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Item 1. Business

2022-03-01 compared with 2021-03-01 · 248 added, 264 removed, 576 unchanged (47% of the section changed)

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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.

Currently, we have three 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.

FDA Accelerated Approval of UKONIQ

FDA Accelerated Approval and U.S.

Launch 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.

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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:

We have initiated and enrolled several Phase 3 and registration-directed Phase 2b clinical trials (i.e., clinical trials that may support a marketing application for approval).

The following are highlights from our current Phase 3 trials and registration-directed Phase 2b clinical trials:

Following FDA approval, we launched UKONIQ, making it available to patients through a distribution network that includes a specialty pharmacy and specialty distributors.

Payor coverage of UKONIQ and inclusion in the NCCN guidelines have been consistent with the FDA-approved indications.

We are committed to helping patients access their prescription for UKONIQ through the TG Patient Support Program, which we launched following the approval of UKONIQ.

Regulatory Developments related to UKONIQ in Combination with Ublituximab (U2) in CLL and UKONIQ in R/R MZL and FL

In March 2021, we submitted a Biologics License Application (BLA) for ublituximab in combination with UKONIQ for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) based on the results of the UNITY-CLL Phase 3 study.

In May 2021, we submitted a supplemental New Drug Application (sNDA) for UKONIQ to add an indication for CLL and SLL in combination with ublituximab.

Both the BLA and sNDA for U2 in CLL and SLL were accepted for filing, with a Prescription Drug User Fee Act (PDUFA) goal date of March 25, 2022 for both applications.

In November 2021, we received notification from the FDA that it planned to host a meeting of the Oncologic Drugs Advisory Committee (ODAC) in connection with its review of the pending BLA/sNDA for U2 for the treatment of adult patients with CLL and SLL.

The FDA’s concern giving rise to the ODAC meeting stems from an early analysis of overall survival from the UNITY-CLL trial, which showed a possible increased risk of death in patients receiving U2 compared to the control arm of obinutuzumab plus chlorambucil.

The potential questions and discussion topics for the ODAC include:

the benefit-risk of the U2 combination for the treatment of CLL or SLL, including the preliminary OS analysis, rates of serious adverse events, rates of dose discontinuations due to adverse events, and rates of dose modifications from the UNITY-CLL trial, and the benefit-risk of UKONIQ for R/R MZL and FL, each of which has been raised as a concern by the FDA.

Due to the concerns that prompted the ODAC meeting, the FDA also placed select clinical trials investigating U2 and its components in CLL and NHL, on partial clinical hold in January 2022.

Most studies included in the partial clinical hold were already closed to new enrollment or were on had been placed on administrative hold to new enrollment by the Company prior to the time the FDA imposed the partial clinical hold.

Registration Directed Clinical Trial Updates:

In 2021, we continued to advance our late-stage pipeline in hematology and multiple sclerosis.

The below are recent updates from our current registration directed clinical trials.

Currently clinical trials enrolling CLL or NHL patients to U2 or its components are on partial clinical hold.

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

o In December 2021, TG presented data from the UNITY-NHL trial during the American Society of Hematology (ASH) 2021 annual meeting which included updates from the U2 cohort in patients with relapsed or refractory MZL and an update from the U2 plus bendamustine cohort in relapsed or refractory Diffuse Large B-cell Lymphoma (DLBCL).

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

UNITY-CLL is a global Phase 3 randomized controlled clinical trial comparing the U2 combination to an active control arm of obinutuzumab plus chlorambucil in patients with both treatment naive and relapsed or refractory CLL.

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

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;

UNITY-CLL is a global, multi-center, Phase 3, randomized, controlled clinical trial comparing the U2 combination to an active control arm of obinutuzumab plus chlorambucil in patients with both treatment naive and relapsed or refractory CLL.

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

o The UNITY-CLL trial met its primary endpoint, 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).

These data, as well as additional sub-analyses from the UNITY-CLL trial were presented at major medical meetings in 2021.

● ULTRA-V Phase 2/3 Trial Evaluating U2 plus Venetoclax in CLL:

The ULTRA-V study is being conducted in two parts.

The ULTRA-V Phase 2 trial is designed to investigate the efficacy and safety of U2 in combination with venetoclax in subjects with treatment-naïve CLL and relapsed or refractory CLL, while the Phase 3 trial will compare U2 vs U2 plus venetoclax in the same population.

o The Phase 2 portion completed enrollment of approximately 165 patients in early 2021.

The Phase 3 portion commenced at approximately the same time.

Multiple Sclerosis:

● 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.

These trials are conducted under a SPA with the FDA.

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.

Each trial is a global, randomized, multi-center, double-blinded, double-dummy, active-controlled study comparing the efficacy and safety/tolerability of ublituximab (450mg dose administered by one hour intravenous infusion every 6 months, following a Day 1 infusion of 150mg over four hours, and a Day 15 infusion of 450mg over one hour) to teriflunomide (14mg oral tablets taken once daily) in subjects with relapsing forms of Multiple Sclerosis (RMS).

o In April 2021, data from the ULTIMATE I & II trials were presented for the first time at the American Academy of Neurology Annual meeting.

Both studies met their primary endpoint with ublituximab treatment demonstrating a statistically significant reduction in annualized relapse rate (ARR) over a 96-week period

(p<0.005 in each trial).

Key secondary MRI endpoints were also met.

Additional data from these trials has been presented at various other medical meetings.

o On December 14, 2021, we announced that the FDA accepted a BLA for ublituximab as a treatment for patients with RMS.

The FDA set a PDUFA goal date of September 28, 2022 and notified the Company that it is not currently planning to hold an advisory committee meeting to discuss this application.

CORPORATE INFORMATION

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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;

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

● 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;

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This approach enables us to minimize target risk while looking for the best available drug candidates around the world.

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.

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 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.

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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 is the second most common form of indolent NHL and accounts for approximately 10.6% of all NHL cases.

More than 8000 new cases of MZL are expected in the US in 2021, with approximately 6000 patients with R/R MZL on therapy each year.

MZL consists of three different subtypes:

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

It is the second most common form of NHL.

It is the 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.

FL accounts for approximately 17.1% of all NHL cases.

More than 13,000 new cases of FL are expected in the US in 2021, with ~12,500 patients with relapsed/refractory (R/R) FL on therapy each year.

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.

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

It is projected to represent 11% of all newly diagnosed hematological malignancies.

About 195,000 Americans are living with CLL, and the prevalence is predicted to rise due to an aging population, high survival rates, and improved outcomes with novel treatments.

The incidence of CLL has also increased in the last 20 years and is disproportionately affecting the elderly.

It is estimated that there will be 21,250 new cases in 2021.

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 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.

MS is the most prevalent chronic inflammatory disease of the CNS.

It is estimated that nearly 1 million people are living with MS in the United States and over 2.3 million people world-wide are living with 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 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.

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

The following table summarizes the current clinical trial status for our most advanced drug candidates as of February 2022.

Clinical Drug Candidate:

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Stage of Development

(pivotal study)

Ublituximab (anti-CD20/mAb)

Chronic Lymphocytic Leukemia

Phase 3 trial (UNITY-CLL)

Multiple Sclerosis

Phase 3 trials (ULTIMATE I and II)

Umbralisib (PI3K delta and CK1 epsilon inhibitor)

Chronic Lymphocytic Leukemia

Ublituximab (anti-CD20 mAb) and UKONIQ (PI3K-delta and CK1-epsilon inhibitor)

Chronic Lymphocytic Leukemia (CLL) and Relapsed or Refractory Marginal Zone Lymphoma (MZL)

Phase 3 trial (UNITY-CLL)

Marginal Zone Lymphoma

Phase 2b trial (UNITY-NHL)

Follicular Lymphoma

Phase 3 trial (ULTRA-V)

Phase 2b trial (UNITY-NHL)

Cosibelimab (anti-PDL1)

Ublituximab (anti-CD20 mAb)

Relapsing Forms of Multiple Sclerosis (RMS)

Phase 3 trials (ULTIMATE I and II)

Cosibelimab/TG-1501 (anti-PDL1 mAb)

B-cell cancers

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Phase 1 trial

TG-1801 (anti-CD47/CD19)

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

B-cell cancers

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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

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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.

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.

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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.

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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

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 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.

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.

In October 2018, final data from this Phase 2 study were presented at the 34 th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Berlin, Germany.

The presentation included final data on all 48 patients enrolled in the study through 48 weeks of treatment.

Ublituximab was well tolerated across all patients including those receiving rapid infusions, as low as a one hour for the 450mg dose currently being studied in the Phase 3 ULTIMATE program and no study drug related discontinuations occurred.

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 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.

Additionally, infusion related reactions (IRRs) were rare during the OLE, occurring in only 5 patients (11%) all Grade 1 or 2.

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

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.”

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.

Additional cohorts were added to this study to explore the triple therapy combination of U2 plus ibrutinib and the triple therapy combination of U2 plus bendamustine.

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

Data highlights include the following:

o Ublituximab plus Umbralisib (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.

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:

In December 2018, updated data for the U2 plus bendamustine cohort was presented at the 60th ASH Annual Meeting.

Overall, the U2 plus bendamustine combination was well tolerated and highly active in patients with advanced indolent and aggressive NHL, including those not eligible for HD/SCT or CD19 CART therapy.

Efficacy highlights from this poster included an 85% (11 of 13) ORR including a 54% CR rate in patients with relapsed or refractory FL.

o U2 plus Ibrutinib:

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.

Efficacy data was available from 44 patients and showed the U2 plus ibrutinib combination to be highly active.

The ORR amongst all evaluable patients was 84%, with 100% (22 of 22) of patients with CLL/SLL achieving a response, including 36% achieving a CR.

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 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.

The estimated median progression free survival (PFS) was 23.5 months (95% confidence interval:

13.1 – Not Estimable).

Enrollment is now closed with patients continuing to be followed.

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.

● 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 BTK inhibitor, in Lancet 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.

The publication includes safety and efficacy information from a total of 42 relapsed or refractory patients, 21 with CLL and 21 with MCL.

In this study, the combination of umbralisib and ibrutinib was well tolerated and consistent with the additive toxicity profile of the two drugs individually.

No dose-limiting toxicities were observed, and the maximum-tolerated dose of umbralisib when combined with ibrutinib was not reached.

The recommended phase 2 dose of umbralisib when given in combination with ibrutinib was 800 mg once daily.

Importantly, serious immune-mediated toxicities were not observed with this combination, as had previously been reported with combinations of different agents targeting this pathway, with only one case of transient Grade 3 transaminitis and no Grade 3/4 colitis or pneumonitis.

The combination of umbralisib and ibrutinib was also clinically active, with 90% of relapsed/refractory CLL patients achieving an overall response (n=19), of which 62% (n=13) achieved a partial response or partial response with lymphocytosis, and 29% (n=6) achieved a complete response.

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.

Sharman, MD, Medical Director, Hematology Research, US Oncology Network, was the Study Chair.

This trial has completed enrollment.

Final data from the MCL cohort of this study was presented at the 57th ASH meeting held in December 2015, with data from the CLL cohort published in the British Journal of Haematology in December 2016.

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.

● 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.

Additional investigator sponsored trials are also underway which are combining umbralisib and or the U2 combination with other approved agents for the treatment of B-cell malignancies.

Shortly after receiving approval, we initiated our commercial launch of UKONIQ in the United States.

We have staffed, trained and prepared a commercialization team comprising a field force of sales representatives and medical affairs professionals with deep experience in hematology.

Current Phase 3 or Registration-Directed Clinical Trials for Ublituximab and Umbralisib:

We have initiated and enrolled several Phase 3 and registration-directed Phase 2b clinical trials (i.e., clinical trials that may support a marketing application for approval).

The following are the current Phase 3 trials and registration-directed Phase 2b clinical trials:

The below are the current Phase 3 trials and registration-directed clinical trials of umbralisib and ublituximab.

Select CLL and NHL trials are currently on partial clinical hold.

(See discussion of UNITY-CLL below for more information on the partial clinical hold).

UNITY-NHL Phase 2b Trial:

UNITY-NHL is a broad, multicenter, open-label, 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.

These indolent lymphoma cohorts of the trial are being led by Nathan H.

Fowler, MD, Associate Professor, Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center.

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

● UNITY-NHL MZL Single Agent Umbralisib Cohort:

The MZL cohort enrolled adult patients who had at least one prior line of therapy that included an anti-CD20 monoclonal antibody.

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.

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

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.

The BTD was based on interim data from the MZL cohort of the UNITY-NHL trial.

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

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

In April 2019, the FDA granted orphan drug designation to umbralisib for the treatment of patients with any of the three types of marginal zone lymphoma (MZL):

nodal, extranodal, and splenic MZL.

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.

In March 2021, results from the UNITY-NHL Phase 2b trial were published in the Journal of Clinical Oncology The results from the MZL single agent cohort supported the FDA approval of UKONIQ in this indication.

● 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).

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.

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

As noted above, in March 2021, results from the UNITY-NHL Phase 2b trial were published in the Journal of Clinical Oncology.

The results from the FL single agent cohort supported the FDA approval of UKONIQ in this indication.

● UNITY-NHL Additional Cohorts :

There are additional exploratory cohorts of the UNITY-NHL trial focused on Diffuse Large B-Cell Lymphoma (DLBCL) and Mantle Cell Lymphoma (MCL).

In total, there are currently four cohorts in the UNITY-NHL trial including, MZL, FL/SLL, DLBCL, and MCL.

Each cohort is enrolled and evaluated separately from the others.

There are additional exploratory cohorts of the UNITY-NHL trial.

● At ASH 2021, we presented data from a cohort of relapsed or refractory (R/R) MZL patients who were treated with the U2 combination.

A total of 72 R/R MZL patients were enrolled.

Patients had a median of 2 prior lines of therapy (range 1 - 9), with 25% refractory to their immediate prior therapy.

Overall Response Rate (ORR) by independent review committee (IRC) was 70%, with 21% complete response (CR) rate (n=71).

Median duration of response (DOR) was not reached at a median follow up of 20 months.

Grade 3/4 AEs of clinical interest included diarrhea (13%), neutropenia (18%), ALT/AST increased (15%) and non-infectious colitis (2.8%).

● At ASH 2021, we also presented data from a cohort of R/R diffuse large B-cell lymphoma (DLBCL).

A total of 226 patients were treated within this cohort, 30 patients received umbralisib monotherapy, 66 patients received U2, and 130 patients received U2 plus bendamustine.

IRC assessed response rates included:

43% ORR and 17% CR for U2 plus bendamustine triple combination (n=130);

32% ORR and 11% CR for U2 double combination (n=66);

13% ORR and 3% CR for umbralisib monotherapy (n=30).

IRC assessed median duration of response (DOR) was 3 months for umbralisib monotherapy, 28 months for U2 combination, and 8 months for U2 plus bendamustine.

Both U2 and U2 + bendamustine demonstrated a manageable safety profile.

Grade 3/4 AEs of special interest occurring in the U2 group (n=66) included ALT/AST increased (12%), non-infectious colitis (2%), diarrhea (2%), neutropenia (11%) and pneumonitis (2%).

AEs of special interest occurring in the U2 plus bendamustine group (n=130) included ALT/AST increased (5%), non-infectious colitis (2%), diarrhea (7%), neutropenia (27%), pneumonitis (1%) and rash (2%).

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

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ublituximab plus umbralisib, ublituximab alone, umbralisib alone, and an active control arm of obinutuzumab plus chlorambucil.

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

The UNITY-CLL trial is being led by John Gribben, MD, professor of Medical Oncology, Barts Cancer Institute, United Kingdom.

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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.

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

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

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;

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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.

Based on data from the UNITY-CLL Phase 3 trial, submissions of a Biologics License Application (BLA) and a supplemental New Drug Application (sNDA) were made for ublituximab, in combination with UKONIQ, as a treatment for patients with CLL and small lymphocytic lymphoma (SLL).

The BLA and sNDA have been accepted by the FDA and a Prescription Drug User Fee Act (PDUFA) goal date of March 25, 2022 was set for both applications.

On November 30, 2021, we announced the FDA notified the Company that it plans to host a meeting of the Oncologic Drugs Advisory Committee (ODAC) in connection with its review of the pending BLA/sNDA.

The FDA’s concern giving rise to the ODAC meeting appears to stem from an early preliminary analysis of overall survival (OS) from the UNITY-CLL trial which showed an imbalance in favor of the control arm (HR:

1.23), though the result was not statistically significant.

However, when excluding deaths related to COVID-19, the two arms were approximately balanced (HR:

1.04) with again no statistically significant difference between the treatment groups with regard to overall survival.

Further, we shared that the FDA notified us that potential questions and discussion topics for the ODAC include:

the benefit-risk of the U2 combination in the treatment of CLL or SLL, and the benefit-risk of UKONIQ in relapsed/refractory marginal zone lymphoma (MZL) or follicular lymphoma (FL).

In addition, as part of the benefit-risk analysis, the FDA has raised concerns regarding the overall safety profile of the U2 regimen, including adverse events (serious and Grade 3-4), discontinuations due to adverse

events, and dose modifications, all of which are expected to be reviewed as part of the ODAC.

The date of the ODAC meeting has not yet been determined, although the FDA has stated that it is targeting holding the ODAC meeting in March or April 2022.

Given this timing, we believe it is unlikely that the FDA will make a decision on the BLA/sNDA by the PDUFA goal date of March 25, 2022.

On January 27, 2022, we shared that we were nearing completion of a submission to the FDA of updated OS analyses from the UNITY-CLL Phase 3 trial that showed an improvement from the preliminary data originally shared with the FDA in November 2021.

The original preliminary OS Hazard Ratio (HR) and the updated information were as of the same data cutoff of September 2021.

On January 27, 2022, we also shared that the FDA imposed a partial clinical hold on select studies of U2 and its components for CLL and NHL.

As a result of the partial clinical hold, no new patients may be enrolled to the select CLL/NHL studies identified by the FDA, however patients on these studies who are deriving clinical benefit can continue on therapy.

The partial clinical hold appears to be based on the same concerns that gave rise to the previously disclosed ODAC meeting and not based on any new information provided by the Company to the FDA.

Most studies included in the partial clinical hold were previously closed to new enrollment or were on Company administrative hold to new enrollment.

On February 3, 2022, the FDA released a Drug Safety Communication in which it announced that it is investigating a possible increased risk of death with UKONIQ based on the same concerns that gave rise to the previously disclosed ODAC meeting and not based on any new information provided by the Company to the FDA.

In the Drug Safety Communication, the FDA stated that it is re-evaluating the benefit-risk profile of UKONIQ for its approved indications.

The FDA encouraged healthcare providers to review patients’ progress on UKONIQ and discuss with them the risks and benefits of continuing UKONIQ in the context of other available treatments.

The communication also encouraged patients to speak with their healthcare providers about the risks and benefits of UKONIQ and possible alternative treatments.

ULTRA-V Phase 2/3 Trial Evaluating U2 plus Venetoclax in CLL:

The ULTRA-V trial is 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 study is being conducted in two parts.

The initial Phase 2 portion completed enrollment of approximately 165 patients in 1Q 2021.

The Phase 3 portion commenced at approximately the same time.

The ULTRA-V trial is being led Dr.

Furman, Morton Coleman, MD Distinguished Professor of Medicine Weill Cornell Medical College.

The ULTRA-V Phase 2 portion of the trial is an open-label, multi-center, clinical trial, evaluating the efficacy and safety of U2 combined with venetoclax in patients with treatment naïve and relapsed or refractory CLL.

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

The ULTRA-V Phase 3 portion of the trial is an open-label, multi-center, randomized, controlled clinical trial comparing the time-limited triple combination of U2 plus venetoclax to an active control arm of continuous U2.

The Phase 3 trial includes two independent randomized cohorts of CLL subjects:

a treatment-naïve cohort and a previously treated cohort, with each cohort being enrolled and evaluated independently of each other.

The primary endpoint for the trial is PFS.

GENUINE Phase 3 Trial Evaluating Ublituximab plus Ibrutinib:

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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 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.

Each trial is a global, randomized, multi-center, double-blinded, double-dummy, active-controlled study evaluating the efficacy and safety/tolerability of ublituximab (450mg dose administered by one hour intravenous infusion every six months, following a Day 1 infusion of 150mg over four hours, and a Day 15 infusion of 450mg over one hour) to teriflunomide (14mg oral tablets taken once daily) in subjects with RMS.

The primary endpoint for each study is ARR following 96 weeks of treatment.

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 the ULTIMATE I and ULTIMATE II trials, for the treatment of RMS.

In August 2017, we reached an agreement with the FDA regarding a 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 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.

Both studies met their primary endpoint of significantly reducing ARR over a 96-week period (p<0.005 in each study) with ublituximab demonstrating an ARR of <0.10 in each of the studies.

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

Key secondary MRI endpoints were also met.

In April 2021, data from the ULTIMATE I & II trials were presented for the first time at the American Academy of Neurology Annual meeting.

Additional data from these trials has been presented at various other medical meetings.

On December 14, 2021, we announced that the FDA accepted a BLA for ublituximab as a treatment for patients with RMS.

The FDA set a PDUFA goal date of September 28, 2022 and notified the Company that it is not currently planning to hold an advisory committee meeting to discuss this application.

Current Early-Stage Clinical Development of Ublituximab and Umbralisib

● Phase 1/2 Study of Umbralisib, Ublituximab and Venetoclax in patients with relapsed or refractory CLL – In September 2021, we presented data from patients with relapsed/refractory CLL treated with the triple therapy combination of ublituximab, umbralisib and venetoclax during the XIX International Workshop on Chronic Lymphocytic Leukemia (iwCLL).

The 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 relapsed or refractory (R/R) CLL.

47 patients have now been treated as of the data cutoff with 57% of patients previously exposed to a BTK inhibitor.

Best Overall Response Rate (ORR) was 100% amongst evaluable patients (n=46), including 37% complete response (CR) rate.

At cycle 12, 91% of patients (n=34) achieved undetectable minimal residual disease (uMRD) in the peripheral blood (PB), and 72% of patients (n=32) achieved uMRD in the bone marrow (BM).

At a median follow up of 24.5 months, median progression-free survival has not been reached.

Grade 3/4 adverse events (AEs) occurring in >5% of patients were neutropenia (28%), leukopenia (15%), lymphocytopenia (15%), infusion related reactions (9%), diarrhea (9%), and anemia (6%).

No TLS events were observed during 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 2021, 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 ASH annual meeting and exposition.

A total of 135 patients with R/R CLL or B-cell lymphoma were included in this presentation, with patients receiving 200 mg of TG-1701 in a dose-expansion cohort (n=61), 300 mg of TG-1701 in a CLL dose-expansion cohort (n=20), TG-1701 in combination with U2 in a dose escalation cohort (TG-1701 doses ranging from 100 – 300 mg once daily and umbralisib at either 600 mg or 800mg) (n=21), and a triple combination expansion cohort of 100mg of TG-1701 plus U2 (400 mg of umbralisib) (n=33).

Overall Response Rate (ORR) and Complete Response (CR) outcomes included:

100% ORR observed in the CLL 300 mg QD TG-1701 monotherapy expansion cohort at a median follow up of 13.8 months (n=19);

95% ORR observed in the CLL 200 mg QD TG-1701 monotherapy expansion cohort at a median follow up of 20 months (n=20);

86% ORR, including 19% CR rate, observed in the 1701+U2 dose escalation cohort (using doses of 100 mg to 300 mg QD of TG-1701) at a median follow up of 20.2 months (n=21);

83% ORR, including 6% CR rate, observed in the 1701+U2 dose expansion cohort (using 100 mg QD of TG-1701 and 400 mg QD of umbralisib) at a median follow up of 2.7 months (n=18).

Grade 3/4 AEs occurring in patients treated with 200 mg QD of TG-1701 (n=61) and 300 mg QD of TG-1701 (n=20), respectively, included neutropenia (8%, 20%), ALT increased (3%, 5%), AST increased (2%, 5%) and anemia (5%, 0%).

Grade 3/4 AEs

occurring in patients treated with the triple combination in the U2 plus TG-1701 expansion cohort (100 mg QD TG-1701 plus 400 mg QD of umbralisib;

n=19) and U2 plus TG-1701 escalation cohort (100 mg to 300 mg QD;

n=21), respectively, included neutropenia (16%, 19%), ALT increased (5%, 19%), and AST increased (5%, 14%).

At the time of data cut-off, no patients had discontinued treatment due to a treatment-related adverse event across all cohorts.

● Phase 2 Study Evaluating the Addition of Ublituximab and Umbralisib (U2) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL):

A Minimal Residual Disease (MRD)-Driven, Time-Limited Approach-Limited Approach – In December 2021 at the ASH annual meeting we presented data from this trial which utilized an “add-on” approach, where the combination of umbralisib and ublituximab (U2) was added to therapy in patients who were on ibrutinib for greater than 6 months and had detectable minimum residual disease (MRD).

Patients who achieve undetectable MRD (uMRD) or those who completed 24 cycles of therapy with detectable MRD stop all therapy and enter a period of treatment-free observation (TFO).

Patients with clinical progression during TFO are eligible for re-treatment with the U2 + ibrutinib combination.

28 patients with chronic lymphocytic leukemia (CLL) were enrolled, with 27 evaluable for efficacy.

Patients were on ibrutinib for a median of 21 months (range 7-67) prior to study entry.

77% of evaluable patients achieved uMRD, with a median time to first uMRD of 7.4 months .

Grade 3/4 AEs included diarrhea (4%), hypertension (7%), ALT/AST increased (4%) and COVID-19 (4%).

● Phase I/II Study of Umbralisib (TGR-1202), Ublituximab (TG-1101), and Pembrolizumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and Richter’s Transformation:

5-Year Follow-up – In September 2021 we presented data from this trial at the XIX iwCLL conference.

A total of 20 patients with R/R CLL or Richter’s Transformation (RT) were treated with the triple combination of ublituximab, umbralisib, and pembrolizumab.

Patients with CLL received 2 cycles of the U2 regimen before pembrolizumab was added for an additional 4 cycles, followed by umbralisib maintenance.

Patients with RT received U2 + pembrolizumab for the first 4 cycles, followed by U2 maintenance.

Twenty patients were evaluable for safety (11 CLL patients and 9 RT patients) and 19 were evaluable for efficacy (11 CLL and 8 RT).

The triple combination was well tolerated, with immune mediated toxicities not appearing above what would be expected with either umbralisib or pembrolizumab alone.

Grade 3/4 AEs occurring in >20% of patients (n=20) include, neutropenia (45%), thrombocytopenia (15%), ALT increase (15%), leukopenia (10%), nausea (5%), fatigue (5%), and anemia (5%).

In this heavily pre-treated cohort with a median of 2 (1-9) prior lines of therapy:

91% ORR in patients with R/R CLL (n=11);

83% ORR in BTK refractory CLL patients (n=6), with 4 of 5 responders achieving a response to U2 alone at the patient’s first efficacy assessment, prior to the addition of pembrolizumab;

% ORR in patients with RT (n=8), including 25% CR.

Early Pipeline Overview and Clinical Development

Cosibelimab (anti-PD-L1 monoclonal antibody) Overview

TG-1501 (Cosibelimab) Overview

Cosibelimab (also referred to as TG-1501) is a fully human monoclonal antibody of IgG1 subtype that binds to Programmed Death-Ligand 1 (PD-L1) and blocks its interactions with PD-1 and B7.1 receptors.

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The in vitro data demonstrated that the affinity, PD-L1 binding capability, relative ability to inhibit PD-1/PDL-1 interactions, and functional activity of cosibelimab in cellular assays are comparable to those of atezolizumab, durvalumab and avelumab - the currently approved products sharing the same mechanism of action.

Cosibelimab is currently being evaluated in an ongoing study (Study CK-301-101:

NCT03212404), enrolling patients with select solid tumors, being conducted by our licensor.

In the dose escalation portion of this trial, doses ranging from 200mg to 800mg were tested with no dose-limiting toxicities observed and no maximum tolerated dose (MTD) was achieved;

therefore, a fixed dose of 800 mg was the selected starting dose of cosibelimab for patients with hematologic malignancies.

Cosibelimab is currently being evaluated in ongoing studies of patients with select solid tumors, by our licensor.

In December 2018, the FDA approved an IND for cosibelimab and a Phase 1 study in subjects with select subtypes of lymphoma commenced in 2019, as did a study of cosibelimab in combination with ublituximab and/or umbralisib.

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

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

Data from this trial was most recently presented at ASH 2021 (described above).

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

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This study is evaluating escalating doses of TG-1801 in patients with B-Cell lymphoma.

The primary objective of the study is to determine the recommended Phase 2 dose and to characterize the safety profile of TG-1801.

The primary objective of the study is to determine the recommended Phase

2 dose and to characterize the safety profile of TG-1801.

Key secondary objectives are to evaluate the pharmacokinetics of TG-1801 and its preliminary anticancer activity

Enrollment is ongoing in this Phase 1 study.

Preclinical Programs

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

In the first half of 2021, we commenced a second Phase 1 study of TG-1801 in the US to continue dose optimization as monotherapy and in combination with ublituximab.

Enrollment in this study is ongoing.

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.

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.

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 USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

In the future, we intend to apply for restoration of patent term for one of our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA or the BLA.

An application for a patent term extension for

UKONIQ has been submitted, and we intend to apply for, or work with our licensing partners to apply for, patent term extensions for any products approved by the FDA in the future, depending on the factors involved in the development program and filing and review of the relevant NDA or the BLA.

Also, under the Hatch-Waxman Amendments, drugs that are new chemical entities (NCEs) are eligible for a five-year period of non-patent marketing exclusivity in the United States.

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Since the enactment of the BPCIA, the FDA has issued several draft guidance’s for industry related to the BPCIA, addressing scientific, quality and procedural issues relevant to an abbreviated application for a biosimilar product.

As of December 2020, FDA had approved 29 biosimilar applications.

As of December 2021, the FDA had approved 33 biosimilar applications.

Orphan drug exclusivity, as described below, may offer a seven-year period of marketing exclusivity, except in certain circumstances.

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In January 2012, we entered into an exclusive license agreement with LFB Biotechnologies, GTC Biotherapeutics, and LFB/GTC LLC, all wholly-owned subsidiaries of LFB Group, relating to the development and commercialization of ublituximab.

Under the license agreement, we have acquired the exclusive worldwide rights (exclusive of France/Belgium) for the development and commercialization of ublituximab.

To date, we have made no payments to LFB Group under the license agreement, excluding an upfront equity payment.

Under the license agreement, we have acquired the exclusive worldwide rights for the development and commercialization of ublituximab.

As of December 31, 2021, we paid LFB Group approximately $7.0 million related to the achievement of certain milestones under the license agreement.

LFB Group is eligible to receive payments of up to an aggregate of approximately $31.0 million upon our successful achievement of certain clinical development, regulatory and sales milestones, in addition to royalty payments on net sales of ublituximab at a royalty rate that escalates from mid-single digits to high-single digits.

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Prior to this, we had been jointly developing umbralisib in a 50:50 joint venture with Rhizen.

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 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.

Rhizen will also be eligible to participate in sublicensing revenue, if any, based on a percentage that decreases as a function of the number of patients treated in clinical trials following the exercise of the license option.

Under the terms of the TGR-1202 License, Rhizen received a $4.0 million cash payment and 371,530 shares of our common stock as an upfront license fee.

For the year ended December 31, 2021, we paid Rhizen $12.0 million as part of a primary indication approval milestone for launch of product in the US in accordance with the terms of the Umbralisib License.

Rhizen will be eligible to receive additional approval and sales-based milestone payments in the aggregate of approximately $175 million payable upon 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 receives tiered royalties that escalate from high single digits to low double digits on any net sales of umbralisib and any New Product.

Rhizen shall also be eligible to participate in sublicensing revenue, if any, based on a percentage that decreases as a function of the number of patients treated in clinical trials following the exercise of the license option.

Rhizen will retain global manufacturing rights to umbralisib, provided that they are price competitive with alternative manufacturers.

The license will terminate on a country by country basis upon the expiration of the last licensed patent right or any other exclusivity right in such country, unless the agreement is earlier terminated (i) by us for any reason, (ii) by either party due to a breach of the agreement.

The license will terminate on a country-by-country basis upon the expiration of the last licensed patent right or any other exclusivity right in such country, unless the agreement is earlier terminated (i) by us for any reason, or (ii) by either party due to a breach of the agreement.

In March 2015, we entered into a global collaboration (the Collaboration) with Checkpoint Therapeutics, Inc.

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In June 2019, we amended our Collaboration Agreement with Checkpoint to cover additional licenses necessary to continue the development of the anti-PD-L1 and anti-GITR research programs.

Under the terms of the initial Collaboration, we made an up-front payment of $500,000, and upon entering into the amended agreement, made an additional payment of $1,000,000.

Under the terms of the initial Collaboration, we made an up-front payment of $0.5 million, and upon entering into the amended agreement, made an additional payment of $1.0 million.

In March 2020, we achieved the first milestone event, and we subsequently paid Checkpoint $1.0 million as part of this milestone.

Under the terms of the amended agreement, we will make development and sales-based milestone payments up to an aggregate of approximately $110 million and will pay a tiered low double-digit royalty on net sales.

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In addition, in July 2019, we paid Jiangsu the first milestone under the agreement of $0.1 million in our common stock.

In July 2020, we paid Hengrui $2.0 million as part of a milestone in accordance with the license agreement.

Hengrui is eligible to receive milestone payments totaling approximately $350 million upon and subject to the achievement of certain milestones.

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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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The license will terminate on a country by country basis upon the expiration of the last licensed patent right or 10 years after the first commercial sale of a product in such country, unless the agreement is earlier terminated by either party due to a breach of the agreement in the event of the insolvency of the other party.

TG-1601 (BET inhibitor)

TG-1601 (BET)

In May 2016, as part of a broader agreement with Jubilant Biosys (Jubilant), we entered into a sub-license agreement (JBET Agreement) with Checkpoint for the development and commercialization of Jubilant’s novel BET inhibitor program in the field of hematological malignancies.

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The resulting changes in standard of care can impact the likelihood of regulatory accelerated approval opportunities for our drug candidates.

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), 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, 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 several kinase inhibitors in earlier stages of development.

For the cancer indications for which we received FDA approval of UKONIQ or for which we are developing U2 and our other product candidates, there are a number of established therapies with which we will compete:

● For the treatment of MZL, we expect UKONIQ to compete with zanubrutinib (BeiGene), ibrutinib (AbbVie and Janssen), and the combination of rituximab and lenalidomide (Bristol-Myers Squibb), as well as established treatments such as rituximab (Roche) and several generically available chemotherapies.

In addition, there are investigational PI3K inhibitors being developed in MZL.

● For the treatment of FL, we expect UKONIQ to compete with recently approved drugs such as axicabtagene ciloleucel (Gilead), obinutuzumab (Roche), tazemetostat (Epizyme), and the combination of rituximab and lenalidomide (Bristol-Myers Squibb), and established treatments such as rituximab (Roche), and several generically available chemotherapies, many of which have FDA-approved indications for earlier lines of therapy (e.g., after two prior lines of systemic therapy) than UKONIQ.

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

● For the treatment of CLL, if U2 is approved, we expect the regimen to compete with approved drugs such as ibrutinib (AbbVie and Janssen), acalabrutinib (AstraZeneca), venetoclax (AbbVie and Roche), obinutuzumab (Roche), idelalisib (Gilead) and duvelisib (Secura Bio, Inc.), 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.

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

● 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.

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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.

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

Additional information can be found under Item “1A - Risk Factors – Other Risks Related to Our Business” within this report.

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We currently do not have any manufacturing capabilities of our own.

We have established contract manufacturing relationships for the supply of ublituximab.

We have established a contract manufacturing relationship for the supply of ublituximab with Samsung Biologics.

For the supply of umbralisib, Rhizen has established contract manufacturing relationships as part of our licensing agreement.

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 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.

Process improvements are common during clinical development to accommodate raw material and component variability, enhance productivity and/or accommodate different or larger equipment utilized during the scale-up process required for commercial manufacture.

Process improvements and other changes are common during clinical development to accommodate raw material and component variability, enhance productivity and/or accommodate different or larger equipment utilized during the scale-up process required for commercial manufacture.

These types of incremental process changes have been made during clinical development for both TG’s small and large molecule programs.

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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.

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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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Our submission of an IND may not result in FDA authorization to commence a clinical trial.

Clinical testing must meet requirements for institutional review board oversight, informed consent and good clinical practices, and must be conducted pursuant to an IND, unless exempted.

In addition, the FDA, equivalent foreign regulatory authority, or a data safety monitoring committee for a trial may place a clinical trial on hold or terminate it if it concludes that subjects are being exposed to an unacceptable health risk, or for futility.

Any drug is likely to produce some toxicity or undesirable side effects in animals and in humans when administered at sufficiently high doses and/or for a sufficiently long period of time.

Unacceptable toxicity or side effects may occur at any dose level at any time in the course of studies in animals designed to identify unacceptable effects of a drug candidate, known as toxicological studies, or clinical trials of drug candidates.

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

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The FDA may require Phase 4 post-marketing studies to find out more about the drug’s long-term risks, benefits, and optimal use, or to test the drug in different populations.

Clinical testing must meet requirements for institutional review board oversight, informed consent and good clinical practices, and must be conducted pursuant to an IND, unless exempted.

Any drug is likely to produce some toxicity or undesirable side effects in animals and in humans when administered at sufficiently high doses and/or for a sufficiently long period of time.

The length of time necessary to complete clinical trials varies significantly and may be difficult to predict.

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For clinical trials that are intended to form the basis of a new drug or biologics license application for approval, sponsors of drugs may apply for an SPA from the FDA, by which the FDA provides official evaluation and written guidance on the design and size of proposed protocols.

While obtaining an SPA provides some assurance the design of a trial should be sufficient for approval, the final marketing approval depends on the results of efficacy, the adverse event profile and an evaluation of the benefit/risk of treatment demonstrated in the Phase 3 trial.

Phase 3 trial.

The SPA agreement may only be changed through a written agreement between the sponsor and the FDA, or if the FDA becomes aware of a substantial scientific issue essential to product safety or efficacy.

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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.

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.

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

Completing the required post-approval clinical studies as designed can be difficult, especially as the treatment landscape evolves.

For example, the challenges in completing such studies have prompted some companies with products that

received accelerated approval for relapsed or refractory FL to withdraw that indication (e.g., duvelisib (December 2021), idelalisib (January 2022)).

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.

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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.

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.

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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.

In addition, the post-marketing 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.

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For example, the Tax Cuts and Jobs Act enacted on December 22, 2017 (the Tax Act), eliminated the shared responsibility payment for individuals who fail to maintain minimum essential coverage under section 5000A of the Internal Revenue Code of 1986, commonly referred to as the individual mandate, effective January 1, 2019.

In December 2018, a United States District Court Judge for the Northern District of Texas ruled (i) that the “individual mandate” was unconstitutional as a result of the associated tax penalty being repealed by Congress as part of the Tax Act;

and (ii) the individual mandate is not severable from the rest of the Affordable Care Act, and as a result the entire Affordable Care Act is invalid.

On December 18, 2019, the U.S.

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.

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.

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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 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.

The Biden administration has indicated that lowering prescription drug prices is a priority and has proposed a number of measures to do so, including allowing the federal government to negotiate prices for some high-cost drugs covered under Medicare Part B and Part D, requiring inflation rebates to limit annual increases in drug prices in Medicare and private insurance, and capping out-of-pocket spending for Medicare Part D enrollees.

Although the fate of these proposals remains uncertain, 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.

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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.

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.

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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 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

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.

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There has also been a recent trend of increased federal and state regulation of payments made to physicians and other healthcare providers.

The Affordable Care Act, among other things, imposes new reporting requirements on drug manufacturers for payments made by them to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

The Affordable Care Act, among other things, imposes reporting requirements on drug manufacturers for payments made by them to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

Failure to submit required information may result in civil monetary penalties of up to an aggregate of $150,000 per year (or up to an aggregate of $1 million per year for “knowing failures”), for all payments, transfers of value or ownership or investment interests that are not timely, accurately and completely reported in an annual submission.

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Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to “business associates,” defined as independent contractors or agents of covered entities that create, receive, maintain or transmit protected health information in connection with providing a service for or on behalf of a covered entity.

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.

HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.

In addition, according to the U.S.

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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.

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.

For example, the California Consumer Protection Act, or CCPA, which went into effect on January 1, 2020, established a privacy framework for covered businesses by creating an expanded definition of personal information, data privacy rights for consumers in California, and a 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.

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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 expect to continue to grow our organization assuming we obtain FDA approval of U2 in CLL/SLL and ublituximab in RMS.

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

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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