On June 13, 2022 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, reported that the U.S. Food and Drug Administration (FDA) has extended the Prescription Drug User Fee Act (PDUFA) goal date by three months to January 20, 2023 for the supplementary new drug application (sNDA) for BRUKINSA as a treatment for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (Press release, BeiGene, JUN 13, 2022, View Source [SID1234615944]).

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The FDA extended the PDUFA goal date to allow time to review additional clinical data submitted by BeiGene, which was deemed a major amendment to the sNDA. The submission included final response analysis from the global ALPINE clinical trial showing BRUKINSA demonstrated superiority versus ibrutinib in overall response rate (ORR) as assessed by an Independent Review Committee (IRC) in adult patients with relapsed or refractory (R/R) CLL or SLL. This final response analysis was announced by the company on April 11, 2022.

"We will continue to work closely with the FDA to facilitate the review of our sNDA for BRUKINSA in CLL/SLL," said John V. Oyler, Co-Founder, Chairman and CEO of BeiGene. "We are confident that the data in our filing demonstrate BRUKINSA’s potential in the treatment of CLL/SLL and are committed to bringing this important medicine to CLL/SLL patients in the U.S. as soon as possible following regulatory approval."

The sNDA filing in CLL/SLL includes data from two pivotal randomized Phase 3 studies and eight supportive studies in B-cell malignancies. The two global Phase 3 trials of BRUKINSA in CLL/SLL are: SEQUOIA (NCT03336333) comparing BRUKINSA to bendamustine and rituximab in treatment-naïve (TN) patients and ALPINE (NCT03734016) comparing BRUKINSA to ibrutinib in relapsed or refractory (R/R) patients. Additionally, the SEQUOIA study enrolled patients with deletion 17p in a non-randomized arm evaluating BRUKINSA monotherapy in this high-risk population. ALPINE and SEQUOIA enrolled patients from a total of 17 countries, including the United States, multiple countries in Europe, China, Australia, and New Zealand. Interim results from the ALPINE trial and the SEQUOIA trial were reported at the 26th European Hematology Association (EHA) (Free EHA Whitepaper) (EHA2021) Virtual Congress in June 2021 and at the 63rd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2021, respectively.

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 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 a planned formal analysis of PFS when the target number of events is reached.

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 has previously been approved for three indications in the United States: for the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy (Nov. 2019)*; for the treatment of adult patients with Waldenström’s macroglobulinemia (WM) (Aug. 2021); and for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen (Sept. 2021)*.

BRUKINSA is supported by a broad clinical program which includes more than 3,900 subjects in 35 trials across 28 markets. To date, BRUKINSA has received approvals covering 50 countries and regions, including the United States, China, the EU and Great Britain, Canada, Australia, South Korea, Switzerland and additional international markets.

*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.

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 hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.4% of patients treated with BRUKINSA monotherapy. Hemorrhage events of any grade occurred in 35% 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 27% of patients, most commonly 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 (26%), thrombocytopenia (11%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia occurred in 3.6% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 8% of patients. Other second primary malignancies included malignant solid tumors (4.0%), melanoma (1.7%) and hematologic malignancies (1.2%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter were reported in 3.2% 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 1.1% 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 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 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, including laboratory abnormalities, in ≥ 30% of patients who received BRUKINSA (N = 847) included decreased neutrophil count (54%), upper respiratory tract infection (47%), decreased platelet count (41%), hemorrhage (35%), decreased lymphocyte count (31%), rash (31%) and musculoskeletal pain (30%).

Drug Interactions

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

CYP3A Inducers: Avoid coadministration 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.

On June 13, 2022 BWX Technologies, Inc. (NYSE: BWXT) reported that subsidiary BWXT Medical Ltd. and TRIUMF, Canada’s particle accelerator centre, have executed a licensing and services agreement that strengthens their existing partnership for the production of medical isotopes (Press release, BWX Technologies, JUN 13, 2022, View Source [SID1234615945]). This agreement will enable BWXT Medical to manufacture high purity Actinium-225 (Ac-225) based products for pharmaceutical companies as it continues to build on its medical isotope production operations on the TRIUMF site.

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Ac-225 is an alpha-emitting isotope used in targeted alpha therapies that combine Ac-225 with specific tumor-seeking targeting vectors to kill metastatic cancer while leaving healthy cells unaffected.

Leveraging existing infrastructure, TRIUMF will irradiate thorium-232 targets for BWXT Medical. From this irradiated thorium, BWXT Medical will process and produce high purity Ac-225, sometimes referred to as non-carrier-added Ac-225, for commercial sale, strengthening BWXT Medical’s position as a leading global manufacturer and supplier of critical medical isotopes and radiopharmaceuticals.

BWXT Medical intends to partner with pharmaceutical and biotechnology companies who intend to develop targeted alpha therapeutics.

"We are very pleased to announce this significant deal with our partner TRIUMF, whose capabilities are truly unique in the world," said Martyn Coombs, president, BWXT Medical. "There is much excitement around targeted alpha therapeutics, which may in the future offer hope to patients where previously no hope remained. We anticipate being the first company to produce non-Russian sourced high purity Ac-225 at semi-scale, starting this summer (2022). Our intention is to partner with a small number of leading pharmaceutical companies, initially supplying the isotope, and with line-of-sight to a deeper relationship including contract development and manufacturing of the finished products."

"TRIUMF and BWXT have been producing isotopes at TRIUMF since 1978; our first therapeutic isotope produced at the Vancouver facility was palladium-103 for prostate brachytherapy. This agreement represents a key and complementary initiative to our strategy to increase the supply of Ac-225, commonly known as ‘the rarest drug on earth,’ to researchers and patients around the world," said Kathryn Hayashi, CEO of TRIUMF Innovations.

Executive Director and CEO for TRIUMF, Dr. Nigel Smith, added, "Working together to increase the supply of cancer-fighting isotopes shows the impact that TRIUMF’s cyclotron infrastructure and expertise can have on the world."

On June 12, 2022 Novartis reported long-term results from the ELIANA pivotal clinical trial of Kymriah (tisagenlecleucel), the first-ever approved CAR-T cell therapy, in children and young adult patients with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL), with a maximum survival follow-up of 5.9 years (Press release, Novartis, JUN 12, 2022, View Source [SID1234615909]). For the 79 patients treated with Kymriah in this study, the five-year overall survival (OS) rate was 55% (95% CI, 43-66), while the median event-free survival (EFS) for patients in remission within three months of infusion (n=65) was 43.8 months. These findings demonstrate the curative potential of Kymriah, the only CAR-T cell therapy available for these patients who previously had limited treatment options. These data were presented as an oral presentation during the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Hybrid Congress (Abstract #S112)1.

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"These data mark a moment of profound hope for children, young adults and their families with relapsed or refractory B-cell ALL, as relapse after five years is rare," said Stephan Grupp, MD, PhD, Section Chief of the Cellular Therapy and Transplant Section, and Inaugural Director of the Susan S. and Stephen P. Kelly Center for Cancer Immunotherapy at Children’s Hospital of Philadelphia (CHOP). "Since the approval of Kymriah nearly five years ago, we have been able to offer a truly game-changing option to patients who previously faced a five-year survival rate of less than 10 percent."

This long-term follow up of ELIANA demonstrated the potential for Kymriah to transform cancer treatment in pediatric and young adult patients with r/r B-cell ALL, significantly improving outcomes with durable responses and a consistent safety profile in this patient population1:

Eighty-two percent of patients experienced remission (either complete remission [CR] or CR with incomplete hematologic recovery within three months after infusion) (95% CI, 72-90)
For patients in remission, the five-year relapse-free survival (RFS) rate was 44% (95% CI, 31-56) and the median RFS was 43 months
No new or unexpected adverse events were reported during long-term follow-up
"At Novartis, we strive for cures. With nearly six-year follow-up data in these pediatric and young adults treated for B-cell ALL, we have our strongest evidence yet that one-time treatment with Kymriah has curative potential," said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development. "These results strengthen our confidence in CAR-T cell therapies as a truly transformative and paradigm-shifting advance in cancer care, as well as our commitment to continue developing this technology with next-generation platforms."

Additional updates on the Novartis CAR-T program presented at the 2022 EHA (Free EHA Whitepaper) Congress include new data from more patients and longer follow-up from the first-in-human dose-escalation trials with YTB323 in adults with r/r diffuse large B-cell lymphoma and PHE885 in adults with r/r multiple myeloma, the first Novartis CAR-T cell therapies developed using the Novartis T-Charge platform2,3,4. Visit View Source to learn more about these data and our ongoing commitment to reimagining cancer care with CAR-T cell therapies.

About Kymriah
Kymriah is the first-ever FDA-approved CAR-T cell therapy. It is a one-time treatment designed to empower patients’ immune systems to fight their cancer. Kymriah is currently approved for the treatment of r/r pediatric and young adult (up to and including 25 years of age) acute lymphoblastic leukemia (ALL), r/r adult diffuse large B-cell lymphoma (DLBCL) and r/r adult follicular lymphoma1.

About the ELIANA Trial
ELIANA was the first pediatric global CAR-T cell therapy registration trial, examining patients in 25 centers in 11 countries across the US, Canada, Australia, Japan and the EU, including: Austria, Belgium, France, Germany, Italy, Norway and Spain. The trial was an open-label, multicenter, single-arm, global Phase II trial investigating the efficacy and safety of Kymriah in pediatric and young adult patients in r/r B-cell ALL who were primary refractory, chemorefractory, relapsed after, or were not eligible for allogeneic stem cell transplantation (SCT). The primary endpoint was overall remission rate (ORR), defined as best overall response of CR or CR with incomplete blood count recovery (CRi) within 3 months and maintained for ≥28 day. The secondary endpoints include CR/CRi with undetectable minimal residual disease (MRD), duration of remission, event-free survival, overall survival, cellular kinetics and safety5.

About T-Charge
T-Charge is a next-generation CAR-T platform, innovated at the Novartis Institutes for BioMedical Research (NIBR), that will serve as the foundation for various new investigational CAR-T cell therapies in the Novartis pipeline. By implementing the T-Charge platform, we aim to revolutionize CAR-T cell therapy with new products that have the potential to offer patients a higher likelihood of better and more durable responses, improved long-term outcomes and a reduced risk of severe adverse events. The T-Charge platform preserves T cell stemness (T cell ability to self-renew and mature), an important T cell characteristic closely tied to its therapeutic potential, which results in a product containing greater proliferative potential and fewer exhausted T cells. With T-Charge, CAR-T cell expansion occurs primarily within the patient’s body (in-vivo), eliminating the need for an extended culture time outside of the body (ex-vivo). The T-Charge platform, which implements important process efficiencies, will be rapid, compared with traditional CAR-T, and reliable, through simplified processes and streamlined quality control. Multiple CAR-T therapies, including YTB323 and PHE885, are being developed using the Novartis T-Charge platform.

About Novartis commitment to Oncology Cell Therapy
As part of the unique Novartis strategy to pursue four cancer treatment platforms – radioligand therapy, targeted therapy, immunotherapy and cell and gene therapy – we strive for cures through cell therapies in order to enable more patients to live cancer-free. We will continue to pioneer the science and invest in our manufacturing and supply chain process to further advance transformative innovation.

Novartis was the first pharmaceutical company to significantly invest in pioneering CAR-T research and initiate global CAR-T trials. Kymriah, the first approved CAR-T cell therapy, developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania, is the foundation of the Novartis commitment to CAR-T cell therapy.

We have made strong progress in broadening our delivery of Kymriah, which is currently available for use in at least one indication in 30 countries and at more than 370 certified treatment centers, with clinical and real-world experience from administration to more than 6,900 patients. We continue to pioneer in cell therapy, leveraging our vast experience to develop next-generation CAR-T cell therapies. These therapies will utilize our new T-Charge platform being evaluated to expand across hematological malignancies and bring hope for a cure to patients with other cancer types.

On June 12, 2022 IASO Biotherapeutics ("IASO Bio"), a clinical-stage biopharmaceutical company engaged in discovering, developing, and manufacturing innovative cell therapies and antibody products, and Innovent Biologics, Inc. ("Innovent," HKEX: 01801), reported that the updated data from phase 1/2 study of Equecabtagene Autoleucel (IASO Bio R&D code: CT103A, Innovent R&D code: IBI326), a fully-human anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy for the treatment of relapsed and/or refractory multiple myeloma (R/R MM), was presented in the form of an oral presentation at the 27th European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting in Vienna on June 9-12, 2022 (Press release, IASO Biotherapeutics, JUN 12, 2022, View Source [SID1234615912]).

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Presentation Title: Updated Phase 1/2 Data of the Safety and Efficacy of CT103A, Fully-Human BCMA-Directed CAR-T Cells in Relapsed/Refractory Multiple Myeloma
Session Title: Relapsed/refractory myeloma: BCMA-directed therapies
Abstract Code: EHA (Free EHA Whitepaper)-S187
Session date and Time: Sunday, June 12, 2022, at 11:30 AM – 12:45 PM CEST
Place: Vienna, Austria or online
Speaker: Chunrui Li, MD, Ph.D., from Department of Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology

The updated data from the Phase 1/2 study with a longer duration of follow-up in more patients has showed durable and deepening efficacy, manageable safety and long-term in vivo persistence, indicating that Equecabtagene Autoleucel has the potential to be a breakthrough therapy for patients with R/R MM.

The updated data is from the 14 clinical sites involved in the Phase 1/2 clinical study of Equecabtagene Autoleucel (ChiCTR1800018137, NCT05066646) in the treatment of patients with R/R MM. As of the data cutoff date of January 21, 2022, 79 patients received recommended phase 2 dose（RP2D）of 1.0×106 CAR-T cells/kg with the median follow-up of nine months (range 1.2, 19.6) and median prior five lines of therapy(range 3,23). Among the 79 patients, 34.2% (27/79) had high-risk cytogenetic abnormalities, 34.2%（27/79）had extramedullary multiple myeloma (EMM), and 15.2%（12/79）had received prior CAR-T therapy.

Equecabtagene Autoleucel demonstrated a favorable and manageable safety profile: Among the 79 patients, 94.9% (75/79) experienced cytokine release syndrome (CRS). The majority experienced 1~2 CRS, and no patient experienced grade 3 CRS. The median time to CRS onset was six days after infusion, and the median duration of CRS was five days. Only two patients experienced immune effector cell-associated neurotoxicity syndrome (ICANS), including one patient who experienced grade 1 ICANS and one who experienced grade 2 ICANS. All patients with CRS or ICANS have recovered.

Equecabtagene Autoleucel showed favorable and durable efficacy: Among the 79 patients, the overall response rate (ORR) was 94.9% (75/79), with 89.9 (71/79) of those patients achieving very good partial response (VGPR) or deeper responses, and the complete response/stringent complete response (CR/sCR) rate was 68.4% (54/79). Equecabtagene Autoleucel also demonstrated favorable efficacy in 10 patients with EMM, achieving an ORR of 100% (10/10) and a CR/sCR rate of 90.0% (9/10). In all 79 patients, 92.4% (73/79) achieved minimal residual disease (MRD) negativity, all CR/sCR subjects achieved MRD negativity, and the median duration of MRD negativity was not reached.

Equecabtagene Autoleucel demonstrated favorable efficacy in patients who had received prior CAR-T therapy: Among the 12 patients who previously received CAR-T therapy, the ORR was 75.0% (9/12), with 41.7% (5/12) of those patients achieving CR/sCR.

Equecabtagene Autoleucel demonstrated robust expansion and prolonged persistence: The expansion of Equecabtagene Autoleucel in peripheral blood reached the peak at a median of 12 days, with a median Cmax of 92,000 copies/ug DNA. Equecabtagene Autoleucel was still detectable in 62.3% (38/61) and 53.3% (8/15) of the subjects who completed 6-months and 12-month follow-ups after infusion. Soluble BCMA in peripheral blood of patients rapidly declined after Equecabtagene Autoleucel infusion and persistently remained below the detectable limit.

Equecabtagene Autoleucel has low immunogenicity: 16.5% (13/79) of the subjects tested anti-drug antibody (ADA)-positive after Equecabtagene Autoleucel infusion. Among them，1.3% (1/79) tested ADA-positive before Equecabtagene Autoleucel infusion, and 2.5% (2/79) tested ADA-positive within three months.

"Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. In our previous studies, Equecabtagene Autoleucel has shown excellent efficacy and manageable safety profiles. Its CAR structure contains fully human single-chain fragment variables (scFvs) to bypass potential anti-CAR immunogenicity of the host while retaining antitumor activity. At the 27th EHA (Free EHA Whitepaper) conference, we updated the data on the efficacy and safety of Equecabtagene Autoleucel in R/R MM patients with longer median follow-up extended to 9.0 months, the CR/sCR deepened to 68.4%, compared with the CR/sCR of 58.2% with a median follow-up of 7.0 months, which were released at 63rd ASH (Free ASH Whitepaper) conference in 2021. The updated data showed long-lasting safety and deepening efficacy of Equecabtagene Autoleucel. We are glad that Equecabtagene Autoleucel also shows favorable efficacy on patients who have relapsed after receiving prior CAR-T therapy. This has meaningful clinical value and is worthy of further exploration in the clinic to potentially bring forth new hope to patients with R/R MM." Prof. Chunrui Li, MD, PhD, from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology.

About Multiple Myeloma (MM)
Multiple Myeloma is a deadly blood cancer that often infiltrates the bone marrow causing anemia, kidney failure, immune problems, and bone fractures. For multiple myeloma patients, common first-line drug treatments include proteasome inhibitors, immunomodulatory drugs, and alkylating agents. While treatment may result in remission, most patients will inevitably enter the relapsed or refractory stage as there’s currently no cure. As a result, there is a significant unmet need for patients with relapsed/refractory multiple myeloma. In the United States, MM accounts for nearly 2% of new cancer cases and more than 2% of all cancer-related deaths. According to Frost & Sullivan, the number of new MM cases in the United States rose from 30,300 in 2016 to 32,300 in 2020 and is expected to increase to 37,800 by 2025. Additionally, the total number of patients diagnosed with MM increased from 132,200 in 2016 to 144,900 in 2020 and is expected to rise to 162,300 by 2025. In China, the number of new MM cases rose from 18,900 in 2016 to 21,100 in 2020 and is expected to increase to 24,500 by 2025. The total number of patients diagnosed with MM in China increased from 69,800 in 2016 to 113,800 in 2020 and is expected to rise to 182,200 by 2025.

About Equecabtagene Autoleucel
Equecabtagene Autoleucel is an innovative therapy co-developed by Innovent and IASO Bio, with a fully-human anti- BCMA CAR-T cell therapy which uses lentivirus as a gene vector to transfect autologous T cells. The CAR contains a fully-human scFv, CD8a hinge and transmembrane, and 4-1BB-mediated co-stimulation and CD3ζ activation domains. Based on rigorous screening and comprehensive in vivo and in vitro evaluation, Equecabtagene Autoleucel is proven to have potent and rapid anti-myeloma activity and outstanding safety, efficacy, and persistence results.

Equecabtagene Autoleucel was granted "Breakthrough Therapy Designation (BTD)" by the NMPA kn February 2021 and was granted "Orphan Drug Designation (ODD)"by the Office of Orphan Products Development (OOPD) of the U.S. Food and Drug Administration (FDA) in February 2022. The NMPA has accepted the New Drug Application for Equecabtagene Autoleucel for the Treatment of Relapsed and/or Refractory Multiple Myeloma in June 2022.

In addition to multiple myeloma, the NMPA has accepted the investigational new drug (IND) application of Equecabtagene Autoleucel for a new expanded indication of Neuromyelitis Optica Spectrum Disorder (NMOSD).

On June 12, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that it has released results from a Phase I study of the company’s novel Bcl-2-selective inhibitor lisaftoclax (APG-2575) in Chinese patients with relapsed/refractory non-Hodgkin lymphoma (r/r NHL) at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Hybrid Congress (EHA 2022) (Press release, Ascentage Pharma, JUN 12, 2022, View Source;ascentage-pharma-releases-encouraging-results-of-bcl-2-inhibitor-lisaftoclax-apg-2575-in-chinese-patients-with-relapsedrefractory-non-hodgkin-lymphoma-301566251.html [SID1234615913]).

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The EHA (Free EHA Whitepaper) Congress is the largest gathering of the hematology field in Europe. It showcases the most cutting-edge research and state-of-the-art innovative therapies, attracting over 10,000 clinical experts and researchers from more than 100 countries every year.

The data presented at this year’s EHA (Free EHA Whitepaper) Congress show that lisaftoclax was well tolerated at doses of up to 800 mg/day, without evidence of tumor lysis syndrome (TLS). In addition, lisaftoclax demonstrated preliminary efficacy in a range of relapsed/refractory hematologic malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and T-cell NHL, having achieved 4 complete responses (CRs) and 8 partial responses (PRs) in 32 efficacy evaluable patients.

In the 11 efficacy evaluable patients with CLL (all of whom were heavily pretreated and had failed prior therapies such as chemoimmunotherapies and Bruton’s tyrosine kinase [BTK] inhibitors, and the majority had at least 1 type of adverse prognostic factors such as 17p deletion/TP53 mutation), there were 8 efficacy evaluable patients in cohorts received 200 mg or higher doses, including 3 CRs and 4 PRs, thus demonstrating an ORR of 87.5%. In the 6 efficacy evaluable patients with MCL, the ORR was 33.3% (1 CR). In the 4 efficacy evaluable patients with MZL, the ORR was 50%. In the 3 efficacy evaluable patients with T-cell NHL, the ORR was 33.3%.

Lisaftoclax is a novel, orally administered small-molecule Bcl-2-selective inhibitor being developed by Ascentage Pharma to treat hematologic malignancies and solid tumors by selectively blocking the antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. Lisaftoclax is the first Bcl-2 inhibitor developed and entering clinical development in China, and is also the second such agent entering pivotal trials globally. Lisaftoclax is being studied in multiple clinical studies encompassing a range of solid tumors and hematologic malignancies, and has shown high clinical potential.

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, commented, "Lisaftoclax is a key drug candidate in Ascentage Pharma’s apoptosis-targeted pipeline. It has shown favorable tolerability and efficacy in multiple clinical studies in patients with solid tumors and hematologic malignancies. The drug candidate’s therapeutic potential was further validated by the data released at EHA (Free EHA Whitepaper) 2022. We will press ahead with the clinical development of lisaftoclax in efforts to bring a much-needed new treatment option to patients."

Highlights of this abstract on lisaftoclax are as follows:

Preliminary Results of a Phase 1 Study of Novel Bcl-2 Inhibitor Lisaftoclax (APG-2575) in Chinese Patients (pts) with Relapsed or Refractory (r/r) Non-Hodgkin Lymphomas (NHLs)

Abstract: #P1106

Highlights:

This multicenter, single-agent, Phase I trial consists of a dose escalation and a dose expansion and is the first-in-human study of lisaftoclax in adults with R/R NHL in China. The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of lisaftoclax in Chinese patients with R/R NHL.
Patients were dosed with lisaftoclax orally once daily in 28-day cycles. A daily ramp-up schedule was used in patients with CLL or NHL with medium/high-risk TLS.
As of January 1, 2022, 40 patients had been treated with lisaftoclax (dose range 20-800 mg), including 20 who remain in the trial. NHL subtypes included: 12 CLL, 9 follicular lymphoma (FL), 7 MCL, 4 MZL, 4 T-cell lymphoma, 2 diffuse large B-cell lymphoma, and 2 Waldenström macroglobulinemia.
With a median treatment duration of 4 cycles, 4 of 32 evaluable patients achieved CR and 8 achieved PR, resulting in an ORR of 37.5%. In the 11 evaluable patients with CLL, the ORR was 63.6%, the CR rate was 27.3%, and the PR rate was 36.4%. In patients with CLL treated at doses ≥ 200 mg, the ORR was 87.5%. In the 6 evaluable patients with MCL, 1 patient achieved CR and 1 achieved PR. In the 4 evaluable patients with MZL, 2 achieved PR. In the 3 evaluable patients with T-cell NHL, 1 achieved PR.
Lisaftoclax was generally well tolerated. Most treatment-emergent adverse events (TEAEs) were grade 1-2 (67.5%). Dose-limiting toxicity (DLT) and laboratory/clinical TLS were not observed in any of the dose cohorts, and there were no dose-reduction or discontinuation due to intolerance.
Conclusions:

Lisaftoclax showed promising antitumor activity and favorable responses in subtypes of NHL including CLL/SLL, MZL, MCL, T-cell NHL. In addition, lisaftoclax demonstrated a favorable safety profile, with no TLS or DLT observed during the dose ramp-up from 20 mg – 800 mg/day.