and marketing of products regulated by the FDA.

In addition to new legislation, FDA regulations, guidance documents, and policies are often revised or reinterpreted by the agency in ways that may significantly affect our business.

It is impossible to predict whether further legislative or FDA regulation or policy changes will be enacted or implemented and what the impact of such changes, if any, may be.

Should we wish to market our products outside the U.S., we must receive marketing authorization from the appropriate foreign regulatory authorities.

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Importantly, the level of evidence of efficacy and safety necessary to apply for marketing authorization for a drug candidate differs from country to country.

In particular, clinical trial endpoints, and the level of clinical evidence that may support an accelerated approval filing with the US FDA, such as the ORR data we intend to use as the basis for a filing for umbralisib in MZL, may be insufficient to file for marketing application outside of the US.

In particular, clinical trial endpoints, and the level of clinical evidence that may support an accelerated approval filing with the FDA, such as the ORR data from the single-arm cohorts of the UNITY-NHL study that we used as the basis for a filing and approval for UKONIQ in MZL and FL, may be insufficient to file for marketing applications outside of the U.S.

At present, companies are typically required to apply for foreign marketing authorizations at a national level.

However, within the European Union, registration procedures are available to companies wishing to market a product in more than one European Union member state.

However, within the European Union, centralized registration procedures are available to companies wishing to market a product across the European Union member states.

Typically, if the regulatory authority is satisfied that a company has presented adequate evidence of safety, quality and efficacy, then the regulatory authority will grant a marketing authorization.

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These third-party payors are increasingly reducing reimbursements for medical drugs and services.

In addition, the containment of healthcare costs has become a priority of federal and state governments, and the prices of drugs have been a focus in this effort.

In addition, the containment of healthcare costs has become a priority of foreign and U.S.

federal and state governments, and the prices of drugs have been a focus in this effort.

government, state legislatures and foreign governments have shown significant interest in implementing cost-containment programs, including price controls, restrictions on reimbursement, importation, and requirements for substitution of generic drugs.

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Decreases in third-party reimbursement for our drug candidates, if approved, or a decision by a third-party payor to not cover our drug candidates could reduce physician usage of such drugs and have a material adverse effect on our sales, results of operations and financial condition.

In the United States, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the Affordable Care Act, enacted in March 2010, has had a significant impact on the health care industry.

In the U.S., the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the Affordable Care Act, enacted in March 2010, has had a significant impact on the health care industry.

The Affordable Care Act expanded coverage for the uninsured while at the same time containing overall healthcare costs.

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Court of Appeals for the Fifth Circuit affirmed the district court’s decision that the individual mandate is unconstitutional, but remanded the case to the district court to reconsider the severability question.

It is unclear how the ultimate decision in this case, or other efforts to repeal, replace, or invalidate the Affordable Care Act or its implementing regulations, or portions thereof, will affect the Affordable Care Act or our business.

Further, on January 20, 2017, U.S.

President Donald Trump signed an Executive Order directing federal agencies with authorities and responsibilities under the Affordable Care Act to waive, defer, grant exemptions from, or delay the implementation of any provision of the Affordable Care Act that would impose a fiscal burden on states or a cost, fee, tax, penalty or regulatory burden on individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

On October 13, 2017, President Trump signed an Executive Order that terminated the cost-sharing subsidies under the Affordable Care Act.

Several state Attorneys General filed suit to stop the administration from terminating these subsidies, but on October 25, 2017, a federal judge in California denied their request for a restraining order.

In addition, CMS has issued regulations giving states greater flexibility, starting in 2020, in the identification of the essential health benefits benchmarks for non-grandfathered individual and small group market health insurance coverage, including plans sold through the health insurance exchanges established under the Affordable Care Act.

There may be further action to repeal, replace or modify the Affordable Care Act.

While any legislative and regulatory changes will likely take time to develop and may or may not have an impact on the regulatory regime to which we are subject, we cannot predict the ultimate content, timing or effect of any healthcare reform legislation or the impact of potential legislation on us.

Thereafter, the U.S.

Supreme Court agreed to hear this case.

Oral argument in the case took place on November 10, 2020, and a ruling by the Court is expected sometime this year.

Although litigation and legislation over the Affordable Care Act are likely to continue, with unpredictable and uncertain results, we expect that the Biden administration may seek to expand and strengthen the Affordable Care Act.

There has been increasing legislative and enforcement interest in the United States with respect to drug pricing practices.

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Congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

The Trump administration is currently assessing additional proposals that are designed to affect drug pricing, such as tying U.S.

drug prices to prices outside the United States.

Congress and the Trump administration have each indicated that they will continue to seek new legislative and/or administrative measures to control drug costs.

We expect that additional U.S.

The Trump administration issued five executive orders intended to lower the costs of prescription drug products but it is unclear whether, and to what extent, these orders will remain in force under the Biden administration, which, like the Trump administration, has indicated lowering prescription drug prices is a priority.

Although we do not know what steps the Biden administration will take with respect to drug pricing, we expect that additional U.S.

federal healthcare reform measures could be adopted in the future, any of which could limit the amounts that the U.S.

federal government will pay for healthcare products and services, which could result in additional pricing pressures and reduced demand for any of our products that receive marketing approval.

In addition, in some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed.

At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control prescription drug pricing, including price and marketing cost disclosure and transparency measures, and, in some cases, authorizing importation of prescription drugs from other countries.

In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs.

These measures could reduce the ultimate demand for our products or put pressure on our product pricing.

We expect that additional state healthcare reform measures will be adopted in the future, which could limit the amounts that state governments will pay for healthcare products and services and result in additional pricing pressures.

In addition, in some foreign countries, the proposed pricing for a prescription drug must be approved before the drug may be lawfully marketed.

The requirements governing drug pricing vary widely from country to country.

For example, the European Union provides options for its member states to restrict the range of medicinal drugs for which their national health insurance systems provide reimbursement and to control the prices of medicinal drugs for human use.

A member state may approve a specific price for the medicinal drug or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal drug on the market.

There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical drugs will allow favorable reimbursement and pricing arrangements for any of our drugs.

Historically, drugs launched in the European Union do not follow price structures of the United States and generally tend to be significantly lower.

Other Healthcare Laws

For example, the United Kingdom and many European Union member states have robust health technology assessment processes to determine pricing and reimbursement for pharmaceuticals through their national health insurance system.

Many European Union members states also include either direct or indirect price referencing, or other price control mechanisms, in determining the price of a pharmaceutical in their market.

Historically, drugs launched in the European Union do not follow price structures of the U.S.

and generally tend to be significantly lower.

Healthcare Laws

We may also be subject to healthcare regulation and enforcement by the federal government and the states and foreign governments where we may market our product candidates, if approved.

These laws include, without limitation, state and federal anti-kickback, fraud and abuse, false claims, privacy and security and physician sunshine laws and regulations.

The federal Anti-Kickback Statute prohibits, among other things, any person from knowingly and willfully offering, soliciting, receiving or paying remuneration, directly or indirectly, to induce either the referral of an individual, for an item or service or the purchasing or ordering of a good or service, for which payment may be made under federal healthcare programs such as the Medicare and Medicaid programs.

The government has enforced the Anti-Kickback Statute to reach large settlements with healthcare companies based on sham consulting and other financial arrangements with physicians.

These laws include, without limitation:

state and federal anti-kickback, fraud and abuse, false claims, privacy and security laws;

laws governing interactions with healthcare professionals and related transparency requirements (such as the federal Sunshine Act and a range of state biopharmaceutical marketing and transparency laws);

and requirements for manufacturers to report certain calculated product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under government healthcare programs.

The compliance and enforcement landscape is informed by government enforcement precedent and settlement history, Advisory Opinions, and Special Fraud Alerts.

The risks we face and our approach to compliance may evolve over time in light of these types of developments.

The potential safe harbors available for, example, relative to the Anti-Kickback Statute, are subject to change through legislative and regulatory action, and we may decide to adjust our business practices or be subject to heightened scrutiny as a result.

The government has enforced the Anti-Kickback Statute to reach large settlements with healthcare companies based on research, consulting and other financial arrangements with physicians that the government alleged were not based on the provision of bona fide services and were intended as an inducement or reward.

A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

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Drug manufacturers are required to submit annual reports to the Centers for Medicare & Medicaid Services, which publicly posts the data on its website.

Effective January 1, 2022, these reporting obligations will extend to include transfers of value made to certain non-physician providers such as physician assistants and nurse practitioners.

Certain states also mandate implementation of compliance programs, impose restrictions on drug manufacturer marketing practices and/or require the tracking and reporting of gifts, compensation and other remuneration to physicians.

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HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.

In addition, we may be subject to state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by any third-party payor, including commercial insurers, and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways, thus complicating compliance efforts.

As of February 14, 2020, we had 134 full and part-time employees.

In addition, according to the U.S.

Federal Trade Commission, or the FTC, failing to take appropriate steps to keep consumers' personal information secure constitutes unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act.

The FTC expects a company's data security measures to be reasonable and appropriate in light of the sensitivity and volume of consumer information it holds, the size and complexity of its business, and the cost of available tools to improve security and reduce vulnerabilities.

Medical data is considered sensitive data that merits stronger safeguards.

The FTC's guidance for appropriately securing consumers' personal information is similar to what is required under HIPAA.

the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways, thus complicating compliance efforts.

For example, the California Consumer Protection Act, or CCPA, which went into effect on January 1, 2020, establishes a new privacy framework for covered businesses by creating an expanded definition of personal information, establishing new data privacy rights for consumers in California, and creating a new and potentially severe statutory damages framework for violations of the CCPA and for businesses that fail to implement reasonable security procedures and practices to prevent data breaches.

The CCPA was recently amended by the California Privacy Rights Act (CPRA), expanding certain consumer rights such as the right to know.

It remains unclear what, if any, additional modifications will be made to these laws by the California legislature or how these laws will be interpreted and enforced.

The potential effects of the CCPA and CPRA are significant and may cause us to incur substantial costs and expenses to comply.

Rest of the World Healthcare Regulation

For other countries outside of the U.S.

and the European Union, the requirements governing the conduct of clinical trials, drug licensing, sales and marketing, pricing and reimbursement vary from country to country.

If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

European Union member states, the United Kingdom, Switzerland and other foreign jurisdictions have adopted data protection laws and regulations, which impose significant compliance obligations.

In the European Union and the United Kingdom, the collection and use of personal data, including clinical trial data, is governed by the provisions of the General Data Protection Regulation, or GDPR.

The GDPR, together with national legislation, regulations and guidelines of the European Union member states and the United Kingdom governing the processing of personal data, impose strict obligations and restrictions on the ability to collect, analyze and transfer personal data, including health data from clinical trials and adverse event reporting.

In particular, these obligations and restrictions concern the consent of the individuals to whom the personal data relates, the information provided to the individuals, the transfer of personal data out of the European Union or the United Kingdom, security breach notifications, security and confidentiality of the personal data and imposition of substantial potential fines for breaches of the data protection obligations.

Compliance with the GDPR is a rigorous and time-intensive process that may increase the cost of doing business to ensure full compliance.

Furthermore, European data protection authorities may interpret the GDPR and national laws differently and impose additional requirements, which add to the complexity of processing personal data in or from the European Union or United Kingdom.

Human Capital

As of February 18, 2021, we had 272 full-time employees.

None of our employees are represented by a collective bargaining agreement, and we have never experienced a work stoppage.

We believe that our future success largely depends upon our continued ability to attract and retain a diverse workforce of highly skilled and dedicated employees.

We provide our employees with competitive salaries and bonuses and opportunities for equity ownership.

In addition, we provide an inclusive and collaborative work environment with learning and development opportunities.

We strive to foster a culture of diversity in backgrounds and ideas as we believe that diversity, equity, and inclusion are paramount to our success.

We understand that in order to perform at maximum capacity, our workforce needs to cultivate a welcoming and inclusive environment wherein employees feel they can represent themselves fully.

We pride ourselves on being an equal opportunity employer and strictly prohibit unlawful discrimination based on color, religion, gender, sexual orientation, gender identity/expression, national origin/ancestry, age, disability, marital and veteran status.

We expect to continue to grow our organizational footprint in 2021 with a focus on expanding our commercialization team in preparation for the potential U.S.

launches of U2 in CLL and ublituximab in MS.

We will continue to evaluate the business needs and market opportunities, balancing in-house expertise and core competencies with outsourced capacity.

Drug development and commercialization requires deep expertise across a broad array of disciplines.

Pharmaceutical companies of all sizes compete for a limited number of qualified applicants to fill specialized positions.

To attract qualified candidates, the Company offers an attractive total rewards package, consisting of base salary, cash bonus, a comprehensive benefit package, equity compensation, and 401(k) plan.

Bonus opportunities and equity compensation increase as a percentage of total compensation based on level of responsibility, and actual bonus awards are based on performance.

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