On June 11, 2021 AbbVie (NYSE: ABBV) reported results from a four-year follow-up analysis of the Phase 3 CLL14 trial, which showed that previously untreated patients with chronic lymphocytic leukemia (CLL) with coexisting conditions who were treated with VENCLYXTO/VENCLEXTA (venetoclax) plus obinutuzumab continued to show longer progression-free survival (PFS) and higher rates of undetectable minimal residual disease (MRD) compared to patients receiving a standard of care chemoimmunotherapy regimen of obinutuzumab and chlorambucil (Press release, AbbVie, JUN 11, 2021, View Source [SID1234583863]). The data were presented for the first time today during the virtual 26th European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress (abstract #S146).

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"The CLL14 trial results observed after four years of follow-up with treatment of venetoclax plus obinutuzumab show that these patients can experience long-lasting responses without disease progression, years after stopping treatment," said Mohamed Zaki, M.D., Ph.D., vice president and head, global oncology development, AbbVie.

After a median follow-up of more than four years (52.4 months), patients treated with the VENCLYXTO/VENCLEXTA and obinutuzumab combination (n=216) continued to demonstrate longer PFS compared to patients on treatment with obinutuzumab and chlorambucil, the risk of disease progression or death was reduced by 67 percent (n=216; median not reached compared to 36.4 months; hazard ratio [HR] 0.33 [95% CI 0.25-0.45]); results are descriptive. At four years after randomization, the PFS rate for patients treated with the VENCLYXTO/VENCLEXTA-based combination was 74 percent compared to 35.4 percent for patients treated with obinutuzumab and chlorambucil. The improvement in PFS was observed across all clinical and biological risk groups, including patients with TP53 mutation, 17p deletion and unmutated IGHV status.1

Additionally, assessment of MRD in peripheral blood 30 months after the end of treatment showed that 26.9 percent of patients treated with the VENCLYXTO/VENCLEXTA-based combination still had undetectable MRD (<10-4) compared to 3.2 percent of patients in the obinutuzumab plus chlorambucil arm.1 Undetectable MRD occurs when less than one CLL cell per 10,000 lymphocytes can be detected in the blood or bone marrow using sensitive analytical methods.2

No new safety signals were observed in the four-year follow-up analysis.1 The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab were pneumonia, sepsis, febrile neutropenia, and TLS.3

"CLL is considered an incurable disease and becomes more difficult to treat each time a patient experiences a relapse, so a key treatment goal is to maintain remission for as long as possible. The four- year results of the CLL14 study show that 74 percent of patients treated with fixed-duration venetoclax-obinutuzumab remain without PFS event, more than three years after treatment cessation," said Othman Al-Sawaf, M.D., lead investigator of the CLL14 study, hematologist-oncologist at the University Hospital Cologne in Germany, and study physician at the German CLL Study Group. "This highlights how durable the remissions are after 12 treatment cycles in the vast majority of patients, suggesting the venetoclax-obinutuzumab combination regimen as an effective option for patients with previously untreated CLL."

CLL is a slow-growing form of leukemia, or blood cancer, in which too many immature lymphocytes (a type of white blood cell) are found predominantly in the blood and bone marrow. CLL is the most common form of leukemia in the Western Hemisphere, accounting for approximately one third of new leukemia diagnoses and nearly 95,000 new cases in Europe each year.4,5,6

VENCLYXTO/VENCLEXTA is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About the CLL14 Phase 3 Trial3,7,8
The prospective, multicenter, open-label, randomized Phase 3 CLL14 trial, which was conducted in close collaboration with the German CLL Study Group (DCLLSG), evaluated the efficacy and safety of a combined regimen of VENCLYXTO/VENCLEXTA and obinutuzumab (n=216) versus obinutuzumab and chlorambucil (n=216) in previously untreated patients with CLL and coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance <70 mL/min). The therapies were administered for a fixed duration of 12 months for VENCLYXTO/VENCLEXTA in combination with six cycles of obinutuzumab. The trial enrolled 432 patients, all of whom were previously untreated according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Efficacy was based on PFS as assessed by an independent review committee.

Key secondary endpoints were rates of MRD in peripheral blood and bone marrow, overall and complete response rates, MRD in complete response in peripheral blood and bone marrow, and overall survival.

The four-year, follow-up analysis showed an OS rate of 85.4% with Ven-Obi versus 83.1% with chlorambucil in combination with obinutuzumab (Obi-Clb; HR 0.85, 95% CI [0.54-1.35]; P=0.49).

In patients with CLL receiving combination therapy with obinutuzumab, serious adverse reactions (ARs) were most often due to febrile neutropenia and pneumonia (5 percent each). The most common ARs (≥20 percent) of any grade were neutropenia (60 percent), diarrhea (28 percent), and fatigue (21 percent). Fatal ARs that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2 percent (4/212) of patients, most often from infection.

About VENCLYXTO (venetoclax)

VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. Venetoclax is approved in more than 80 countries, including the U.S.

Indication and Important VENCLYXTO (venetoclax) EU Safety Information3

Indications

Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of CLL:

In the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
In the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumour lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as Venclyxto efficacy may be reduced.

Special Warnings & Precautions for Use

Tumour Lysis syndrome, including fatal events, has occurred in patients when treated with Venclyxto. For CLL and AML, please refer to the indication-specific recommendations for prevention of TLS in the Venclyxto summary of product characteristic (SmPC).

Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS. The risk of TLS is a continuum based on multiple factors, including comorbidities. Venclyxto poses a risk for TLS at initiation and during the dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venclyxto and at each dose increase.

Neutropenia (grade 3 or 4) has been reported. Complete blood counts should be monitored throughout the treatment period.

In patients with AML, neutropenia (grade 3 or 4) is common before starting treatment. The neutrophil counts can worsen with Venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy. Dose modification and interruptions for cytopenias are dependent on remission status.

For CLL and AML, please refer to the indication-specific recommendations for dose modifications for toxicities in the Venclyxto SmPC.

Serious infections including sepsis with fatal outcome have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections should receive prompt treatment including antimicrobials and dose interruption or reduction as appropriate.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions

In CLL and AML CYP3A inhibitors may increase Venclyxto plasma concentrations.

In CLL, at initiation and dose-titration phase, Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, please refer to the recommendations for dose modifications in the Venclyxto SmPC.

In AML, please refer to the AML-specific recommendation for dose modifications for potential interactions with CYP3A inhibitors, in the VENCLYXTO SmPC.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease Venclyxto plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions

CLL

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (>=2%) were pneumonia and febrile neutropenia.

Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in combination with obinutuzumab or rituximab in the CLL14 and Murano studies, respectively. In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions.

Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of venetoclax and obinutuzumab in CLL14, in 15% of patients treated with the combination of venetoclax and rituximab in Murano, and in 14% of patients treated with venetoclax in the monotherapy studies. The most common adverse reaction that led to dose interruptions was neutropenia.

AML

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in combination with azacitidine or decitabine in the VIALE-A and M14-358, respectively, were thrombocytopenia, neutropenia, febrile neutropenia, nausea, diarrhoea, vomiting, anaemia, fatigue, pneumonia, hypokalaemia, and decreased appetite, haemorrhage, dizziness/syncope, hypotension, headache, abdominal pain, and anaemia.

The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax in combination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage. In M14-358, the most frequently reported serious adverse reactions (≥5%) were febrile neutropenia, pneumonia, bacteraemia and sepsis.

Discontinuations due to adverse reactions occurred in 24% of patients treated with venetoclax in combination with azacitidine in the VIALE-A study, and 26% of patients treated with venetoclax in combination with decitabine in the M14-358 study, respectively.

Dosage reductions due to adverse reactions occurred in 2% of patients in VIALE-A, and in 6% of patients in M14-358. Venetoclax dose interruptions due to adverse reactions occurred in 72% and 65% of patients, respectively. The most common adverse reaction that led to dose interruption (>10%) of Venetoclax in VIALE-A, were febrile neutropenia, neutropenia, pneumonia, and thrombocytopenia. The most common adverse reactions that led to dose interruption (≥5%) of venetoclax in M14-358 were febrile neutropenia, neutropenia/neutrophil count decreased, pneumonia, platelet count decreased, and white blood cell count decreased.

Special Populations

Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined.

For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

Venclyxto may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See Venclyxto (venetoclax) SmPC at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology
At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world’s most widespread and debilitating cancers. As we work to have a remarkable impact on people’s lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit View Source

On June 11, 2021 Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat genetically defined diseases, reported positive results from its Phase 2, open-label, multicenter study of mitapivat in adults with non-transfusion dependent α- or β-thalassemia (Press release, Agios Pharmaceuticals, JUN 11, 2021, View Source [SID1234583887]). Data from the study will be featured in an oral presentation on Tuesday, June 15, at the European Hematology Association (EHA) (Free EHA Whitepaper) Virtual Congress.

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Consistent with previously announced proof-of-concept data, the study met its primary endpoint, with 16 of the 20 patients (80%) achieving a hemoglobin increase of ≥1.0 g/dL from baseline at one or more assessments during Weeks 4-12. Additionally, a sustained hemoglobin response and improvements in hemolysis and ineffective erythropoiesis were observed in both α- or β-thalassemia patients treated with mitapivat. Mitapivat was well tolerated, and the safety profile was consistent with previous studies. Mitapivat is a first-in-class, investigational, oral, small molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase R (PKR) enzymes.

"These data continue to validate the potential of PK activation as an entirely new mechanism for treating thalassemia, a disease for which there have been few medical advancements. In particular, we are excited to see data generated, for the first time, in α-thalassemia, demonstrating an increase in hemoglobin from baseline in all five patients in this subgroup," said Kevin Kuo, M.D., hematologist at University Health Network, University of Toronto, and an investigator in the study. "The impressive results reported today underscore the potential of mitapivat to meaningfully improve hallmarks of this disease, including hemolysis and ineffective erythropoiesis."

Mitapivat Phase 2 Proof-of-concept Study
The open-label Phase 2 study evaluated the efficacy, safety, pharmacokinetics and pharmacodynamics of mitapivat treatment in adults with either non-transfusion-dependent α- or β-thalassemia who have a baseline hemoglobin (Hb) concentration of ≤10 g/dL. The trial enrolled 20 patients. All patients were treated with an initial dose of mitapivat 50 mg twice daily followed by a dose-level increase to 100 mg twice daily at the Week 6 visit based on safety evaluations and hemoglobin concentrations. Following the completion of the 24-week core period, patients had the opportunity to enroll in an optional 10-year extension period which will evaluate long-term efficacy and safety of mitapivat in this population.

Of the 20 patients, 5 patients had α-thalassemia, and 15 patients had β-thalassemia.
Median hemoglobin at baseline was 8.43 (range 5.13-9.8) g/dL.
Median age was 44 (range 29-67) years.
Efficacy Data

The primary endpoint, defined as a ≥1.0 g/dL increase in hemoglobin concentration from baseline at one or more assessments between Week 4 and Week 12, was met by 16 of 20 (80%) patients (1-sided p<0.0001), including all 5 (100%) α-thalassemia patients and 11 of 15 (73.3%) β-thalassemia patients. The 1-sided p-value associated with the test of H0: hemoglobin response rate =30% vs H1: hemoglobin response rate >30%, based on the Clopper-Pearson method.
The secondary endpoint of sustained hemoglobin response, defined as a primary endpoint response and a ≥1.0 g/dL increase in hemoglobin concentration from baseline at two or more assessments between Week 12 and Week 24, was met by 13 of 20 (65%) patients, including all 5 (100%) α-thalassemia patients and 8 of 15 (53.3%) patients with β-thalassemia.
During Weeks 12-24, the mean hemoglobin change from baseline was 1.3 g/dL. The mean change was 1.2 g/dL for α-thalassemia patients, and 1.3 g/dL for β-thalassemia patients.
Among hemoglobin responders, mean time to first ≥1.0 g/dL increase in hemoglobin concentration was 4.5 weeks.
Markers of hemolysis and erythropoiesis – including indirect bilirubin, lactate dehydrogenase and erythropoietin – demonstrated improvements that were consistent with the hemoglobin increase in both α- and β-thalassemia patients.
Adenosine triphosphate (ATP) levels showed mean increases of up to 86.7% from baseline.
Safety Data
The majority of adverse events (AEs) observed were consistent with previously published data for mitapivat in healthy volunteers and patients with pyruvate kinase (PK) deficiency.

Dose escalation to 100 mg twice daily was well tolerated.
The most commonly reported AEs were initial insomnia (n=10 [50%]), dizziness (n=6 [30%]) and headache (n=5 [25%]).
One patient (5%) discontinued treatment during the study; the adverse event leading to study drug discontinuation was not treatment-related.
Seventeen patients continued to the extension period of the study, and as of March 27, 2021, 17 patients remain on study drug.
"We are pleased to present data from our Phase 2 trial of mitapivat, which is the first clinical study of a PK activator in thalassemia and the first drug trial in α-thalassemia, and represents a potentially innovative therapeutic approach for these patients who are in need of new treatment options," said Chris Bowden, chief medical officer at Agios. "Our focus now is to advance the development of mitapivat in thalassemia as quickly and efficiently as possible, with the initiation of two Phase 3 studies of mitapivat, ENERGIZE and ENERGIZE-T, in not regularly transfused and regularly transfused adults with thalassemia. Additionally, we look forward to further advancing mitapivat as a potential treatment for other underserved patients with hemolytic anemias, including individuals with pyruvate kinase deficiency, where our U.S. and EU regulatory filing plans are on track, and sickle cell disease, where our pivotal development program is on track to initiate by year-end."

Oral Presentation Information

Title: Results from a Phase 2, open-label, multicenter study of the oral pyruvate kinase activator mitapivat in adults with non-transfusion dependent alpha- or beta-thalassemia
Live Q&A Session Date and Time: Tuesday, June 15, 2021, at 8:45 p.m. CEST / 2:45 p.m. ET
Oral Abstract Session: Changing the scene on thalassemias
Abstract: S267
Presenter: Kevin H. M. Kuo, M.D., Division of Hematology, University of Toronto, Toronto, Canada

Mitapivat Clinical Development
In addition to the Phase 2 extension study of mitapivat in adults with non-transfusion-dependent α- and β-thalassemia, Agios is initiating two Phase 3 studies of mitapivat in adults with thalassemia in the second half of 2021. They are:

ENERGIZE: A placebo-controlled trial with a 2:1 randomization evaluating patients who do not receive regular transfusions. The primary endpoint of the trial is hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration from Week 12 through Week 24 compared with baseline.
ENERGIZE-T: A placebo-controlled trial with a 2:1 randomization evaluating patients who receive regular transfusions. The primary endpoint of the trial is transfusion reduction response, defined as a ≥50% reduction in transfused red blood cell units with a reduction of ≥2 units of transfused red blood cells in any consecutive 12-week period through Week 48 compared with baseline.
In addition to its Phase 2 study of mitapivat in adults with non-transfusion-dependent α- or β-thalassemia, Agios has completed two global, pivotal trials in adults with pyruvate kinase (PK) deficiency. Final data from these studies will be presented in an oral session at the EHA (Free EHA Whitepaper) Virtual Congress. They are:

ACTIVATE: A placebo-controlled trial with a 1:1 randomization evaluating patients who do not receive regular transfusions. The primary endpoint of the study was hemoglobin response, defined as a ≥1.5 g/dL increase in hemoglobin concentration from baseline that is sustained at two or more scheduled assessments at Weeks 16, 20 and 24 during the fixed dose period.
ACTIVATE-T: A single arm trial of regularly transfused patients with a primary endpoint of reduction in transfusion burden, a reduction of ≥33 percent in the number of red blood cell units transfused during the 24-week fixed dose period compared with the historical transfusion burden standardized to 24 weeks.
ACTIVATE and ACTIVATE-T are intended to support global regulatory filings for mitapivat in adults with PK deficiency in the U.S. in the second quarter of 2021 and in the EU in mid-2021. Agios also is conducting an extension study for adults with PK deficiency previously enrolled in ACTIVATE or ACTIVATE-T, which is designed to evaluate the long-term safety, tolerability and efficacy of treatment with mitapivat.

In addition, mitapivat is being evaluated as a potential treatment for sickle cell disease under a Cooperative Research and Development Agreement (CRADA) with the U.S. National Institutes of Health. Mitapivat has been shown to decrease 2,3-diphosphoglycerate (2,3-DPG) and increase adenosine triphosphate (ATP), and through this mechanism, it may reduce hemoglobin S polymerization and red blood cell sickling. Preliminary clinical data establishing proof-of-concept for mitapivat in sickle cell disease were disclosed in June 2020, and updated data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2020. Agios is initiating its pivotal Phase 2/3 study in sickle cell disease by year-end 2021.

Mitapivat has been granted orphan drug designation for the treatment of PK deficiency by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. Additionally, mitapivat has received orphan drug designation from the FDA for the treatment of thalassemia and sickle cell disease.

Mitapivat is not approved for use by any regulatory authority.

CONFERENCE CALL INFORMATION

Agios will host a virtual investor event today at 7:30 a.m. ET to review the mitapivat clinical data. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors and Media section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

On June 11, 2021 TG Therapeutics, Inc. (NASDAQ: TGTX), reported data from TG-1701, the Company’s investigational once-daily, oral BTK inhibitor, as a monotherapy and as a triple therapy in combination with ublituximab, the Company’s novel glycoengineered anti-CD20 monoclonal antibody, and UKONIQ (umbralisib), the Company’s once-daily, inhibitor of PI3K-delta and CK1-epsilon in patients with front line or relapsed/refractory non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) (Press release, TG Therapeutics, JUN 11, 2021, View Source [SID1234583903]). Data from this trial were made available on demand this morning during the 3032 European Hematology Association (EHA) (Free EHA Whitepaper) Virtual Congress. The data presented today were previously presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting.

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PRESENTATION HIGHLIGHTS:

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

A total of 125 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), 200 mg in a dose-expansion cohort (n=61), 300 mg in a CLL dose-expansion cohort (n=20), or TG-1701 in combination with U2 in the dose escalation cohort (n=19).
TG-1701 monotherapy was well tolerated and the maximum tolerated dose was not reached up to 400 mg QD.
Adverse Events (AEs) of special interest in patients treated with 200 mg and 300 mg QD of TG-1701 (n=81), included Grade 3 hypertension (4.9%), atrial fibrillation (1.2%), and no instances of major bleeding observed. Grade 3 AEs occurring in ≥10% of patients treated with U2+1701 included diarrhea (11%), neutropenia (11%), ALT increase (16%), and AST increase (16%), and Grade 4 AEs occurring in ≥10% of patients treated with U2+1701 included neutropenia (11%).
At a median follow up of 12.2 months in the 200 mg QD monotherapy expansion cohorts, overall response rates (ORR) were: 95% (19/20) in CLL, 65% (13/20) in mantle cell lymphoma (MCL), and 95% (19/20) in Waldenstrom macroglobulinemia (WM).
100% ORR observed at a median follow up of 8.6 months in the 300 mg CLL monotherapy cohort (n=19).
At a median follow up of 15.6 months, the 1701+U2 dose escalation (using doses of 100mg to 300 mg QD of TG-1701) resulted in 79% ORR, with 21% CR rate across patients with WM, CLL, marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (n=19).
Data presented at EHA (Free EHA Whitepaper) 2021 is available on the Publications page of the Company’s website at View Source

On June 11, 2021, OncoCyte Corporation (the "Company") reported that it entered into an at-the-market sales agreement (the "Agreement") with BTIG, LLC, as sales agent and/or principal (the "Agent") pursuant to which the Company may sell up to an aggregate of $50,000,000 of shares of Company common stock (the "Shares") from time to time through the Agent (the "ATM Offering") (Filing, 8-K, Oncocyte, JUN 11, 2021, View Source [SID1234583944]). If the Company determines to sell Shares directly to BTIG, as principal (each such transaction, a "Principal Transaction"), the Company and BTIG will enter into a separate agreement that governs such Principal Transaction.

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Under the Agreement, the Company will set the parameters for the sale of Shares, including the number of Shares to be issued, the time period during which sales are requested to be made, limitations on the number of Shares that may be sold in any one trading day and any minimum price below which sales may not be made. Sales of the Shares, if any, under the Agreement may be made in transactions that are deemed to be an "at the market offering" as defined in Rule 415 under the Securities Act of 1933, as amended, including sales made directly on the Nasdaq Stock Market LLC or sales made to or through a market maker other than on an exchange. The Company will pay the Agent a commission equal to 3.0% of the gross proceeds of any Shares sold through the Agent under the Agreement. The Agreement contains customary representations, warranties and agreements by the Company, indemnification obligations of the Company and the Agent, other obligations of the parties and termination provisions. The Company has no obligation to sell any of the Shares, and may at any time suspend offers under the Agreement.

Offers and sales of the Shares by the Company under the Agreement, if any, will be made pursuant to the Company’s previously filed Registration Statement on Form S-3 (File No. 333-256650) that was declared effective by the Securities and Exchange Commission (the "SEC") on June 8, 2021, as supplemented by a prospectus supplement related to the ATM Offering filed with the SEC on June 11, 2021.

On June 11, 2021 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a global biotechnology company focused on developing and commercializing innovative medicines worldwide, reported results from the interim analysis of the Phase 3 ALPINE trial comparing its BTK inhibitor BRUKINSA (zanubrutinib) to ibrutinib in adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), including superiority in the primary endpoint of investigator-assessed overall response rate (ORR) and superiority in a key secondary endpoint of atrial fibrillation or flutter (Press release, BeiGene, JUN 11, 2021, View Source [SID1234583865]).

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These results were reported in an oral presentation as part of the Presidential Symposium and featured during the congress press briefing at the 26th European Hematology Association (EHA) (Free EHA Whitepaper) 2021 (EHA2021) Virtual Congress, taking place virtually on June 9-17, 2021.

"While ibrutinib has transformed the outlook for patients with chronic lymphocytic leukemia, or CLL, not all patients respond to treatment and toxicities associated with prolonged exposure remain an issue," commented Peter Hillmen, MBChB, Ph.D., Professor of Experimental Haematology at University of Leeds and principal investigator of the ALPINE trial. "The ALPINE trial is the only head-to-head study in CLL to demonstrate an efficacy advantage for a more selective BTK inhibitor over ibrutinib. Compared to ibrutinib, BRUKINSA demonstrated superiority in investigator-assessed overall response rate in patients with relapsed or refractory CLL. Additionally, the event rate of atrial fibrillation or flutter, an important indicator of cardiac toxicity, was also significantly lower with BRUKINSA."

"The positive data from the interim analysis of the ALPINE trial, including a superior overall response rate by investigator assessment, supportive initial data in progression-free survival and overall survival, and a significantly lower rate of atrial fibrillation of any grade, reinforce our belief that the differentiated profile of BRUKINSA can provide clinical benefits for patients with CLL," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "As evidenced in ALPINE and ASPEN, our head-to-head trials of BRUKINSA against the first-generation BTK inhibitor ibrutinib, this potentially best-in-class molecule can provide meaningful responses and consistent safety advantages for these patients. In addition to ALPINE, we are evaluating BRUKINSA in the Phase 3 SEQUOIA trial in treatment-naïve CLL, and expect to share topline results as early as later this year."

Interim Analysis of the ALPINE Trial Comparing BRUKINSA to Ibrutinib in R/R CLL

Oral presentation; Abstract code: LB1900

Results from the planned interim analysis presented at EHA (Free EHA Whitepaper) were based on the first 415 patients enrolled in the ALPINE trial, including 207 on BRUKINSA treatment and 208 on ibrutinib treatment.

In the interim analysis, with a median follow-up time of 15.3 months, the trial met the primary endpoint with BRUKINSA demonstrating superiority in ORR, defined as the combined rate of complete responses (CRs) and partial responses (PRs), per investigator assessment. In the ORR analysis conducted by independent review committee (IRC), BRUKINSA demonstrated non-inferiority in the interim analysis. Efficacy results included:

As assessed by investigator, BRUKINSA achieved an ORR of 78.3% (95% CI: 72.0, 83.7), a statistically significant improvement compared to 62.5% (95% CI: 55.5, 69.1) with ibrutinib (p=0.0006);
As assessed by IRC, BRUKINSA achieved an ORR of 76.3%, numerically higher but not statistically significant compared to 64.4% with ibrutinib (p=0.0121 compared to the pre-specified stringent statistical boundary of p<0.0099 set for the interim analysis);
In patients whose tumor exhibited chromosome 17p deletion (del[17p]), the ORR was 83.3% in the BRUKINSA arm, compared to 53.8% in the ibrutinib arm, as assessed by investigator;
PFS data were early at the time of interim analysis and formal analysis will be performed when the target number of events is reached. The PFS rate at 12 months was 94.9% in the BRUKINSA arm, compared to 84.0% in the ibrutinib arm (descriptive p=0.0007; descriptive hazard ratio [HR]=0.40 [95% CI: 0.23, 0.69]), as assessed by investigator; and
OS data were early at the time of interim analysis. The OS rate at 12 months was 97.0% in the BRUKINSA arm, compared to 92.7% in the ibrutinib arm (descriptive p=0.1081; descriptive HR=0.54 [95% CI: 0.25, 1.16]).
In the interim analysis, the ALPINE trial also met a pre-specified key secondary endpoint related to safety, with BRUKINSA demonstrating a statistically significant lower risk of atrial fibrillation or flutter and advantages in the overall cardiac safety profile, compared to ibrutinib. Treatment discontinuation was more common in the ibrutinib arm. Safety results included:

195 patients (95.6%) in the BRUKINSA arm experienced at least one adverse event (AE) of any grade, compared to 205 patients (99.0%) in the ibrutinib arm, and the most common (≥10%) AEs included anemia (BRUKINSA vs. ibrutinib: 13.2% vs. 15.0%), arthralgia (9.3% vs. 14.0%), contusion (10.3% vs. 8.7%), cough (12.7% vs. 6.3%), diarrhea (16.7% vs. 19.3%), hypertension (15.7% vs. 13.0%), muscle spasm (2.9% vs. 11.1%), neutropenia (19.6% vs. 15.5%), upper respiratory tract infection (21.6% vs. 14.0%), and urinary tract infection (10.8% vs. 8.2%);
114 patients (55.9%) in the BRUKINSA arm experienced Grade ≥3 AEs, compared to 106 patients (51.2%) in the ibrutinib arm;
56 patients (27.5%) in the BRUKINSA arm experienced serious AEs, compared to 67 patients (32.4%) in the ibrutinib arm;
Dose reduction and interruption due to AEs occurred in 23 patients (11.3%) and 81 patients (39.7%) in the BRUKINSA arm, respectively, compared to 25 patients (12.1%) and 84 patients (40.6%) in the ibrutinib arm;
16 patients (7.8%) discontinued BRUKINSA treatment due to AEs, with none caused by cardiac disorders; in comparison, 27 patients (13.0%) discontinued ibrutinib treatment due to AEs, with seven caused by cardiac disorders, including two of atrial fibrillation, and one each of cardiac arrest, cardiac failure, myocardial infarction, palpitations, and ventricular fibrillation;
Fatal AEs were reported in eight patients (3.9%) in the BRUKINSA arm, compared to 12 patients (5.8%) in the ibrutinib arm;
A key secondary endpoint of atrial fibrillation or flutter of any grade occurred in five patients (2.5%) in the BRUKINSA arm, significantly lower than the 21 patients (10.1%) in the ibrutinib arm (p=0.0014);
Grade ≥3 atrial fibrillation or flutter occurred in two patients (1.0%) in the BRUKINSA arm, compared to four patients (1.9%) in the ibrutinib arm;
Additional AEs of special interest of any grade included cardiac disorders (BRUKINSA vs. ibrutinib: 13.7% vs. 25.1%), hemorrhage (35.8% vs. 36.2%), major hemorrhage (2.9% vs. 3.9%), hypertension (16.7% vs. 16.4%), infections (59.8% vs. 63.3%), neutropenia (28.4% vs. 21.7%), secondary primary malignancies (8.3% vs. 6.3%), skin cancers (3.4% vs. 4.8%), and thrombocytopenia (9.3% vs. 12.6%); and
Grade ≥3 AEs of special interest included cardiac disorders (BRUKINSA vs. ibrutinib: 2.5% vs. 6.8%), hemorrhage (2.9% vs. 2.9%), major hemorrhage (2.9% vs. 2.9%), hypertension (10.8% vs. 10.6%), infections (12.7% vs. 17.9%), neutropenia (18.6% vs. 15.0%), secondary primary malignancies (4.9% vs. 1.9%), skin cancers (1.5% vs. 1.0%), and thrombocytopenia (3.4% vs. 3.4%).
Summary of ALPINE Interim Results

ALPINE
Summary

BRUKINSA
(n=207)

Ibrutinib
(n=208)

Efficacy Results

Investigator-
Assessed ORR
(Primary Endpoint)

78.3%
(95% CI: 72.0, 83.7)

62.5%
(95% CI: 55.5, 69.1)

p=0.0006

IRC-Assessed ORR

76.3%

64.4%

p=0.0121 compared to the pre-specified stringent
statistical boundary of p<0.0099

ORR in del(17p)

83.3%

53.8%

12-Month PFS Rate*

94.9%

84.0%

descriptive p=0.0007;
descriptive HR=0.40 (95% CI: 0.23, 0.69)

* PFS data were early at the time of interim analysis and formal analysis will be performed when the target number of events is reached.

Overall Safety Results

AEs of any grade

95.6%

99.0%

Grade ≥3 AEs

55.9%

51.2%

Serious AEs

27.5%

32.4%

AEs leading to treatment discontinuation

7.8%

13.0%

Fatal AEs

3.9%

5.8%

Adverse Events of Special Interest (Any Grade)

Atrial Fibrillation
or Flutter
(Key Secondary Endpoint)

2.5%

10.1%

p=0.0014

Cardiac Disorders

13.7%

25.1%

Hemorrhage

35.8%

36.2%

Major Hemorrhage

2.9%

3.9%

Hypertension

16.7%

16.4%

Infections

59.8%

63.3%

Neutropenia

28.4%

21.7%

Secondary Primary Malignancies

8.3%

6.3%

Skin Cancers

3.4%

4.8%

Thrombocytopenia

9.3%

12.6%

To learn more about BeiGene’s research and development and activities around EHA (Free EHA Whitepaper)2021, please visit View Source

BeiGene EHA (Free EHA Whitepaper)2021 Investor Conference Call and Webcast Information

BeiGene will host an investor and analyst conference call and webcast to discuss results from the interim analysis of the ALPINE trial, other data presented at EHA (Free EHA Whitepaper)2021, and the BRUKINSA clinical program, today Friday, June 11, at 12:00 p.m. (noon) ET (18:00 CEST).

A live webcast of the conference call can be accessed from the investors section of BeiGene’s website at View Source or View Source An archived replay will be available two hours after the event for 90 days.

About Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults, with a global incidence of approximately 114,000 new cases in 2017.1,2 CLL affects white blood cells or lymphocytes in the bone marrow.1 Proliferation of cancer cells (leukemia) in the marrow result in reduced ability to fight infection and spread into the blood, which affects other parts of the body including the lymph nodes, liver and spleen.1,3 The BTK pathway is a known route that signals malignant B cells and contributes to the onset of CLL.4 Small lymphocytic lymphoma (SLL) is a non-Hodgkin’s lymphoma affecting the B-lymphocytes of the immune system, which shares many similarities to CLL but with cancer cells found mostly in lymph nodes.5

About ALPINE

ALPINE is a randomized, global Phase 3 trial (NCT03734016) comparing BRUKINSA against ibrutinib in previously treated patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

In the trial, a total of 652 patients were randomized into two arms, with the first receiving BRUKINSA (160 mg orally twice daily) and the second receiving ibrutinib (420 mg orally once daily) until disease progression or unacceptable toxicity. The primary analysis of overall response rate (ORR), defined by pre-specified non-inferiority of BRUKINSA versus ibrutinib, was assessed by investigator and independent review committee (IRC) using the modified 2008 iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL, and per Lugano Classification for non-Hodgkin’s lymphoma for patients with SLL. There was hierarchical testing of non-inferiority followed by superiority in ORR as assessed by investigator and IRC. Key secondary endpoints include progression-free survival (PFS) and event rate of atrial fibrillation or flutter; other secondary endpoints include duration of response, overall survival, and incidence of adverse events. The study is ongoing, with pre-specified final analysis of ORR superiority by IRC assessment and formal analysis of PFS when the target number of events is reached. Results are expected in 2022.

About BRUKINSA

BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Because new BTK is continuously synthesized, BRUKINSA was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.

BRUKINSA is approved in the following indications and regions:

For the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy (United States, November 2019)*;
For the treatment of MCL in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of relapsed or refractory MCL (United Arab Emirates, February 2021); and
For the treatment of Waldenström’s macroglobulinemia (WM) in adult patients (Canada, March 2021).
To-date, more than 30 marketing authorization applications in multiple indications have been submitted outside of the United States and China, covering countries in the European Union and more than 20 other countries.

* This indication was approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

** This indication was approved under conditional approval. Complete approval for this indication may be contingent upon results from ongoing randomized, controlled confirmatory clinical trials.

IMPORTANT U.S. SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (27%), thrombocytopenia (10%), and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.

Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

The most common adverse reactions in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For co-administration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid co-administration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

INDICATION

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.