On December 11, 2021 Kite, a Gilead Company (Nasdaq: GILD), reported results from the primary analysis of ZUMA-7, a global Phase 3 study evaluating Yescarta (axicabtagene ciloleucel) as a one-time infusion, in a head-to-head study against standard of care (SOC) for adults with large B-cell lymphoma (LBCL) who relapsed or were refractory to first-line treatment (Press release, Gilead Sciences, DEC 11, 2021, View Source [SID1234596837]). Yescarta was evaluated against the current SOC which is a multi-step process intended to culminate in a stem cell transplant. ZUMA-7 was initiated in 2017 and is the first and largest Phase 3 randomized study of any CAR T-cell therapy in the second-line setting, enrolling 359 patients in 77 centers around the world. ZUMA-7 is considered a landmark trial for being the only study to reach the clinically meaningful two-year follow-up milestone. The findings were featured in the American Society of Hematology (ASH) (Free ASH Whitepaper) press briefing today at their 63rd ASH (Free ASH Whitepaper) Annual Meeting & Exposition and in a simultaneous publication in the New England Journal of Medicine (NEJM). The data will also be presented in full at the ASH (Free ASH Whitepaper) plenary session on Sunday, December 12 (Abstract #2).

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With a median follow-up of over two years, the study met the primary endpoint of event-free survival (EFS; hazard ratio 0.398; 95% CI: 0.308-0.514, P<0.0001). Yescarta demonstrated a 2.5 fold increase in patients who were alive at two years and did not require the need for additional cancer treatment or experienced cancer progression (40.5% vs. 16.3%) and a four-fold greater median EFS (8.3 mo. vs. 2.0 mo.) compared to SOC. These statistically significant and clinically meaningful results were not confounded by any bridging chemotherapy. Improvements in EFS with Yescarta were consistent across key patient subgroups, including the elderly (HR: 0.276 [95% CI: 0.164-0.465]), primary refractory disease (HR: 0.426 [95% CI: 0.319-0.570]), high-grade B-cell lymphoma including double-hit and triple-hit lymphoma (HGBL; HR: 0.285 [95% CI: 0.137-0.593]), and double expressor lymphoma (HR: 0.424 [95% CI: 0.268-0.671]).

"The majority of patients with relapsed/refractory LBCL do not achieve long-term remission with currently available treatments and as we saw in this trial, are often not able to complete the multi-step process that culminates in a transplant," said Frederick L. Locke, MD, ZUMA-7 Lead Principal Investigator and Co-Leader of the Immuno-Oncology Program at Moffitt Cancer Center, Tampa, Florida. "The results of ZUMA-7 are remarkable and represent a paradigm shift in the way that we should treat patients with LBCL in the second-line setting."

Globally, LBCL is the most common type of non-Hodgkin lymphoma (NHL). In the United States, more than 18,000 people are diagnosed with LBCL each year. About 30-40% of patients with LBCL will need second-line treatment as their cancer will either relapse (return) or become refractory (not respond) to initial treatment. SOC therapy with curative intent for this patient population is a multi-step process intended to lead to a stem cell transplant as definitive treatment. The process starts with chemoimmunotherapy, and if a patient responds and can tolerate further treatment, they move on to high-dose chemotherapy (HDT) followed by a stem cell transplant (ASCT). Unfortunately, many patients do not advance through this lengthy process for a variety of reasons including lack of response to second-line chemotherapy, treatment complications or further disease progression.

In ZUMA-7, nearly three times as many patients randomized to Yescarta ultimately received the definitive CAR T-cell therapy treatment (94%) versus those randomized to SOC (36%) who received HDT+ASCT. Among randomized patients, overall response (ORR) and complete response (CR) rates were also higher with Yescarta (ORR: 83% vs. 50%, odds ratio: 5.31 [95% CI: 3.1-8.9; P<0.0001]; CR rate: 65% vs. 32%). Median overall survival (OS), evaluated as a preplanned interim analysis, favored Yescarta compared to SOC (not reached vs. 35.1 months, respectively). The primary analysis of OS will occur at approximately 210 deaths.

In a separate ZUMA-7 analysis of patient-reported outcomes (PROs) which will also be shared in an ASH (Free ASH Whitepaper) oral presentation on December 12 (Abstract #430), patients receiving Yescarta and eligible for the PROs portion of the study (n=165) showed significant and clinically meaningful improvements in quality of life (QoL) at Day 100 compared with those who received SOC (n=131) using a prespecified analysis for three PRO domains (EORTC QLQ-C30 Physical Functioning, EORTC QLQ-C30 Global Health Status/QOL, and EQ-5D-5L visual analog scale [VAS]). The data also suggest faster recovery to pretreatment QoL for patients treated with Yescarta versus SOC.

"Beyond the poor prognosis, patients with relapsed or refractory LBCL also face substantially decreased quality of life with chemotherapy and stem cell transplant treatments," said Mahmoud Elsawy, MD, MSc, ZUMA-7 Investigator and Medical Director of Immune Effector Cell Therapy Program at Queen Elizabeth II Health Sciences Centre and Assistant Professor at Dalhouse University, Halifax, NS, Canada. "With the primary results of ZUMA-7, we see that axicabtagene ciloleucel offers superior clinical outcomes, and with the PRO analysis we also have support that it provides a better quality of life for these patients. Giving patients not just more but also better quality time is always our goal."

In the ZUMA-7 trial, Yescarta had a manageable safety profile that was consistent with previous studies. Among the 170 Yescarta-treated patients evaluable for safety, Grade ≥3 cytokine release syndrome (CRS) and neurologic events were observed in 6% and 21% of patients, respectively. No Grade 5 CRS or neurologic events occurred. In the SOC arm, 83% of patients had high grade events, mostly cytopenias (low blood counts).

Global regulatory filings to expand the indication for Yescarta to include second-line relapsed or refractory LBCL based on the ZUMA-7 data are currently underway. The U.S. Food and Drug Administration (FDA) has accepted the supplemental Biologics License Application (sBLA) and granted Priority Review designation to Yescarta for this patient population with a target action date under the Prescription Drug User Fee Act (PDUFA) of April 1, 2022. Regulatory submissions have also been filed with other global health authorities, including the European Medicines Agency (EMA).

"The ZUMA-7 trial demonstrates the power of CAR T-cell therapy when used earlier in the course of treatment and for the first time shows the promise of CAR T to replace a standard of care that has been in place for decades," said Frank Neumann, MD, PhD, Kite’s Global Head of Clinical Development. "Kite is the world’s leading company dedicated exclusively to cell therapy, and we are committed to continuing to conduct groundbreaking research like the ZUMA-7 study to bring the hope of survival to more patients through this technology."

About ZUMA-7 Study Design

ZUMA-7 is a randomized, open-label, global, multicenter, Phase 3 study evaluating the safety and efficacy of Yescarta versus current standard of care (SOC) for second-line therapy (platinum-based salvage combination chemoimmunotherapy regimen followed by high-dose therapy [HDT] and autologous stem cell transplant [ASCT] in those who respond to salvage chemotherapy) in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy. In the study, 359 patients in 77 centers around the world were randomized (1:1) to receive a single infusion of Yescarta or current SOC second-line therapy. The primary endpoint is event free survival (EFS) as determined by blinded central review, and defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause. Key secondary endpoints include objective response rate (ORR) and overall survival (OS). Additional secondary endpoints include patient reported outcomes (PROs) and safety.

About Yescarta

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Yescarta is a CD19-directed genetically modified autologous T cell immunotherapy currently indicated for the treatment of:

Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Limitations of Use: Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.
Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program.
CYTOKINE RELEASE SYNDROME (CRS), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade ≥3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade ≥3 in 13%. Among patients with LBCL who died after receiving Yescarta, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade ≥3 in 8% (11/146). Among patients with iNHL who died after receiving Yescarta, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL. Key manifestations of CRS (≥10%) in all patients combined included fever (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. Ensure that 2 doses of tocilizumab are available prior to Yescarta infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving Yescarta, including Grade ≥3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade ≥3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including Grade ≥3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days for patients with iNHL. 98% of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of Yescarta infusion. Neurologic toxicities occurred within the first 7 days of infusion for 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (≥10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including leukoencephalopathy and seizures, as well as fatal and serious cases of cerebral edema, have occurred. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). The most common neurologic toxicities were consistent with the overall LBCL population treated with Yescarta. Following Yescarta infusion, monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program called the Yescarta and Tecartus REMS Program which requires that: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 47% (119/254) of all patients with NHL. Grade ≥3 infections occurred in 19% of patients, Grade ≥3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, and fungal infections in 1%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. In immunosuppressed patients, including those who have received Yescarta, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade ≥3 cytopenias not resolved by Day 30 following Yescarta infusion occurred in 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common adverse reactions (incidence ≥20%) in patients with LBCL included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. The most common non-laboratory adverse reactions (incidence ≥20%) in patients with iNHL included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

On December 11, 2021 BeiGene (NASDAQ: BGNE; HKEX: 06160), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, reported results from a planned interim analysis of the Phase 3 SEQUOIA trial in patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL), including the randomized Cohort 1 comparing BRUKINSA to bendamustine plus rituximab (B+R) and Cohort 3 (Arm D) of BRUKINSA in combination with venetoclax in patients with deletion of chromosome 17p (del[17p]) and/or pathogenic TP53 variants (Press release, BeiGene, DEC 11, 2021, View Source [SID1234596858]). These data were reported in two oral presentations at the 63rd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"In the positive SEQUOIA trial, BRUKINSA delivered the therapeutic promise of a selective BTK inhibitor as a frontline treatment for CLL patients, with demonstrated superiority over chemoimmunotherapy. These robust data, along with the results from our previously reported Phase 3 ALPINE trial, strengthen our belief that BRUKINSA could become an important new treatment option for patients with CLL," remarked Jane Huang, M.D., Chief Medical Officer of Hematology at BeiGene. "In addition, BRUKINSA achieved favorable safety advantages in both trials such as lower rates of atrial fibrillation."

"Compared to chemoimmunotherapy, BRUKINSA demonstrated superior PFS benefit for CLL patients receiving frontline treatment, including those harboring high-risk characteristics, such as unmutated IGHV status and del(11q)," said Constantine Tam, MBBS, M.D., Peter MacCallum Cancer Center, and a principal investigator of the study. "Safety findings in SEQUOIA were similar to what has been reported in other BRUKINSA clinical trials, with consistently low rates of atrial fibrillation. Based on these results, BRUKINSA, as a highly selective BTK inhibitor, can potentially provide a chemo-free treatment option for CLL patients."

For more information on BeiGene’s clinical program and company updates, please visit BeiGene’s virtual booth at this year’s ASH (Free ASH Whitepaper) Annual Meeting at View Source

SEQUOIA Cohort 1: BRUKINSA vs. B+R in TN CLL Patients Without del (17p)

Oral Presentation; Abstract #396; Plain language summary available at View Source

A total of 479 patients with TN CLL whose tumor did not exhibit del(17p) were enrolled in Cohort 1 of the SEQUOIA trial, with 241 patients randomized to receive BRUKINSA (Arm A) and 238 patients randomized to receive B+R (Arm B). Patient characteristics were balanced between the two arms, with more than 50% with unmutated IGHV gene and 18% with del(11q) in each. Patients with del(17p) typically have poor response to chemoimmunotherapy and were assigned to receive BRUKINSA treatment in Cohort 2. Results from Cohort 2 were previously presented at the 2020 ASH (Free ASH Whitepaper) Annual Meeting.

The primary endpoint of the SEQUOIA trial is progression-free survival (PFS) per independent review committee (IRC) assessment in the randomized Cohort 1.

At the interim analysis, with a median follow-up of 26.15 months, BRUKINSA demonstrated superiority in PFS over B+R, as assessed by IRC. Results included:

The 24-month PFS rate was 85.5% (95% CI: 80.1, 89.6) in Arm A, compared to 69.5% (95% CI: 62.4, 75.5) in Arm B, with a hazard ratio (HR) of 0.42 (95% CI: 0.27, 0.63), p < 0.0001;
PFS benefit was consistently observed across key patient subgroups, including patients with del(11q), unmutated IGHV status, Binet stage C, and bulky disease; and
Overall survival (OS) results were early, and at 24 months, OS probability was similar between two arms, with 94.3% (95% CI: 90.4, 96.7) in Arm A and 94.6% (95% CI: 90.6, 96.9) in Arm B.
Safety analysis was based on 240 patients in Arm A and 227 patients in Arm B who received at least one dose of respective treatment. BRUKINSA was generally well tolerated with a safety profile consistent with its broad clinical program, including a low rate of atrial fibrillation. Results included:

224 patients (93.3%) in Arm A experienced at least one adverse event (AE) of any grade, with the most common (≥12%) being contusion (19.2%), upper respiratory tract infection (17.1%), neutropenia (15.4%), diarrhea (13.8%), and arthralgia (13.3%);
In comparison, 218 patients (96.0%) in Arm B experienced at least one AE of any grade, with the most common (≥12%) being neutropenia (56.8%), nausea (32.6%), pyrexia (26.4%), rash (19.4%), anemia (18.9%), constipation (18.9%), infusion-related reaction (18.9%), fatigue (15.9%), vomiting (14.5%), thrombocytopenia (13.7%), and diarrhea (13.2%);
126 patients (52.5%) in Arm A experienced at least one Grade ≥3 AE, compared to 181 patients (79.7%) in Arm B, with the most common in both arms being neutropenia (11.3% in Arm A vs. 51.1% in Arm B) and thrombocytopenia (1.7% in Arm A vs. 7.0% in Arm B);
88 patients (36.7%) in Arm A experienced at least one serious AE, compared to 113 patients (49.8%) in Arm B;
AEs leading to dose reduction, interruption or delay, and discontinuation occurred in 18 patients (7.5%), 111 patients (46.3%), and 20 patients (8.3%), respectively, in Arm A, compared to 84 patients (37.4%), 154 patients (67.8%), and 31 patients (13.7%), respectively, in Arm B;
Fatal AEs were reported in 11 patients (4.6%) in Arm A, compared to 11 patients (4.8%) in Arm B;
AEs of interest of any grade included anemia (Arm A vs. Arm B: 4.6% vs. 19.4%), arthralgia (13.3% vs. 8.8%), atrial fibrillation (3.3% vs. 2.6%), bleeding (45.0% vs. 11.0%), diarrhea (13.8% vs. 13.7%), hypertension (14.2% vs. 10.6%), infections (62.1% vs. 55.9%), myalgia (3.8% vs. 1.3%), neutropenia (15.8% vs. 56.8%), other cancers (12.9% vs. 8.8%), and thrombocytopenia (4.6% vs. 17.6%).
In addition, efficacy results with an extended follow-up from Cohort 2 (Arm C) of BRUKINSA as a monotherapy in patients with del(17p) were reported at ASH (Free ASH Whitepaper). With a median follow-up of 30.5 months, the 24-month PFS rate was 88.9% (95% CI: 81.3, 93.6).

Summary of SEQUOIA Cohort 1 Interim Analysis

SEQUOIA Cohort 1

Summary

BRUKINSA

(n=241)

Bendamustine + Rituximab

(n=238)

Efficacy Results

IRC-Assessed

24-month PFS (Primary Endpoint)

85.5%

(95% CI: 80.1, 89.6)

69.5%

(95% CI: 62.4, 75.5)

Hazard Ratio=0.42 (95%CI: 0.27, 0.63)

2-sided p <0.0001

Overall Safety Results

AEs of any grade

93.3%

96.0%

Grade ≥3 AEs

52.5%

79.7%

Serious AEs

36.7%

49.8%

AEs leading to dose reduction

7.5%

37.4%

AEs leading to dose interruption or delay

46.3%

67.8%

AEs leading to treatment discontinuation

8.3%

13.7%

Fatal AEs

4.6%

4.8%

Adverse Events of Interest (Any Grade)

Anemia

4.6%

19.4%

Neutropenia

15.8%

56.8%

Thrombocytopenia

4.6%

17.6%

Arthralgia

13.3%

8.8%

Atrial fibrillation

3.3%

2.6%

Bleeding

45.0%

11.0%

Diarrhea

13.8%

13.7%

Hypertension

14.2%

10.6%

Infections

62.1%

55.9%

Myalgia

3.8%

1.3%

Other cancers

12.9%

8.8%

SEQUOIA Cohort 3 (Arm D): BRUKINSA + Venetoclax in TN CLL Patients with del(17p) and/or TP53 Mutations

Oral Presentation; Abstract #67

Cohort 3 of SEQUOIA was designed to examine the hypothesis that the addition of venetoclax to BRUKINSA can drive tumors into deeper remission. Building on the demonstrated efficacy and safety of BRUKINSA in Cohort 2, Cohort 3 is planned to enroll approximately 80 patients with TN CLL whose tumor exhibits del(17p) or TP53 mutations, with key endpoints being safety, overall response rate (ORR), PFS, and duration of response (DoR). These patients will receive BRUKINSA treatment at 160 mg twice daily for three months, followed by combination treatment of BRUKINSA at the same dosing and venetoclax with a ramp-up dosing to 400 mg once daily for 12 to 24 cycles until progressive disease, unacceptable toxicity, or confirmed undetectable measurable residual disease (uMRD).

"Unfavorable prognosis is often seen in CLL patients with del(17p) or pathogenic TP53 variants, even in the front-line setting. While the follow-up in Cohort 3 was relatively short, the high response rate and the deepened responses observed among those treated for longer periods suggested the potential of BRUKINSA in combination with venetoclax in these high-risk CLL patients. The combination treatment also appeared generally well tolerated," commented Alessandra Tedeschi, M.D., Grande Ospedale Metropolitano Niguarda in Italy, a principal investigator on the study. "We look forward to the continued evaluation of BRUKINSA in combination with venetoclax in untreated CLL patients with del(17p) or TP53 mutations."

At the data cutoff on September 7, 2021, 49 patients were enrolled in Cohort 3, including 46 patients (93.9%) with centrally confirmed positive del(17p) status and three patients (6.1%) with a pathogenic TP53 variant alone. Patients enrolled in Cohort 3 also exhibited other markers of high risk, including 87.8% with unmutated IGHV, 91.9% with concurrent TP53 mutation, and 83.3% with complex karyotype (at least three abnormalities).

With a short median follow-up of 12.0 months, a high ORR was observed in the 36 patients who had at least one post-baseline response evaluation by the data cutoff date. Preliminary efficacy results per investigator assessment included:

Of the 14 patients who received combination treatment for more than 12 months, five patients (36%) achieved a confirmed complete response (CR) or CR with incomplete bone marrow recovery (CRi) in a bone marrow assessment and four additional patients met the criteria for CR or CRi but not confirmed in bone marrow assessment due to COVID-19 restrictions; and
In all 36 patients evaluable for efficacy, the ORR was 97.2% (95% CI: 85.5, 99.9) and the CR/CRi rate was 13.9% (all CRs or CRis were in patients who received combination treatment for more than 12 months).
With a median follow-up of 7.9 months, safety results in all 49 enrolled patients included:

40 patients (81.6%) experienced at least one AE of any grade, with the most common (≥12%) being infections (16.3%), neutropenia (14.3%), bruising (12.2%), diarrhea (12.2%), minor bleeding (12.2%), and nausea (12.2%);
16 patients (32.7%) experienced at least one Grade ≥3 AE and four patients (8.2%) experienced at least one serious AE;
AEs leading to dose interruption, dose reduction, and treatment discontinuation occurred in 10 patients (20.4%), no patients (0.0%), and one patient (2.0%), respectively; and
One patient (2.0%) experienced a fatal AE.
With a median follow-up of 13.5 months, safety results in the 34 patients who received combination treatment included:

29 patients (85.3%) experienced at least one AE of any grade, with the most common (≥12%) being infections (23.5%), neutropenia (20.6%), diarrhea (14.7%), fatigue (14.7%), nausea (14.7%), and bruising (11.8%);
13 patients (38.2%) experienced at least one Grade ≥3 AE and three patients (8.8%) experienced at least one serious AE; and
AEs leading to dose interruption occurred in 10 patients (29.4%), with no AEs leading to dose reduction or treatment discontinuation.
About SEQUOIA

SEQUOIA is a randomized, multicenter, global Phase 3 trial (NCT03336333) designed to evaluate the efficacy and safety of BRUKINSA compared to B+R in patients with TN CLL or SLL. The trial consists of three cohorts:

Cohort 1 (n=479): randomized 1:1 to receive BRUKINSA (n=241) or B+R (n=238) until disease progression or unacceptable toxicity, in patients not harboring del(17p); data from this group comprise the primary endpoint;
Cohort 2 (n=110): patients with del(17p) receiving BRUKINSA as a monotherapy; and
Cohort 3 (enrollment ongoing): patients with del(17p) or pathogenic TP53 variant receiving BRUKINSA in combination with venetoclax.
Patients with del(17p) were not randomized to B+R, as they experience poor clinical outcomes and poor response to chemoimmunotherapy. The primary endpoint of the trial is IRC-assessed PFS. Secondary endpoints include investigator-assessed PFS, IRC- and investigator-assessed overall response rate (ORR), overall survival (OS), PFS and ORR in patients with del(17p), and safety.

Cohort 2 (Arm C), representing high-risk patients treated with BRUKINSA monotherapy, was previously presented at the American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2020. This cohort of patients with del(17p) achieved significant efficacy with an 18-month PFS of 90.6%, as assessed by investigator.

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 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 received 12 approvals covering 40 countries 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 (CLL) or small lymphocytic lymphoma (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);
For the treatment of Waldenström’s macroglobulinemia (WM) in adult patients (Canada, March 2021);
For the treatment of adult patients with WM who have received at least one prior therapy (China, June 2021)**;
For the treatment of MCL in adult patients who have received at least one prior therapy (Canada, July 2021);
For the treatment of MCL in adult patients who have received at least one prior therapy (Chile, July 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Brazil, August 2021);
For the treatment of adult patients with WM (United States, August 2021);
For the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen (United States, September 2021)*;
For the treatment of adult patients with MCL who have received at least one previous therapy (Singapore, October 2021);
For the treatment of MCL in patients who have received at least one prior therapy (Israel, October 2021);
For the treatment of adult patients with WM who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy (Australia, October 2021);
For the treatment of adult patients with MCL who have received at least one prior therapy (Australia, October 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Russia, October 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Saudi Arabia, November 2021); and
For the treatment of adult patients with WM who have received at least one prior therapy or first-line treatment of patients unsuitable for chemo-immunotherapy (European Union plus Iceland and Norway, November 2021).
To date, more than 20 marketing authorization applications have been submitted for BRUKINSA for various indications.

* 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 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.

Please see full U.S. Prescribing Information at www.beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at www.beigene.com/PDF/BRUKINSAUSPPI.pdf.

BeiGene Oncology

BeiGene is committed to advancing best and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe. We have a growing R&D team of approximately 2,750 colleagues dedicated to advancing more than 90 ongoing or planned clinical trials that have involved more than 14,000 patients and healthy volunteers. Our expansive portfolio is directed predominantly by our internal colleagues supporting clinical trials in more than 45 countries and regions. Hematology-oncology and solid tumor targeted therapies and immuno-oncology are key focus areas for the Company, with both mono- and combination therapies prioritized in our research and development. BeiGene currently has three approved medicines discovered and developed in our own labs: BTK inhibitor BRUKINSA in the United States, China, the EU, Canada, Australia and additional international markets; and the non-FC-gamma receptor binding anti-PD-1 antibody tislelizumab as well as the PARP inhibitor pamiparib in China.

BeiGene also partners with innovative companies who share our goal of developing therapies to address global health needs. We commercialize a range of oncology medicines in China licensed from Amgen and Bristol Myers Squibb. We also plan to address greater areas of unmet need globally through our collaborations including with Amgen, Bio-Thera, EUSA Pharma, Mirati Therapeutics, Seagen, and Zymeworks. BeiGene has also entered into a collaboration with Novartis granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

On December 11, 2021 Imago BioSciences, Inc. ("Imago") (Nasdaq: IMGO), a clinical stage biopharmaceutical company discovering new medicines for the treatment of myeloproliferative neoplasms (MPNs), today presented positive data from its ongoing global Phase 2 clinical study evaluating bomedemstat in patients with advanced myelofibrosis (MF) (Press release, Imago BioSciences, DEC 11, 2021, View Source [SID1234596813]). The data were presented in an oral session during the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place December 11-14, 2021. Previously, a Phase 2 data set with a cut-off date of May 17, 2021 was presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Congress.

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Updated Highlights (as of November 1, 2021 cutoff):

Of the evaluable patients at 24 weeks:
74% (17/23) showed a decrease in Total Symptom Score (TSS).
26% (6/23) showed a ≥50% decrease in TSS.
75% (30/40) showed spleen volume reductions.
81% (103/127) of mutant allele frequencies (MAFs) were either stable (45%) or reduced (36%), including driver and high molecular risk (HMR) mutations such as ASXL1.
89% (32/36) of patients who were transfusion-independent at baseline had stable or improved hemoglobin at 12 weeks.
No new mutations or transformation to acute myeloid leukemia (AML) in more than 600 days of follow-up in patients with high risk of progression.
"Today’s ASH (Free ASH Whitepaper) 2021 data further demonstrates the potential of bomedemstat as a unique and differentiated treatment option for patients living with advanced myelofibrosis," said Wan-Jen Hong, M.D., CMO, Imago BioSciences. "We were gratified to reach full enrollment in our myelofibrosis trial earlier this year and remain pleased with the safety and tolerability profile observed to date. Looking ahead, we anticipate continued momentum in this program through an investigator-sponsored trial evaluating bomedemstat in combination with ruxolitinib in MF patients who are either treatment naïve or respond sub-optimally to ruxolitinib treatment."

Safety & Tolerability

Bomedemstat was generally well-tolerated to date in patients with myelofibrosis.
The most common non-hematologic AE related to bomedemstat was dysgeusia (altered taste), which occurred in 27 patients (30%).
"Bomedemstat continues to show strong potential as a monotherapy that may offer distinct clinical benefits for patients living with advanced myelofibrosis," said Hugh Y. Rienhoff, Jr., M.D., CEO, Imago BioSciences. "A large majority of the patients enrolled in this trial saw improvements in symptom scores, spleen volumes and occurrence of anemia. Altogether, these data show that bomedemstat may have a significant impact on this progressive and often debilitating disease."

Details on Imago’s ASH (Free ASH Whitepaper) Presentation

Oral Presentation Title: A Phase 2 Study of the LSD1 Inhibitor IMG-7289 (Bomedemstat) for the Treatment of Advanced Myelofibrosis
Session: Myeloproliferative Syndromes: Clinical and Epidemiological: Novel Therapies for MPNs and JAK inhibitors for Myelofibrosis
Presenter: Harinder Gill, M.D., study investigator and presenter of the data, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pok Fu Lam, Hong Kong
Date and Time: December 11, 2021, at 12:00 PM ET

For further details, please see the ASH (Free ASH Whitepaper) 2021 abstract and presentation on the Imago website here.

About Imago’s Phase 2 Advanced Myelofibrosis Program

Myelofibrosis (MF) is a progressive cancer in which the bone marrow is gradually replaced by fibrous, scar-like tissue. There is a significant unmet need for a disease-modifying therapy. The need is greatest in patients with MF whose disease is not adequately managed with current JAK inhibitors, the current standard of care.

This Phase 2b multi-center, open-label study is designed to assess the safety, efficacy, pharmacodynamics, and spleen volume reduction of bomedemstat, an oral inhibitor of the lysine-specific demethylase 1 (LSD1). Eligible patients aged 18 or over with MF who are refractory or resistant to, intolerant of, are inadequately controlled by or ineligible for approved therapies were considered for the study. Exploratory assessments include symptom reduction, changes in cytokine profiles, changes in the frequency of mutant alleles and bone marrow fibrosis. The trial is being conducted in the United States, United Kingdom, European Union and Hong Kong. This ongoing 24-week study completed enrollment in May 2021 for a total of 89 patients.

On December 11, 2021 Harpoon Therapeutics, Inc. (NASDAQ: HARP), a clinical-stage immunotherapy company developing novel T cell engagers, reported a poster with interim data from the ongoing dose-escalation portion of the Phase 1/2 trial for HPN217 in patients with relapsed/refractory multiple myeloma (R/R MM) at the 63rd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Harpoon Therapeutics, DEC 11, 2021, View Source [SID1234596838]). HPN217 targets B-cell maturation antigen (BCMA) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC) platform designed to recruit a patient’s own immune cells to kill tumor cells.

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As of November 10, 2021, the data cutoff date for the interim clinical data presentation, 37 patients have been dosed across 10 cohorts at fixed doses of 5 to 2860 µg/week and in step dosing cohorts up to 3240 µg/week administered as an intravenous infusion. These interim data demonstrated:

HPN217 is generally well tolerated with one dose limiting toxicity (DLT) reported of Grade 4 AST elevation that resolved, MTD has not been reached
HPN217 is clinically active at higher dose levels with clinical benefit, disease control rate (DCR) of 88%, demonstrated in 7 of 8 disease evaluable patients in the 2150 µg/week cohort
2 stringent complete responses (SCRs) have been observed, one in each of the higher dose 2150 and 2860 µg/week cohorts
Transient and manageable cytokine release syndrome (CRS) reported in 9 of 37 patients (24%) were all Grade 1 or 2
Introduction of step dose regimens has allowed for the administration of higher target doses, currently at 3240 µg/week
"These encouraging data for HPN217 demonstrate robust clinical activity at higher doses, strong target engagement, and a manageable safety profile in this heavily refractory patient population," said Natalie Sacks, M.D., Chief Medical Officer of Harpoon Therapeutics. "Dose escalation is ongoing to determine the RP2D for advancement into the expansion phase of the trial."

Interim Results from the Ongoing HPN217 Phase 1/2 Trial Presented at ASH (Free ASH Whitepaper)

This Phase 1/2 trial is a multicenter, open-label study designed to evaluate safety, tolerability, pharmacokinetics and clinical activity in patients with R/R MM who have had at least three prior systemic treatments including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 antibody. The initial ongoing phase of the trial is dose escalation, with the goal of determining a recommended dose for the expansion phase. The escalation phase began with single patient cohorts and transitioned to a 3+3 design when Grade 2 toxicity was observed. HPN217 is being administered to patients once weekly by intravenous infusion and the primary outcome measures are an assessment of safety and tolerability, pharmacokinetics and pharmacodynamics. Secondary endpoints include duration of response, progression free and overall survival. Tumor assessment is based on International Myeloma Working Group (IMWG) Response Criteria.

As of the November 10, 2021 data cut-off date, 37 patients have been treated in 10 cohorts with fixed doses ranging from 5 to 2860 µg/week or a step dosing regimen of 1620 µg priming dose followed by a 3240 µg/week target dose. Premedication to minimize CRS includes dexamethasone and other standard therapies. Enrolled patients had a median of 7 prior therapies. The most frequent treatment-emergent adverse events (TEAEs) occurring in greater than 20% were anemia, 17 patients (46%), fatigue, 12 patients (32%), and transient CRS, 9 patients (24%), No grade 3 or higher CRS was reported and one dose limiting toxicity (DLT) was reported, grade 4 AST, which resolved. Maximum tolerated dose has not been reached.

Clinical benefit was observed in the patients receiving higher doses. In 8 disease evaluable patients enrolled at 2150 µg/week an ORR of 63% was reported (5/8 patients) consisting of 1 stringent CR, 1 VGPR, and 3 PRs. including 1 patient with prior BCMA-targeting therapy exposure. The disease control rate, (DCR), was 88% based on 7/8 patients. For the 2860 µg/week cohort consisting of 5 evaluable patients, the ORR was 2/5 (40%) including a second stringent CR, with a DCR of 60%. As of the data cutoff, all responders remained on study treatment.

HPN217 demonstrated a dose proportional increase in Cmax and AUC with a median serum half-life of 74 hours (range of 38 – 197 hours), confirming half-life extension. Half-life, clearance rate, and volume of distribution were dose-independent, suggesting linear PK kinetics. Pharmacodynamic analysis shows a dose-dependent, transient increase in serum cytokines and chemokines (IL-6, IL-8, IL-10, TNFα).

Patients continue to be enrolled in the escalation phase of the trial, with a goal to identify a recommended Phase 2 dose for an expansion phase. The expansion phase of the trial will further evaluate the safety and activity of HPN217 in patients with R/R MM. This trial is titled, "A Phase 1/2 Open-label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and PK of HPN217 in Patients With R/R MM". For additional information about the trial, please visit www.clinicaltrials.gov using the identifier NCT04184050.

Preclinical Data for HPN217 Presented at ASH (Free ASH Whitepaper)

The poster titled "The Effects of BCMA Expression, Soluble BCMA, and Combination Therapeutics on the Anti-Tumor Activity of HPN217, a BCMA-Targeting Tri-Specific T Cell Engager Against Multiple Myeloma" showcased translational studies to examine factors that may impact the therapeutic efficacy of HPN217. These factors include the target BCMA, in membrane-bound or soluble form, and concomitant or combination therapeutics such as gamma secretase inhibitor (GSI) and dexamethasone.

Preclinical data from this presentation for HPN217 demonstrated:

In a patient derived cell culture system, HPN217 was able to mediate multiple myeloma cell killing by autologous T cells in 80% of the cultures
Presence of dexamethasone appeared to have limited effect on the anti-tumor activity of HPN217-redirected T cells
GSI increased the expression of BCMA on multiple myeloma cells and enhanced the effect of HPN217
Preclinical evaluation of HPN217 in combination with approved and experimental multiple myeloma therapeutics is ongoing

Conference Call and Webcast Details

Harpoon’s management will host a webcast and conference call on Monday, December 13, 2021 at time 4:30 p.m. ET / 1:30 p.m. PT to review the data presented at ASH (Free ASH Whitepaper) and provide an update on other pipeline programs. The live call may be accessed by dialing 866-951-6894 for domestic callers or 409-216-0624 for international callers using conference ID # 2760075.

A live webcast of the call will be available from the Events and Presentations section of the company’s website here and will be archived there shortly after the live event.

On December 11, 2021 IGM Biosciences, Inc. (Nasdaq: IGMS), a clinical-stage biotechnology company focused on creating and developing engineered IgM antibodies, reported the presentation of clinical results from the Company’s Phase 1 trial evaluating IGM-2323, a novel bispecific IgM antibody targeting CD20 x CD3, at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, IGM Biosciences, DEC 11, 2021, View Source [SID1234596814]). The data was featured today in an oral presentation titled "A Phase 1 Dose Escalation Study of IGM-2323, a Novel Anti-CD20 x Anti-CD3 IgM T Cell Engager (TCE) in Patients with Advanced B-Cell Malignancies".

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The multicenter, open-label Phase 1 dose escalation trial was intended to assess the safety, pharmacokinetics and preliminary efficacy of intravenous IGM-2323 in patients with advanced B cell malignancies. As of September 10, 2021, the data cutoff date for the presentation, 40 patients were enrolled and treated at escalating dose levels of IGM-2323.

All 40 patients received at least one dose and were evaluable for safety. There were no dose limiting toxicities (DLTs), no neurotoxicity adverse events (AEs), a relatively low rate of cytokine release syndrome (CRS) and no patients discontinued due to an AE.

Of the 10 patients treated in the 100 mg cohort, 3 of 6 diffuse large B cell lymphoma (DLBCL) patients had a complete response and 2 of 3 follicular lymphoma (FL) patients had a complete response. Additionally, the one mantle cell patient treated in the 100 mg dose cohort had a partial response. Overall, of the 38 patients evaluable for efficacy, 11 patients showed a response, 8 of which were complete responses.

Based on these promising results, two Phase 2 studies are being initiated to assess the safety and efficacy of two doses of IGM-2323, 100 mg and 300 mg, in patients with DLBCL and FL. If supportive, the data from this Phase 2 multicenter, open-label study could potentially be used as the basis for accelerated review and approval of IGM-2323.

"Data presented today demonstrate that IGM-2323 is highly active against multiple subtypes of relapsed/ refractory non-Hodgkin’s lymphoma and shows an excellent safety profile with low rates of CRS, no CRS-associated neurotoxicity and minimal neutropenia," said Dr. Elizabeth Budde, M.D., Ph.D., Assistant Professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center. "Results to date from this Phase 1 study are encouraging, and I look forward to continuing to investigate this important novel therapy’s potential in these difficult-to-treat disease areas. Patients with non-Hodgkin’s lymphoma need efficacious and well-tolerated treatments, and IGM-2323 is potentially well-suited to help with this unmet need."

"We are pleased to show multiple complete responses in patients with diffuse large B cell lymphoma and follicular lymphoma at the 100 mg dose level and encouraging, consistent safety data," said Chris Takimoto, M.D., Ph.D., F.A.C.P., Chief Medical Officer of IGM Biosciences. "We are excited to continue the development of IGM-2323 by moving forward with our Phase 2 expansion studies and by initiating combination studies in earlier lines of treatment. We believe these clinical results are also encouraging for the development of the IgM T cell engagers targeting CD38 and CD123 in our hematologic pipeline."

Conference Call and Webcast
The conference call may be accessed by dialing (866) 649-1996 (domestic) or (409) 217-8769 (international) and referring to conference ID 9695193. A live webcast of the presentation will be available on the "Events and Presentations" page in the "Investors" section of the Company’s website at View Source A replay of the webcast will be archived on the Company’s website for 90 days following the presentation.

About IGM-2323
IGM-2323 is a CD20 x CD3 bispecific IgM antibody designed to treat patients with B cell non-Hodgkin’s lymphoma (NHL) and other B cell malignancies. CD20 is a protein that is frequently expressed on the surface of malignant B cells, while CD3 is a protein that is expressed on the surface of T cells and is an essential activating molecule of the T cell. IGM-2323 has 10 binding domains to CD20 and a single binding domain to CD3 (specifically CD3ɛ).

IGM-2323 is designed to simultaneously and stably bind a CD20 expressing cancer cell as well as CD3 on a cytotoxic T cell, bringing both cells into close proximity. This interaction mimics the normal T cell activation pathway leading the T cell to recognize and kill the cancer cell by releasing cytotoxic biochemicals (perforins and granzymes) that penetrate and perforate the cancer cell. In contrast to other bispecific antibody formats that bind to one or two CD20 molecules on the surface of the cancer cell and to one CD3 molecule on the surface of the T cell, IGM-2323 has 10 binding units to CD20 and one binding unit to CD3. The Company believes that IGM-2323 with its 10 binding units for CD20 may successfully bind to CD20 expressing cancer cells with more avidity compared to an IgG bispecific antibody with only one binding unit for CD20.

IGM-2323 also employs an additional mechanism to kill CD20 expressing cancer cells, known as complement dependent cytotoxicity (CDC). CDC is a mechanism by which antibodies can mediate specific targeted cell killing by activating the complement system. Components of the complement system are naturally present in humans, and IgM antibodies are the most efficient antibodies at engaging the complement system for CDC, with an approximately 100-fold increase in CDC relative to comparable IgG CD20 antibodies.