On September 20, 2021 TG Therapeutics, Inc. (NASDAQ: TGTX), reported data presentations at the XIX International Workshop on Chronic Lymphocytic Leukemia (iwCLL) (Press release, TG Therapeutics, SEP 20, 2021, View Source [SID1234587998]). Data highlights from each presentation are included below.

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The Company will also host a virtual investor and analyst event today, September 20, 2021 at 8:30 AM ET, to review the updated Phase 1 data evaluating the investigational combination of UKONIQ (umbralisib) and ublituximab (U2) plus venetoclax presented at iwCLL, as well as provide an overview of the ULTRA-V Phase 2/3 trial.

Michael S. Weiss, the Company’s Chairman and Chief Executive Officer, stated, "The iwCLL conference this past weekend was an exciting meeting, where we were able to share data from four combination trials, including updated data from our Phase 1/2 study of U2 plus venetoclax. Our goal has been to develop combination therapies utilizing U2 as a backbone and we believe the data presented this weekend showcase the breadth of the program, which includes combinations with targeted therapy as well as immunotherapy. With a March 25, 2022 PDUFA date in the US, we are excited about the potential approval of the U2 regimen for CLL patients and hope you all can join us this morning for our virtual event to review some of the encouraging data presented this past weekend."

IwCLL 2021 DATA HIGHLIGHTS

Oral Presentation Title: Umbralisib Plus Ublituximab (U2) Is Superior to Obinutuzumab Plus Chlorambucil (O+Chl) in Patients with Treatment-Naïve (TN) and Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): Results from the Phase 3 UNITY-CLL Study

421 patients were randomized to the U2 (n=210) or O+Chl (n=211) arms; 57% of patients were treatment-naïve and 43% had relapsed/refractory (R/R) CLL
At a median follow-up of 36.7 months, U2 significantly prolonged independent review committee (IRC) assessed progression-free survival (PFS) vs O+Chl (median 31.9 months vs 17.9 months; hazard ratio 0.546 (p<0.0001))
PFS improvement with U2 vs O+Chl was consistent across all subgroups examined including treatment naïve patients (median 38.5 months vs 26.1 months, hazard ratio 0.482) and relapsed/refractory patients (median 19.5 months vs 12.9 months, hazard ratio 0.601)
Overall response rate (ORR) was significantly higher with U2 compared to O+Chl (83.3% vs 68.7%; p<0.001)
For the U2 arm, at a median treatment exposure of 21 months, most adverse events (AEs) were Grade 1 or 2 in severity and were relatively balanced between the treatment naïve and previously treated populations
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. 1.5%)
Oral Presentation Title: A Phase 1/2 Study of Umbralisib, Ublituximab, and Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

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. 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.
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
Oral Poster Presentation Title: TG-1701, a Selective Bruton Tyrosine Kinase (BTK) Inhibitor, as Monotherapy and in Combination with Ublituximab and Umbralisib (U2) in Patients with Chronic Lymphocytic Leukemia

A total of 50 patients with R/R CLL have been treated with TG-1701, with patients receiving monotherapy in the dose-escalation cohort (n=6), 200 mg in a dose-expansion cohort (n=20), 300 mg in a dose-expansion cohort (n=20), or TG-1701 in combination with U2 in the dose escalation cohort (n=4).
TG-1701 monotherapy was well tolerated and the maximum tolerated dose was not reached up to 400 mg QD.
Grade 3/4 AEs occurring in patients treated with 200 mg QD of TG-1701 (n=20), included neutropenia (10%), anemia (5%) and arthralgia (5%). Grade 3/4 AEs occurring in patients treated with 300 md QD of TG-1701 (n=20), included neutropenia (20%), COVID-19 (5%), ALT increased (5%) and AST increased (5%).
100% ORR observed in the 300 mg QD monotherapy expansion cohort at a median follow up of 12 months (n=19)
95% ORR observed in the 200 mg QD monotherapy expansion cohort at a median follow up of 19 months (n=20)
100% ORR observed in the 1701+U2 dose escalation (using doses of 100 mg to 300 mg QD of TG-1701) at a median follow up of 19 months (n=3)
Poster Presentation Title: 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

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
— 25% ORR in patients with RT (n=8), including 25% CR rate
The above data presentations are available on the Publications page, located within the Pipeline section, of the Company’s website at www.tgtherapeutics.com/publications.cfm.

INVESTOR & ANALYST VIRTUAL EVENT INFORMATION
The Company will host a virtual event today, September 20, 2021 at 8:30 AM ET, to discuss the updated Phase 1 data evaluating UKONIQ (umbralisib) and ublituximab (U2) in combination with venetoclax in patients with CLL as well as provide an overview of the Phase 2/3 ULTRA-V program.

To attend the live event, please visit the Events page, located within the Investors & Media section, of the Company’s website at View Source Following the live event, an archive file will be available for replay, for a period of 30 days after the call.

ABOUT U2 PLUS VENETOCLAX PHASE 1 TRIAL
The Phase 1/2 trial, (NCT03379051), is a multi-center, dose-escalation trial designed to assess the safety and efficacy of UKONIQ and ublituximab (U2) plus venetoclax in patients with relapsed or refractory CLL. The primary objective of the trial is to evaluate the safety of venetoclax after U2 induction. The secondary objectives are clinical efficacy as defined by overall response rate (ORR), including complete response (CR) rate, progression-free survival (PFS), and undetectable minimal residual disease (uMRD) rate after 12 cycles of therapy. The trial enrolled approximately 50 CLL patients and is being led by Dr. Paul Barr of the Wilmot Cancer Institute, University of Rochester Medical Center.

ABOUT ULTRA-V PHASE 2 TRIAL
The ULTRA-V Phase 2 trial, (NCT03801525), is an open-label, multicenter, trial designed to investigate the efficacy and safety of UKONIQ and ublituximab (U2) combined with venetoclax in subjects with CLL. The primary endpoint of the trial is overall response rate (ORR) and complete response (CR) rate. The trial enrolled approximately 165 patients with front-line and previously treated CLL at 26 sites throughout the United States.

ABOUT ULTRA-V PHASE 3 TRIAL
The ULTRA-V Phase 3 trial is an open-label, multicenter, randomized controlled clinical trial comparing the time-limited triple combination of UKONIQ and ublituximab (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 progression-free survival (PFS). This trial is being led by Richard R. Furman, MD, Director of CLL Research Center at Weill Cornell Medicine and targeting over 60 U.S. trial sites.

On September 20, 2021 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that new data from the Phase III IMpower010 study at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 Presidential Symposium, reinforcing the significant disease-free survival (DFS) benefit offered by Tecentriq (atezolizumab) for people with Stage II-IIIA non-small cell lung cancer (NSCLC) whose tumors express PD-L1≥1%. Data from the IMpower010 trial were published simultaneously in The Lancet (Press release, Genentech, SEP 20, 2021, View Source [SID1234588029]). In IMpower010, treatment with Tecentriq, following surgery and chemotherapy, reduced the risk of disease recurrence or death (DFS) by 34% (hazard ratio [HR]=0.66, 95% CI: 0.50–0.88) in people with Stage II-IIIA NSCLC whose tumors express PD-L1≥1%, compared with best supportive care (BSC). Safety data for Tecentriq were consistent with its known safety profile and no new safety signals were identified.

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"IMpower010 shows how, for the first time, a cancer immunotherapy may help many of these patients live longer without their disease returning. The data presented at ESMO (Free ESMO Whitepaper) and WCLC further contribute to our understanding of Tecentriq in this treatment setting."

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"Today more than half of all people with early-stage NSCLC experience recurrence following surgery," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "IMpower010 shows how, for the first time, a cancer immunotherapy may help many of these patients live longer without their disease returning. The data presented at ESMO (Free ESMO Whitepaper) and WCLC further contribute to our understanding of Tecentriq in this treatment setting."

At the 2021 ESMO (Free ESMO Whitepaper) Virtual Congress, new real-world data show that almost three-quarters of patients with early-stage NSCLC in the U.S. did not receive adjuvant treatment, despite guideline recommendations. Data presented from IMpower010 show that adjuvant Tecentriq offers a DFS benefit in the Stage II-IIIA patient population, irrespective of the stage of disease and across the main prior therapies. Specifically, time to relapse appeared to be improved with Tecentriq, compared with BSC, among people with Stage II-IIIA NSCLC whose tumors express PD-L1 TC ≥1%, for both locoregional and distant sites. There was no clear difference in patterns of relapse. An extended analysis of PD-L1 subgroups in the Stage II-IIIA population shows there is a higher magnitude of benefit from adjuvant Tecentriq in people with PD-L1 expression ≥50%, compared with those with 1-49% PD-L1 expression. The exploratory nature of the analysis in patients with 1-49% PD-L1 expression prevents any firm conclusions, and these data will be further analyzed and shared at a future medical congress.

Additional IMpower010 data, recently presented at the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer (WCLC) Presidential Symposium, showed that treatment with Tecentriq improved DFS in the PD-L1≥1% Stage II-IIIA NSCLC population, compared with BSC, regardless of most surgery types and adjuvant chemotherapy regimens.

Based on the IMpower010 data, the U.S. Food and Drug Administration (FDA) recently granted Priority Review to Tecentriq as an adjuvant treatment for certain people with early NSCLC and is reviewing the application under the Real-Time Oncology Review pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible. The FDA is expected to make a decision on approval by December 1, 2021.

Tecentriq has previously shown clinically meaningful benefit in various types of lung cancer, with five currently approved indications in markets around the world. It was the first approved cancer immunotherapy for front-line treatment of adults with extensive-stage small cell lung cancer (SCLC) in combination with carboplatin and etoposide (chemotherapy). Tecentriq also has four approved indications in advanced NSCLC as either a single agent or in combination with targeted therapies and/or chemotherapies. Tecentriq is available in three dosing options, providing the flexibility to choose administration every two, three or four weeks.

Genentech has an extensive development program for Tecentriq, including multiple ongoing and planned Phase III studies across different settings in lung, genitourinary, skin, breast, gastrointestinal, gynecological, and head and neck cancers. This includes studies evaluating Tecentriq both alone and in combination with other medicines, as well as studies in metastatic, adjuvant and neoadjuvant settings across various tumor types.

About the IMpower010 study

IMpower010 is a Phase III, global, multicenter, open-label, randomized study evaluating the efficacy and safety of Tecentriq compared with BSC, in participants with Stage IB-IIIA NSCLC (UICC 7th edition), following surgical resection and up to 4 cycles of adjuvant cisplatin-based chemotherapy. The study randomized 1,005 people with a ratio of 1:1 to receive either Tecentriq (up to 16 cycles) or BSC. The primary endpoint is investigator-determined DFS in the PD-L1-positive Stage II-IIIA, all randomized Stage II-IIIA and intent-to-treat (ITT) Stage IB-IIIA populations. Key secondary endpoints include overall survival (OS) in the overall study population, ITT Stage IB-IIIA NSCLC.

About lung cancer

According to the American Cancer Society, it is estimated that more than 235,000 Americans will be diagnosed with lung cancer in 2021, and NSCLC accounts for 80-85% of all lung cancers. Today, about half of all people with early lung cancer still experience a cancer recurrence following surgery, but treating lung cancer early, before it has spread, may help prevent the disease from returning and provide people with the best opportunity for a cure.

About Tecentriq (atezolizumab)

Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1. Tecentriq is designed to bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the re-activation of T cells. Tecentriq may also affect normal cells.

Tecentriq U.S. Indications

Tecentriq is a prescription medicine used to treat adults with:

A type of lung cancer called non-small cell lung cancer (NSCLC).

Tecentriq may be used alone as their first treatment when their lung cancer:
has spread or grown, and
their cancer tests positive for "high PD-L1", and
their tumor does not have an abnormal "EGFR" or "ALK" gene
Tecentriq may be used with the medicines bevacizumab, paclitaxel, and carboplatin as their first treatment when their lung cancer:
has spread or grown, and
is a type called "non-squamous NSCLC," and
their tumor does not have an abnormal "EGFR" or "ALK" gene
Tecentriq may be used with the medicines paclitaxel protein-bound and carboplatin as their first treatment when their lung cancer:
has spread or grown, and
is a type called "non-squamous NSCLC," and
their tumor does not have an abnormal "EGFR" or "ALK" gene
Tecentriq may also be used when their lung cancer:
has spread or grown, and
they have tried chemotherapy that contains platinum, and it did not work or is no longer working
if their tumor has an abnormal "EGFR" or "ALK" gene, they should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working
A type of lung cancer called small cell lung cancer (SCLC).

Tecentriq may be used with the chemotherapy medicines carboplatin and etoposide as their first treatment when their lung cancer:
is a type called "extensive-stage small cell lung cancer," which means that it has spread or grown
It is not known if Tecentriq is safe and effective in children.

Important Safety Information

What is the most important information about Tecentriq?

Tecentriq can cause the immune system to attack normal organs and tissues in any area of the body and can affect the way they work. These problems can sometimes become severe or life threatening and can lead to death. Patients can have more than one of these problems at the same time. These problems may happen anytime during their treatment or even after their treatment has ended.

Patients should call or see their healthcare provider right away if they develop any new or worse signs or symptoms, including:

Lung problems

cough
shortness of breath
chest pain
Intestinal problems

diarrhea (loose stools) or more frequent bowel movements than usual
stools that are black, tarry, sticky, or have blood or mucus
severe stomach-area (abdomen) pain or tenderness
Liver problems

yellowing of the skin or the whites of the eyes
severe nausea or vomiting
pain on the right side of their stomach area (abdomen)
dark urine (tea colored)
bleeding or bruising more easily than normal
Hormone gland problems

headaches that will not go away or unusual headaches
eye sensitivity to light
eye problems
rapid heartbeat
increased sweating
extreme tiredness
weight gain or weight loss
feeling more hungry or thirsty than usual
urinating more often than usual
hair loss
feeling cold
constipation
their voice gets deeper
dizziness or fainting
changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
Kidney problems

decrease in their amount of urine
blood in their urine
swelling of their ankles
loss of appetite
Skin problems

rash
itching
skin blistering or peeling
painful sores or ulcers in mouth or nose, throat, or genital area
fever or flu-like symptoms
swollen lymph nodes
Problems can also happen in other organs.

These are not all of the signs and symptoms of immune system problems that can happen with Tecentriq. Patients should call or see their healthcare provider right away for any new or worse signs or symptoms, including:

Chest pain, irregular heartbeat, shortness of breath, or swelling of ankles
Confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs
Double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight
Persistent or severe muscle pain or weakness, muscle cramps
Low red blood cells, bruising
Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:

chills or shaking
itching or rash
flushing
shortness of breath or wheezing
dizziness
feeling like passing out
fever
back or neck pain
Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if patients undergo transplantation either before or after being treated with Tecentriq. A healthcare provider will monitor for these complications.

Getting medical treatment right away may help keep these problems from becoming more serious. A healthcare provider will check patients for these problems during their treatment with Tecentriq. A healthcare provider may treat patients with corticosteroid or hormone replacement medicines. A healthcare provider may also need to delay or completely stop treatment with Tecentriq if patients have severe side effects.

Before receiving Tecentriq, patients should tell their healthcare provider about all of their medical conditions, including if they:

have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
have received an organ transplant
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
have received radiation treatment to their chest area
have a condition that affects their nervous system, such as myasthenia gravis or Guillain-Barré syndrome
are pregnant or plan to become pregnant. Tecentriq can harm an unborn baby. Patients should tell their healthcare provider right away if they become pregnant or think they may be pregnant during treatment with Tecentriq. Females who are able to become pregnant:
A healthcare provider should do a pregnancy test before they start treatment with Tecentriq
They should use an effective method of birth control during their treatment and for at least 5 months after the last dose of Tecentriq
are breastfeeding or plan to breastfeed. It is not known if Tecentriq passes into the breast milk. Patients should not breastfeed during treatment and for at least 5 months after the last dose of Tecentriq
Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of Tecentriq when used alone include:

feeling tired or weak
nausea
cough
shortness of breath
decreased appetite
The most common side effects of Tecentriq when used in lung cancer with other anti-cancer medicines include:

feeling tired or weak
nausea
hair loss
constipation
diarrhea
decreased appetite
Tecentriq may cause fertility problems in females, which may affect the ability to have children. Patients should talk to their healthcare provider if they have concerns about fertility.

These are not all the possible side effects of Tecentriq. Patients should ask their healthcare provider or pharmacist for more information about the benefits and side effects of Tecentriq.

Report side effects to the FDA at 1-800-FDA-1088 or View Source

Report side effects to Genentech at 1-888-835-2555.

Please see View Source for full Prescribing Information and additional Important Safety Information.

About Genentech in cancer immunotherapy

Genentech has been developing medicines to redefine treatment in oncology for more than 35 years, and today, realizing the full potential of cancer immunotherapy is a major area of focus. With more than 20 immunotherapy molecules in development, Genentech is investigating the potential benefits of immunotherapy alone, and in combination with various chemotherapies, targeted therapies and other immunotherapies with the goal of providing each person with a treatment tailored to harness their own unique immune system.

In addition to Genentech’s approved PD-L1 checkpoint inhibitor, the company’s broad cancer immunotherapy pipeline includes other checkpoint inhibitors, individualized neoantigen therapies and T cell bispecific antibodies. For more information visit View Source

About Genentech in lung cancer

Lung cancer is a major area of focus and investment for Genentech, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have five approved medicines to treat certain kinds of lung cancer and more than 10 medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

On September 20, 2021, Lixte Biotechnology Holdings, Inc. ("we," "our" or the "Company") reported that it entered into an at-the-market sales agreement (the "Sales Agreement") with WestPark Capital, Inc. (the "Agent") pursuant to which we may offer and sell from time to time through the Agent, acting as agent, shares of our common stock, $0.0001 par value per share, having an aggregate offering price of up to $10,000,000, subject to the terms and conditions of the Agreement (Filing, 8-K, Lixte Biotechnology, SEP 20, 2021, View Source [SID1234588075]). The issuance and sale, if any, of shares of common stock through the Agent under the Sales Agreement will be will be made pursuant to the Company’s effective shelf registration statement on Form S-3 (File No. 333-252430) (the "Registration Statement") filed with the Securities and Exchange Commission, or "SEC," on January 26, 2021, and declared effective on February 5, 2021, and are described in detail in the related base prospectus, dated February 5, 2021 and prospectus supplement, dated September 20, 2021, included as part of our Registration Statement.

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Under the sales agreement, the Agent may sell shares of our common stock by any method permitted by law deemed to be an "at-the-market" offering as defined in Rule 415 of the Securities Act of 1933, as amended, including, but not limited to, sales made directly on the Nasdaq Capital Market, on any other existing trading market for our common stock or to or through a market maker other than on an exchange or otherwise, in negotiated transactions at market prices prevailing at the time of sale or at prices related to such prevailing market prices, and/or any other method permitted by law. The Agent has agreed in the sales agreement to use its commercially reasonable efforts consistent with its respective normal trading and sales practices to sell shares in accordance with our instructions (including any price, time or size limit or other customary parameters or conditions we may impose). Actual sales will depend on a variety of factors to be determined by the Company from time to time, including (among others) market conditions, the trading price of the Company’s common stock, capital needs and determinations by the Company of the appropriate sources of funding for the Company. The Company is not obligated to make any sales of common stock under the Sales Agreement and the Company cannot provide any assurances that it will issue any shares pursuant to the Sales Agreement.

We have agreed to pay the Agent a commission rate of 2.5% of the gross sales price per share of any of our shares of common stock sold through the Agent under the sales agreement, and have provided the Agent with customary indemnification and contribution rights. In addition, we have agreed to reimburse certain legal expenses and filing fees incurred by the Agent in connection with the offering pursuant to the Sales Agreement, including fees and expenses of the Agent’s legal counsel not to exceed $50,000, plus certain ongoing disbursements of its legal counsel up to $1,250 per calendar quarter.

The offering of shares of our common stock pursuant to the Sales Agreement will terminate upon the earliest of (i) the sale of the maximum dollar amount of shares of common stock subject to the Sales Agreement, (ii) the termination of the Sales Agreement by us or the Agent, and (iii) the expiration of the shelf registration statement on Form S-3 (File No. 333-252430) on the third anniversary of the initial effective date of such registration statement.

A copy of the Sales Agreement is filed as Exhibit 10.1 to this Current Report on Form 8-K (this "Report") and is incorporated herein by reference. The description of the Agreement is qualified in its entirety by reference to Exhibit 10.1 to this Report.

This Report, including the exhibits filed herewith, is not an offer to sell or the solicitation of an offer to buy the shares or any other securities of the Company, nor shall there by any offer, solicitation or sale of the shares or any other securities of the Company in any state in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of such state.

A copy of the opinion of TroyGould PC relating to the legality of the shares is filed as Exhibit 5.1 to this Report and is filed with reference to, and is hereby incorporated by reference into, the Registration Statement.

On September 20, 2021 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM: HCM; HKEX: 13) reported that it has initiated a Japan registration-enabling bridging study for surufatinib to support the registration of surufatinib in the treatment of patients with advanced neuroendocrine tumors ("NETs") (Press release, Hutchison China MediTech, SEP 20, 2021, View Source [SID1234590539]). The first patient was dosed on September 15, 2021.

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Based on dialogue with the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), it was agreed that the surufatinib Japanese new drug application ("NDA") for the treatment of advanced NETs include results from a pivotal study to be conducted in Japan, to complement the registration data package supporting the NDA to the U.S. Food and Drug Administration ("FDA") (accepted for review in June 2021) and the Marketing Authorization Application ("MAA") to the European Medicines Agency ("EMA") (validated in July 2021). The basis for the NDA and the MAA includes data from a U.S. Phase I/II study, as well as the completed Phase III SANET-ep and SANET-p studies used to support marketing authorization in China in advanced NETs, where surufatinib is currently marketed under the brand name SULANDA.

This Japan study is a two-stage, open label study of surufatinib where approximately 34 patients are expected to be recruited. In Part 1 of the study, the safety and tolerability of surufatinib 300mg once daily after 28 days of treatment will be assessed in patients with relapsed/refractory non-hematological malignancies; pharmacokinetics ("PK") and anti-tumor activity of surufatinib are secondary endpoints. In Part 2 of the study, efficacy will be assessed in patients with locally advanced or metastatic NETs; the primary outcome measure is objective response rate (ORR). The secondary outcome measures include disease control rate (DCR), progression free survival ("PFS"), duration of response (DoR), safety, and PK.

Surufatinib is the third potential new medicine discovered by HUTCHMED to enter into clinical development in Japan. A global Phase III registration study for fruquintinib, known as the FRESCO-2 study, is ongoing in patients with refractory metastatic colorectal cancer and is expected to enroll over 680 patients from over 150 sites in 14 countries, including Japan. A global single-arm, open-label study, known as the SAVANNAH study, is ongoing for savolitinib (partnered with AstraZeneca PLC) in combination with TAGRISSO in non-small cell lung cancer patients whose disease progressed following TAGRISSO due to MET amplification or overexpression.

About NETs
NETs form in cells that interact with the nervous system or in glands that produce hormones. They can originate in various parts of the body, most often in the gut or the lungs and can be benign or malignant. NETs are typically classified as pancreatic NET ("pNET") or extra-pancreatic (non-pancreatic) NET ("epNET").

According to Frost & Sullivan, there were 19,000 newly diagnosed cases of NET in the U.S. in 2020. Rates across the European Union (E.U.) appear largely similar to the U.S. This is supported by an analysis of global epidemiologic trends, which also show growth in the incidence of NETs worldwide.[i] Importantly, NETs are associated with a relatively long duration of survival compared to other tumors. As a result, there were approximately 140,000 estimated patients living with NET in France, Germany, Italy, Spain, and the United Kingdom in 2020.[ii] In Japan, approximately 6,700 people were diagnosed with gastro-entero-pancreatic neuroendocrine neoplasms in 2016.[iii]

About Surufatinib
Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumor effects.

HUTCHMED currently retains all rights to surufatinib worldwide.

About Surufatinib Development
epNETs in China: On December 29, 2020, surufatinib was granted drug registration approval by the National Medical Products Administration of China ("NMPA") for the treatment of epNET. Surufatinib is marketed in China under the brand name SULANDA. The approval was based on results from the SANET-ep study, a Phase III trial (clinicaltrials.gov identifier: NCT02588170) in patients with advanced epNETs conducted in China. The study met the pre-defined primary endpoint of PFS at a preplanned interim analysis, and was published in The Lancet Oncology[iv]. Median PFS was significantly longer for patients treated with surufatinib at 9.2 months, compared to 3.8 months for patients in the placebo group (HR 0.334; 95% CI: 0.223-0.499; p<0.0001). Surufatinib had an acceptable safety profile, with the most common treatment related adverse events of grade 3 or worse being hypertension (36% of surufatinib patients vs. 13% of placebo patients), proteinuria (19% vs. 0%) and anemia (5% vs. 3%).

pNETs in China: On June 16, 2021, surufatinib was granted drug registration approval by the NMPA for the treatment of pNET. The approval was based on results from the SANET-p study, a Phase III trial (clinicaltrials.gov identifier: NCT02589821) in patients with advanced pNET in China. The pre-defined primary endpoint of PFS was met at a preplanned interim analysis and was published in The Lancet Oncology[v], demonstrating that surufatinib reduces the risk of disease progression or death by 51% in patients, with a median PFS of 10.9 months compared to 3.7 months on placebo (HR 0.491; 95% CI: 0.391-0.755; p=0.0011). The safety profile of surufatinib was manageable and consistent with observations in prior studies.

Immunotherapy combinations: HUTCHMED entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with anti-PD-1 monoclonal antibodies, including with tislelizumab (BGB-A317), TUOYI (toripalimab) and TYVYT (sintilimab), which are approved as monotherapies in China.

NETs in the U.S. and Europe: A FDA NDA submission was accepted in June 2021, followed by a MAA submission to the EMA validated in July 2021. The basis to support these filings includes the completed SANET-ep and SANET-p studies, along with existing data from surufatinib in U.S. epNET and pNET patients (clinicaltrials.gov identifier: NCT02549937). In the U.S., surufatinib was granted Fast Track Designations for development in pNET and epNET in April 2020, and Orphan Drug Designation for pNET in November 2019.

HUTCHMED has initiated an Expanded Access Protocol (EAP) in the U.S. to ensure patients with NET with limited therapeutic options have access to this treatment. Regulatory clearance of this protocol has been granted by the FDA and this program is open for site activation (clinicaltrials.gov identifier: NCT04814732).

On September 20, 2021 THERADIAG (ISIN: FR0004197747, Ticker: ALTER), a company specializing in in vitro diagnostics and Theranostics, reported its half-year results to June 30, 2021, as approved by the Board of Directors on September 16, 2021 (Press release, Theradiag, SEP 20, 2021, View Source [SID1234587946]).

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Bertrand de Castelnau, CEO of Theradiag, commented: "Over the last year we have been reaping the fruit of the efforts undertaken on controlling our operating costs and on our marketing strategy. Indeed, the effectiveness of our strategic refocus is demonstrated by the considerable improvement in all our financial indicators in the first half despite an economic and public health context that remains uncertain. On the basis of buoyant activity for our innovative solutions and a healthier cost structure, we are intending to accelerate Theradiag’s development by implementing a strategic plan that is in keeping with our growth ambitions on our target markets. Biotherapy monitoring is a vast global market, and the coming semesters look promising for Theradiag".

"The solid improvement in these results demonstrate the success of the Company’s structuring phase initiated some semesters ago. They also materialize the work of Theradiag’s teams, who I would like to congratulate. We now have to accelerate our growth on our markets of choice, and in particular on the Theranostics market", added Chairman of the Board Pierre Morgon.

Revenue up 12.5% despite an uncertain public health situation

Over the six months to June 30, 2021, Theradiag generated revenue of €5.5 million, compared with €4.9 million in the first half of 2020, despite an economic and public health context characterized by persistent difficulties accessing hospital treatment for patients undergoing immunotherapy in all countries.

Theranostics activity continued its growth, increasing by +14.7% in H1, notably driven by dynamic sales of the automated i-Track10. Marked by strong growth for a number of semesters now, for the first time Theranostics activity accounted for the majority of Theradiag’s revenue over the first 6 months of 2021.

Theranostics activity undertaken in the United States in partnership with HalioDX generated revenue of €0.5 million, in line with the Company’s development plan, and was thus up by 33.6%. In its export business, the Company has maintained a buoyant level of activity, with sales increasing by 27.4% to €1.3 million. Penalized by the maintaining of plans blancs emergency plans in hospitals, activity in France slowed slightly, slipping 5.2% compared with the first half of 2020.

IVD (In Vitro Diagnostics) activity generated growth of +10.4%, with revenue totaling €2.7 million over the six months to June 30, 2021.

Substantial improvement in financial indicators thanks to better control over operating costs and a refocusing of Theradiag’s strategy on its fundamentals

Following strong growth in the second half of 2020, the operating loss continued to shrink significantly, by 57.9%, in the first half of 2021. This improvement illustrates Theradiag’s ability to develop commercially while continuing to ensure strict operating cost management. At the same time, as in previous semesters, Theradiag intensified its investments in R&D and in its commercial development in the United States in order to strengthen its leadership position in biotherapy monitoring in France and abroad. Furthermore, the Company has expanded its Quality team to be in a position to comply with the requirements of the new European Union directive with regard to in vitro diagnostic medical devices (IVDR).

In a similar vein, the net result before recurring items improved by a buoyant 84.3% compared with the same period of 2020. It is now close to breakeven, representing -0.4% of revenue.

The overall net loss, including non-recurring items, improved by 59.8% to -€92 thousand at June 30, 2021 versus -€229 thousand at June 30, 2020.

Cash position and financial structure

At June 30, 2021, Theradiag had €1.4 million in net available cash, compared with €3.5 million at December 31, 2020. This difference is the result of cash lags, now resolved, totaling €0.5 million, while investments in R&D and international development are in line with Theradiag’s strategic plan.

To finance its growth strategy on the biotherapy monitoring market while maintaining a solid financial structure, Theradiag is not ruling out the possibility of raising additional funds depending on market conditions and the progress of its strategic plan.

Reminder of the main H1 2021 highlights

· January 2021: CE marking for the four new i-Tracker test kits: i-Tracker Vedolizumab, i-Tracker Anti-Vedolizumab, i-Tracker Ustekinumab and i-Tracker Anti-Ustekinumab, on originator and biosimilar molecules

· January 2021: Signing of a contract to supply quality control reagents to Orgentec, a specialist in in vitro diagnostics notably in the field of autoimmunity, infectious diseases and molecular biology

May 2021: Participation in Humabdiag, a large-scale research project undertaken with the University of Tours targeting the bioproduction of monoclonal antibodies dedicated in particular to Theradiag and the entire biotherapy market.