On June 15, 2024 IASO biotechnology ("IASO Bio"), a biopharmaceutical company engaged in discovering, developing, manufacturing and marketing innovative cell therapies and antibody products, reported clinical data on the use of Equecabtagene Autoleucel (Eque-cel), the world’s first approved fully human CAR-T product, for the treatment of transplant-ineligible patients with high-risk newly diagnosed multiple myeloma (NDMM) in an oral presentation at the 2024 European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress (Press release, IASO Biotherapeutics, JUN 15, 2024, View Source [SID1234644359]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Presentation Title: Eque-cel, A Novel Fully Human BCMA-Targeting CAR-T Therapy in Patients with High Risk Newly Diagnosed Multiple Myeloma

Presentation Type: Oral report

Session Date and Time: June 15, 2024, 16:30 – 17:45 (Central European Summer Time)

Location: Madrid, Spain

Publication Number: S206

Presenter: Professor Bing Chen, Nanjing Drum Tower Hospital

The FUMANBA-2 study is a multicenter, open-label, phase I, single-arm study initiated by researchers, with the principal investigators being Professor Lijuan Chen from Jiangsu Province Hospital and Professor Bing Chen from Nanjing Drum Tower Hospital. This study aims to assess the efficacy, safety, and pharmacokinetics/pharmacodynamics characteristics of Eque-cel for the treatment of high-risk NDMM. Subjects must complete four cycles of induction treatment before the infusion of Eque-cel. After the third induction treatment cycle, patients deemed unsuitable for autologous hematopoietic stem cell transplantation (ASCT) by the researcher will undergo peripheral blood mononuclear cell collection and subsequently receive Eque-cel treatment, with an infusion dose of 1×106 CAR-T/kg.

The primary endpoints were the proportion of minimal residual disease (MRD) negative subjects and progression-free survival (PFS), and secondary endpoints included overall response rate (ORR), duration of response (DOR), safety, and pharmacokinetics/pharmacodynamics (PK/PD).

As of January 25th, 2024, 16 subjects received Eque-cel therapy. High-risk cytogenetics were detected in all subjects, including 62.5 percent double-hit and 12.5 percent triple-hit. 25 percent subjects had extramedullary disease. 37.5 percent subjects had R-ISS stage III disease, among whom 6.3 percent with double-hit and 6.3 percent with triple-hit.

Efficacy: After the infusion of Eque-cel, the median follow-up time was 7.46 months (range: 2.8-18.1), the median PFS had not been reached, the 12-month PFS rate was 84.4% (95% CI: 49.31-96.00), all subjects achieved MRD negativity, of which 71.4% (95% CI: 25.8-92.0) maintained MRD negativity for more than 12 months; the overall response rate (ORR) was 100%, with 93.8% achieving stringent complete response (sCR).

Safety: After the infusion of Eque-cel, the incidence of grade 1-2 cytokine release syndrome (CRS) was 68.8%, no grade 3 or above CRS was observed, and no immune effector cell-related neurotoxicity syndrome (ICANS) or other neurological toxicities occurred. The median time of CRS occurrence was the 7th day after infusion (range: 2-9 days), and the median duration of CRS was 3 days (range: 1-8 days). The most common grade 3 or above drug-related adverse event wase blood cell count reduction, and the incidence of grade 3 or above infectious disease adverse events was 25.0%.

PK/PD: The median peak time of CAR copy number in peripheral blood was 10 days after infusion (range: 7-21 days), with a median peak level of 79,681.299 copies/μg DNA. 81.25% of subjects achieved clearance of free B-cell maturation antigen (sBCMA) within one month after infusion; the median peak time of cytokine detection IL-6 and CRP after infusion were the 7th and 10th day, respectively, and the serum ferritin level did not change significantly.

Professor Lijuan Chen from Jiangsu Province Hospital stated: " Eque-cel, as a novel fully human BCMA CAR-T therapy, has shown encouraging efficacy and safety in high-risk patients with newly diagnosed multiple myeloma who are ineligible for transplantation. This is the world’s first report on CAR-T therapy being used as a first-line treatment in this specific patient population. For NDMM patients who are not suitable for transplantation, the application of CAR-T therapy as a first-line treatment is expected to further improve the remission rate, extend survival, and improve patient prognosis compared to traditional chemotherapy and other targeted drug treatments. This allows us to see the application potential of Eque-cel in the front-line treatment of MM. Advancing CAR-T therapy to the first line will provide patients with more diverse and promising treatment options. With further research and the continuous improvement of treatment strategies, we look forward to CAR-T therapy benefiting more patients in the future."

Professor Bing Chen from Nanjing Drum Tower Hospital stated: "High-risk newly diagnosed multiple myeloma patients have a poor prognosis in standard first-line treatment. For high-risk NDMM patients who do not meet the conditions for ASCT, Eque-cel has shown superior efficacy and safety, achieving deep and sustained remission, with all patients achieving MRD negativity. This opens up a new approach to reverse the poor prognosis of high-risk myeloma patients. Moreover, compared with relapsed/refractory multiple myeloma (RRMM) patients, the incidence and severity of CRS in high-risk NDMM patients treated with Eque-cel are lower, showing a more favorable safety profile. We will further investigate the clinical benefits of Eque-cel for high-risk newly diagnosed multiple myeloma patients with longer follow-up."

On June 15, 2024 CARsgen Therapeutics Holdings Limited (Stock Code: 2171.HK), a company focused on innovative CAR T-cell therapies for the treatment of hematologic malignancies and solid tumors, reported that the initial results from the ongoing first-in-human study of CT071 have been presented at the 29th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Press release, Carsgen Therapeutics, JUN 15, 2024, View Source [SID1234644361]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The preliminary results of Phase I of CT071 (NCT05838131) were presented as a poster at the 29th EHA (Free EHA Whitepaper) Annual Congress on June 14, 18:00 – 19:00 CEST, which was titled "First-in-human study of GPRC5D-targeted CAR T cells (CT071) with an accelerated manufacturing process in patients with relapsed/ refractory multiple myeloma (RRMM)".[1]

"Multiple myeloma is a common yet incurable hematologic malignancy with high unmet need. Despite the numerous recent advances, most patients relapse and become refractory to available therapies and therefore, novel therapies are needed. GPRC5D, a protein highly expressed on the surface of malignant plasma cells with limited expression on normal tissues, represents a promising target for treating multiple myeloma. CT071 is a fully human GPRC5D-targeting autologous second-generation CAR T-cell product manufactured using our expedited CARcelerateTM platform that shortens the manufacturing time to around 30 hours, supporting a shorter vein-to-vein time and younger T cells. The preliminary results of the ongoing study presented at EHA (Free EHA Whitepaper) shows that CT071 has the potential to be the best-in-class GPRC5D targeting CAR-T therapy," said Raffaele Baffa, M.D., Ph.D., Chief Medical Officer of CARsgen Therapeutics. "We are excited about advancing CT071 and look forward to sharing future updates with the medical community."

As of February 28, 2024, 10 patients were dosed with CT071—7 patients at 1.0×105 cells/kg and 3 patients at 3.0×105 cells/kg. Among them, 80% had high-risk cytogenetics, 30% had one or more extramedullary plasmacytomas (EMD), and 40% were at R-ISS stage III. This was a heavily pre-treated population with a median of 5 prior lines of therapy, including 90% double-class refractory, 70% triple-class refractory, 40% penta-drug refractory, 50% having received autologous stem cell transplantation, and 20% had previously been treated with BCMA/CD19 dual-targeting CAR T cells. None of the patients on the study required bridging therapy due to rapid manufacturing turnaround.

The median follow-up at the time of data cut-off was 4.07 months (range: 2.8-7.4). There were no Grade 3 or higher cytokine release syndrome (CRS) events. No immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. No adverse events of special interest or dose limiting toxicity (DLT) occurred. Four patients experienced treatment-related SAE, including pneumonia (n=1), decreased appetite (n=1) and thrombocytopenia (n=2), and all recovered.

The overall response rate was 90%, including 5 patients (50%) with stringent complete response (sCR), 2 patients (20%) with very good partial response (VGPR), and 2 patients (20%) with partial response (PR). All the 9 patients with evaluable MRD assessment at Week 4 achieved MRD negativity (10-6 threshold) ), including all 5 patients with sCR/CR. The pharmacokinetic analysis demonstrated robust cell expansion and persistence, with median Tmax of 14 days (range: 12-28) and median Cmax of 32280.5 copies/μg gDNA (range: 8372-106060).

About CT071
CT071 is a CAR T-cell therapy candidate developed utilizing CARsgen’s proprietary CARcelerateTM platform targeting GPRC5D for the treatment of R/R MM or relapsed/refractory plasma cell leukemia ("R/R PCL"). An investigator-initiated trial (NCT05838131) is ongoing in China to evaluate the safety and efficacy of CT071 for the treatment of R/R MM or R/R PCL. Another investigator-initiated trial (NCT06407947) is ongoing in China for the treatment of newly diagnosed multiple myeloma (NDMM).

On June 14, 2024 Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) reported one oral and four poster presentations at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Hybrid Congress in Madrid, Spain being held June 13-16, 2024, and online (Press release, Rigel, JUN 14, 2024, View Source [SID1234644322]). The oral presentation includes five-year results from the pivotal cohort of the registrational Phase 2 trial of REZLIDHIA (olutasidenib) for the treatment of relapsed or refractory (R/R) mutated isocitrate dehydrogenase-1 (mIDH1) acute myeloid leukemia (AML).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The oral presentation will be given by Dr. Jorge E. Cortes, Director, Georgia Cancer Center, Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer, and Phase 2 trial investigator, who will present an overview of the five-year study results, including transfusion independence, overall survival and patients R/R to prior venetoclax. In May, Dr. Cortes was published in the Expert Review of Hematology outlining the drug profile and summarizing key safety and efficacy data for olutasidenib, including in patients previously treated with venetoclax or ivosidenib.

"Olutasidenib offers patients with R/R mIDH1 AML a treatment option with rapid and durable responses, and a well-characterized and manageable safety profile. Furthermore, a post-hoc analysis of patients previously treated with venetoclax regimens demonstrated consistent durable responses, supporting the clinical benefit of olutasidenib in R/R mIDH1 AML," stated Dr. Cortes.

The company’s poster presentations include data on the safety and efficacy of olutasidenib treatment in multiple subgroups, including elderly patients, patients who had previously failed venetoclax treatment and as a bridge to allogeneic hematopoietic stem cell transplantation (HSCT) in patients with R/R mIDH1 AML. In addition, data from olutasidenib treatment in patients with mIDH1 AML secondary to myeloproliferative neoplasms (MPN) will be presented.

"The collective data being presented at EHA (Free EHA Whitepaper) support REZLIDHIA’s strong efficacy and durability of response in several mIDH1 AML patient populations," said Raul Rodriguez, Rigel’s president and CEO. "Additionally, we are excited about the compelling data in patients with mIDH1 AML secondary to MPN, supporting a role for REZLIDHIA in the treatment of this population which has no standardized treatment options and where patients have historically had poor responses to available treatments."

Oral Presentation

Saturday, June 15, 17:30 to 17:45 CEST
Abstract #: S144
Title: Olutasidenib for Mutated IDH1 Acute Myeloid Leukemia: Final Five-year Results from the Phase 2 Pivotal Cohort
Presenter: Jorge E. Cortes, M.D.
Location: IFEMA Madrid Recinto Ferial (Halls of the Fairgrounds), Hall Dali 1

An additional two years of data, beyond the results that led to FDA approval of olutasidenib, further demonstrates the durable responses observed with olutasidenib in heavily pretreated patients with mIDH1 AML, including those R/R to prior venetoclax. The safety profile was consistent with what was previously reported.
Of 147 efficacy evaluable patients, complete remission (CR) or CR with partial hematologic recovery (CRh) was achieved in 35%. The median time to CR/CRh was 1.9 months and median duration of CR/CRh was 25.3 months, with maximum duration ongoing at 54.6 months. Overall response rate was 48%, with median duration 15.5 months and maximum duration ongoing at 54.6 months. Median overall survival was 11.6 months.
Transfusion independence (for ≥56 days) from red blood cells was achieved in 34 patients (39%) who were dependent at baseline and from platelets was achieved in 28 patients (41%) who were dependent at baseline.
In the 12 patients that were R/R to prior venetoclax, 33% achieved a CR/CRh; median duration of CR/CRh was not reached (ongoing at 50.6 months), and median overall survival was 16.2 months.
Poster Presentations

Friday, June 14, 18:00 to 19:00 CEST
Abstract #: P605
Title: Olutasidenib Demonstrates Clinical Activity in Mutated IDH1 Acute Myeloid Leukemia (AML) Secondary to Myeloproliferative Neoplasms (MPN)
Presenter: Stéphane de Botton, M.D., Ph.D.
Location: IFEMA Madrid Recinto Ferial (Halls of the Fairgrounds), Hall 7

Olutasidenib was well tolerated in patients with post-MPN mIDH1 AML, supporting a role for olutasidenib based therapy in mIDH1 AML secondary to MPN.
Of the 15 patients in the Phase 2 study of olutasidenib who had prior history of MPNs that transformed into AML, five had newly diagnosed AML and 10 had R/R AML.
Six patients (40%) achieved CR with a median duration of response of 15.6 months. Two additional patients had a complete response with incomplete hematologic recovery (CRi), and one patient had morphologic leukemia free state (MLFS) giving a composite complete response (CRc) in 53% and an overall response rate (ORR) of 60%. Median overall survival was 13.8 months.
Olutasidenib-based therapy may serve as a bridge to allogeneic stem cell transplantation.
Friday, June 14, 18:00 to 19:00 CEST
Abstract #: P614
Title: Response to Olutasidenib in Patients with Acute Myeloid Leukemia (AML) Following Venetoclax Failure
Presenter: Jorge E. Cortes, M.D.
Location: IFEMA Madrid Recinto Ferial (Halls of the Fairgrounds), Hall 7

Olutasidenib induced complete remissions in patients with mIDH1 AML who were R/R to prior venetoclax-based regimens from the Phase 2 pivotal cohort.
The ORR in the 18 patients was 50%, including CR in six patients (33%), CR/CRh in seven patients (39%), and CRc in nine patients (50%).
In the 16 R/R patients, ORR was 44%, including CR/CRh in five patients (31%). Median time to CR/CRh was 2.1 months. Kaplan–Meier (KM) estimate of CR/CRh duration ≥18 months was 75%.
Two patients in the maintenance cohort had CRi at baseline; both achieved a CR, lasting 15.7 months and ongoing at 31.3+ months. Although only a small number of patients receiving maintenance therapy were included in this analysis, the data show that maintenance of a CR and even improvement of response from CRi to CR is possible with olutasidenib.
The demonstrated activity is clinically meaningful and reveals a therapeutic advance in the treatment of this poor-prognosis patient population with R/R mIDH1 AML.
Friday, June 14, 18:00 to 19:00 CEST
Abstract #: P611
Title: Safety and Efficacy of Olutasidenib Treatment in Elderly Patients with Relapsed/Refractory mIDH1 Acute Myeloid Leukemia
Presenter: Stéphane de Botton, M.D., Ph.D.
Location: IFEMA Madrid Recinto Ferial (Halls of the Fairgrounds), Hall 7

Olutasidenib was generally well tolerated in elderly patients with R/R mIDH1 AML and induced durable remissions, consistent with the population in the pivotal cohort of the Phase 2 registrational trial. Despite the challenges of treating elderly patients who had already failed prior AML treatment, the results suggest that elderly patients can benefit from therapy with olutasidenib.
In this subgroup analyses of the registrational Phase 2 trial of olutasidenib in 45 participants aged 75 and older with R/R mIDH1 AML, 31% of patients achieved CR/CRh; median time to CR/CRh was 1.5 months and median duration of CR/CRh was 25.3 months.
Of the five elderly patients who were R/R to prior venetoclax, four patients (80%) achieved an overall response, including two patients (40%) with CR/CRh.
Friday, June 14, 18:00 to 19:00 CEST
Abstract #: P1373
Title: Olutasidenib as Bridge-to-Transplant Treatment in Patients with Relapsed/Refractory mIDH1 Acute Myeloid Leukemia (AML)
Presenter: Stéphane de Botton, M.D., Ph.D.
Location: IFEMA Madrid Recinto Ferial (Halls of the Fairgrounds), Hall 7

Olutasidenib helped achieve remission in patients with mIDH1 R/R AML and served as a bridging strategy towards potentially curative allogeneic transplantation in a substantial subset of these previously ineligible patients.
153 patients with mIDH1 R/R AML received olutasidenib monotherapy, and 16 patients (11%) proceeded to allogeneic HSCT. Of the 16 patients, eight patients (50%) were refractory to prior therapy, three patients (19%) had prior HSCT, and 15 patients (94%) had prior intensive chemotherapy (IC), 50% of whom were IC-refractory.
Of the 16 patients proceeding to transplant, 12 patients (75%) achieved CR/CRh prior to proceeding to transplant, including 11 patients (69%) with CR, and all 16 patients were alive at 100 days. Median survival from start of olutasidenib treatment has not been reached. Overall survival probability was 83% at 12 months and 50% at 18 months.
About AML
Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow that affects myeloid cells, which normally develop into various types of mature blood cells. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that there will be about 20,800 new cases in the United States, most in adults, in 2024.1

Relapsed AML affects about half of all patients who, following treatment and remission, experience a return of leukemia cells in the bone marrow.2 Refractory AML, which affects between 10 and 40 percent of newly diagnosed patients, occurs when a patient fails to achieve remission even after intensive treatment.3 Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed or refractory disease remain an unmet need.

About REZLIDHIA

INDICATION
REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome
REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dose interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence.

Hepatotoxicity
REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin. Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity.

ADVERSE REACTIONS
The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis.

DRUG INTERACTIONS

Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers.
Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
LACTATION
Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose.

GERIATRIC USE
No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age.

HEPATIC IMPAIRMENT
In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome.

Click here for Full Prescribing Information, including Boxed WARNING.

To report side effects of prescription drugs to the FDA, visit www.fda.gov/medwatch or call 1-800-FDA-1088 (800-332-1088).

REZLIDHIA is a registered trademark of Rigel Pharmaceuticals, Inc.

On June 14, 2024 Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported clinical and preclinical data from RVU120 at the 2024 European Hematology Association (EHA) (Free EHA Whitepaper) Congress (EHA) (Free EHA Whitepaper), June 13-16, Madrid, Spain (Press release, Ryvu Therapeutics, JUN 14, 2024, View Source [SID1234644345]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are thrilled to share the advancements in RVU120 research and its clinical development, emphasizing its significant potential in addressing unmet needs in hematologic malignancies.", states Dr. Hendrik Nogai, Chief Medical Officer, Ryvu Therapeutics. "We are proud of the successful initiation of our Phase II studies. It is reassuring that the initial clinical safety data of RVU120 in combination with venetoclax, allow us to continue testing the compelling preclinical evidence of synergism in patients. Beyond AML and HR-MDS, we continue to work hard on new therapeutic strategies for patients with myeloproliferative neoplasms. Over the upcoming months, we are expecting a ramp up of patient enrollment and data readouts, and we remain committed to developing innovative treatments that can provide improved outcomes for patients in need." – underlines Dr. Hendrik Nogai, Chief Medical Officer, Ryvu Therapeutics.

Poster highlights:

Poster Title: RVU120, a first-in-class CDK8 inhibitor for the treatment of relapsed/refractory AML and high-risk MDS: preliminary results from two ongoing studies.
Poster Number: P600

Session date and time: Friday, June 14 (9:00 CET on the online platform, 18:00 CET for the poster presentation)

The poster includes data on 30 evaluable patients out of 38 total dosed patients in the Phase I trial (RIVER-51) and initial data from the Phase II trial (RIVER-52).

RVU120 as single agent showed clinical benefit in heavily pretreated patients with AML and HR-MDS in the Phase I trial CLI120-001 (RIVER-51). The strongest evidence of benefit was observed in patients with NPM1 and/or DNMT3A mutations, and in patients with HR-MDS.
At the poster presentation’s cut-off date, the data from the Phase II RIVER-52 trial of RVU120 as a monotherapy for patients with relapsed/refractory AML and HR-MDS were not yet mature enough for efficacy assessment in the target population, but preliminary signs of clinical benefit have been observed in ongoing patients.
The safety and tolerability of RVU120 at the RP2D of 250 mg administered every other day was confirmed in patients treated in both trials, with mild or moderate gastrointestinal events being the most frequently reported.
Poster Title: Synergistic potential of RVU120, a first-in-class CDK8/CDK19 inhibitor, with venetoclax in AML: preclinical and initial clinical insights.
Poster Number: P525

Session date and time: Friday, June 14 (9:00 CET on the online platform, 18:00 CET for the poster presentation)

Ryvu presents a mechanism of synergy between RVU120 and venetoclax in preclinical models of acute myeloid leukemia (AML).
The combination of RVU120 and venetoclax leads to caspase-dependent degradation of MCL-1 protein and represses inflammatory and AML oncogenic pathways at the transcriptomic level in AML cells.
RVU120, when combined with venetoclax, exerts cytotoxic and differentiating effects on leukemic stem cells (LSCs) from a hierarchical AML model, exceeding the efficacy of venetoclax alone.
By countering therapeutic failure caused by persistent LSCs and MCL-1-mediated venetoclax resistance, this combination offers hope to patients with AML in both the refractory and the frontline setting.
Initial data from the ongoing Phase II study RIVER-81 demonstrate the safety of RVU120 in combination with venetoclax at the initial dose level in patients with relapsed/refractory AML. Enrollment is currently ongoing in Cohort 2.
Poster Title: CDK8/19 Inhibition: A Promising Therapeutic Strategy in Myeloproliferative Neoplasms.
Poster Number: P1018

Session date and time: Friday, June 14 (9:00 CET on the online platform, 18:00 CET for the poster presentation)

In murine models of disease, RVU120 effectively attenuates myeloproliferative neoplasms (MPN) phenotypes (single-agent or combined with ruxolitinib (RUX)) partly through downregulation of pro-inflammatory cytokines.
RVU120 exhibits synergy with JAK inhibitors as a class and BET inhibitor – pelabresib. These findings open new potential therapeutic options for MPN patients, including myelofibrosis.
The combination of RVU120 and RUX acts synergistically by downregulating JAK/STAT signaling and inflammatory pathways at the transcriptomic level.
Based on compelling preclinical results, Ryvu is launching the clinical study POTAMI-61 (NCT06397313), evaluating RVU120 as a single agent or in combination with ruxolitinib in patients with myelofibrosis.
Investor Event:

Ryvu will host a webinar on Friday, June 14, at 9:30 CET, covering the latest data and potential of RVU120. To join the webcast, please register here: View Source

On June 14, 2024 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) reported longer-term data for CASGEVY (exagamglogene autotemcel [exa-cel]) from global clinical trials in people with severe sickle cell disease (SCD) or transfusion-dependent beta thalassemia (TDT) (Press release, Vertex Pharmaceuticals, JUN 14, 2024, View Source [SID1234644323]). The results, presented at the annual European Hematology Association (EHA) (Free EHA Whitepaper) Congress, confirm the transformative, consistent and durable clinical benefits of CASGEVY over time. CASGEVY is the first and only approved CRISPR-based gene-editing therapy.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The data being presented are from more than 100 patients (46 SCD; 56 TDT) treated with exa-cel in clinical trials, with the longest follow-up now extending more than 5 years. The efficacy results are consistent with the previously reported primary and key secondary endpoints analyses from these exa-cel studies and continue to demonstrate transformative clinical benefit with durable and stable levels of fetal hemoglobin (HbF) and allelic editing.

"The transformative benefit seen in patients with sickle cell disease in the trial is impressive given the significant and cumulative burden of disease faced by people living with this blood disorder," said Haydar Frangoul, M.D., M.S., Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute and HCA Healthcare’s TriStar Centennial Children’s Hospital. "I am eager to offer this therapy and the opportunity of a potential functional cure to my eligible patients."

"The comprehensive data set presented today for adult and adolescent TDT patients adds to the growing body of evidence for CASGEVY, and it is important to now ensure the availability of this innovative treatment to patients in the real world as soon as possible," said Franco Locatelli, M.D., Ph.D., Professor of Pediatrics at the Catholic University of the Sacred Heart of Rome, Director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital. "With the longest follow up now more than five years, alongside stable editing and sustained fetal hemoglobin levels, I have conviction in the durable benefit to the patients treated with CASGEVY."

New data presented from CASGEVY pivotal trials

In SCD 36/39 (92.3%) evaluable patients (those with at least 16 months of follow-up) were free from vaso-occlusive crises (VOCs) for at least 12 consecutive months (VF12), consistent with the previously reported primary endpoint data. Mean duration of VOC-free was 27.9 months, with a maximum of 54.8 months.
38/39 (97.4%) patients with at least 16 months of follow-up were free from hospitalizations related to VOCs for at least 12 consecutive months (HF12), consistent with the previously reported key secondary endpoint data.
In TDT 49/52 (94.2%) evaluable patients (those with at least 16 months of follow-up) were transfusion-independent for at least 12 consecutive months with a mean weighted hemoglobin of at least 9 g/dL (TI12), consistent with the previously reported primary endpoint data. Mean duration of transfusion independence was 31.0 months, with a maximum of 59.4 months.
All TDT patients dosed with at least 16 months of follow up are transfusion free.
Two of the three patients who did not achieve TI12 in CLIMB-111 achieved TI12 in the long-term follow-up study, CLIMB-131, and have been transfusion independent for over one year. The third has been transfusion free for 3.4 months.
Both SCD and TDT patients reported sustained and clinically meaningful improvements in their quality of life, including physical, emotional, social/family and functional well-being, and overall health status.
In both SCD and TDT patients, edited levels of BCL11A alleles were stable over time in bone marrow and peripheral blood indicating successful editing in the long-term hematopoietic stem cells. All patients engrafted neutrophils and platelets after exa-cel infusion. The safety profile of exa-cel was generally consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant.

These longer-term data for CASGEVY from the CLIMB clinical trials will be shared as outlined below:

Abstracts S273 and S274 will be oral presentations entitled "Exagamglogene Autotemcel For Severe Sickle Cell Disease," and "Exagamglogene Autotemcel For Transfusion-Dependent Beta-Thalassemia," on Sunday, June 16 at 12:15 CEST and 12:30 CEST, respectively.
Abstracts P1493 and P1525 will be poster presentations entitled "Health-Related Quality Of Life Improvements After Exagamglogene Autotemcel In Patients With Severe Sickle Cell Disease," and "Health-Related Quality Of Life Improvements After Exagamglogene Autotemcel In Patients With Transfusion-Dependent Βeta-Thalassemia," on Friday, June 14 at 18:00 CEST.
These presentations will include updated pivotal trial data from patients treated with CASGEVY in CLIMB-111 and CLIMB-121 and followed in CLIMB-131.
Vertex will also share five health economics abstracts at the EHA (Free EHA Whitepaper) Congress.

Abstract P1483 is entitled "Adherence, Treatment Use, and Clinical Outcomes in Patients With Sickle Cell Disease With Recurrent Vaso-Occlusive Crises Treated With L-Glutamine, Voxelotor, or Crizanlizumab in the United States."
Abstract P1506 is entitled "Mortality and Clinical Complications Among Patients with Sickle Cell Disease With Recurrent VOCs in Canada."
Abstract P1507 is entitled "Treatment Utilization and Clinical Complications in Patients with Sickle Cell Disease Receiving Frequent Red Blood Cell Transfusions in the United States."
Abstract P2191 is entitled "Clinical Complications and Treatment Use Among Patients With Sickle Cell Disease With Recurrent Vaso-Occlusive Crises in the Netherlands."
Abstract PB3248 is entitled "Clinical Complications Among Patients With Transfusion-Dependent Beta-Thalassemia in the Netherlands."
About Sickle Cell Disease (SCD)

SCD is a debilitating, progressive, life shortening genetic disease. SCD patients report health-related quality of life scores well below the general population and significant health care resource utilization. SCD affects the red blood cells, which are essential for carrying oxygen to all organs and tissues of the body. SCD causes severe pain, organ damage and shortened life span due to misshapen or "sickled" red blood cells. The clinical hallmark of SCD is vaso-occlusive crises (VOCs), which are caused by blockages of blood vessels by sickled red blood cells and result in severe and debilitating pain that can happen anywhere in the body at any time. SCD requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life and reduced lifetime earnings and productivity. In Europe, the mean age of death for patients living with SCD is around 40 years. Stem cell transplant from a matched donor is a potentially curative option but is only available to a small fraction of people living with SCD because of the lack of available donors.

About Transfusion-Dependent Beta Thalassemia (TDT)

TDT is a serious, life-threatening genetic disease. TDT patients report health-related quality of life scores below the general population and significant health care resource utilization. TDT requires frequent blood transfusions and iron chelation therapy throughout a person’s life. Due to anemia, patients living with TDT may experience fatigue and shortness of breath, and infants may develop failure to thrive, jaundice and feeding problems. Complications of TDT can also include an enlarged spleen, liver and/or heart, misshapen bones and delayed puberty. TDT requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life and reduced lifetime earnings and productivity. In Europe, the mean age of death for patients living with TDT is 50-55 years. Stem cell transplant from a matched donor is a potentially curative option but is only available to a small fraction of people living with TDT because of the lack of available donors.

About CASGEVY (exagamglogene autotemcel [exa-cel])

CASGEVY is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy for eligible patients with SCD or TDT, in which a patient’s own hematopoietic stem and progenitor cells are edited at the erythroid specific enhancer region of the BCL11A gene through a precise double-strand break. This edit results in the production of high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth.

CASGEVY has been shown to reduce or eliminate VOCs for patients with SCD and transfusion requirements for patients with TDT.

CASGEVY is approved for certain indications in multiple jurisdictions for eligible patients.

About the CLIMB Studies

The ongoing Phase 1/2/3 open-label trials, CLIMB-111 and CLIMB-121, are designed to assess the safety and efficacy of a single dose of CASGEVY in patients ages 12 to 35 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now closed for enrollment. Patients will be followed for approximately two years after CASGEVY infusion. Each patient will be asked to participate in the ongoing long-term, open-label trial, CLIMB-131. CLIMB-131 is designed to evaluate the safety and efficacy of CASGEVY in patients who received CASGEVY in other CLIMB studies. The trial is designed to follow patients for up to 15 years after CASGEVY infusion.

U.S. INDICATIONS AND IMPORTANT SAFETY INFORMATION FOR CASGEVY (exagamglogene autotemcel)

WHAT IS CASGEVY?

CASGEVY is a one-time therapy used to treat people aged 12 years and older with:

sickle cell disease (SCD) who have frequent vaso-occlusive crises or VOCs
beta thalassemia (β-thalassemia) who need regular blood transfusions
CASGEVY is made specifically for each patient, using the patient’s own edited blood stem cells, and increases the production of a special type of hemoglobin called hemoglobin F (fetal hemoglobin or HbF). Having more HbF increases overall hemoglobin levels and has been shown to improve the production and function of red blood cells. This can eliminate VOCs in people with sickle cell disease and eliminate the need for regular blood transfusions in people with beta thalassemia.

IMPORTANT SAFETY INFORMATION

What is the most important information I should know about CASGEVY?

After treatment with CASGEVY, you will have fewer blood cells for a while until CASGEVY takes hold (engrafts) into your bone marrow. This includes low levels of platelets (cells that usually help the blood to clot) and white blood cells (cells that usually fight infections). Your doctor will monitor this and give you treatment as required. The doctor will tell you when blood cell levels return to safe levels.

Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of platelet cells:
severe headache
abnormal bruising
prolonged bleeding
bleeding without injury such as nosebleeds; bleeding from gums; blood in your urine, stool, or vomit; or coughing up blood
Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of white blood cells:
fever
chills
infections
You may experience side effects associated with other medicines administered as part of the treatment regimen for CASGEVY. Talk to your physician regarding those possible side effects. Your healthcare provider may give you other medicines to treat your side effects.

How will I receive CASGEVY?

Your healthcare provider will give you other medicines, including a conditioning medicine, as part of your treatment with CASGEVY. It’s important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment.

After receiving the conditioning medicine, it may not be possible for you to become pregnant or father a child. You should discuss options for fertility preservation with your healthcare provider before treatment.

STEP 1: Before CASGEVY treatment, a doctor will give you mobilization medicine(s). This medicine moves blood stem cells from your bone marrow into the blood stream. The blood stem cells are then collected in a machine that separates the different blood cells (this is called apheresis). This entire process may happen more than once. Each time, it can take up to one week.

During this step rescue cells are also collected and stored at the hospital. These are your existing blood stem cells and are kept untreated just in case there is a problem in the treatment process. If CASGEVY cannot be given after the conditioning medicine, or if the modified blood stem cells do not take hold (engraft) in the body, these rescue cells will be given back to you. If you are given rescue cells, you will not have any treatment benefit from CASGEVY.

STEP 2: After they are collected, your blood stem cells will be sent to the manufacturing site where they are used to make CASGEVY. It may take up to 6 months from the time your cells are collected to manufacture and test CASGEVY before it is sent back to your healthcare provider.

STEP 3: Shortly before your stem cell transplant, your healthcare provider will give you a conditioning medicine for a few days in hospital. This will prepare you for treatment by clearing cells from the bone marrow, so they can be replaced with the modified cells in CASGEVY. After you are given this medicine, your blood cell levels will fall to very low levels. You will stay in the hospital for this step and remain in the hospital until after the infusion with CASGEVY.

STEP 4: One or more vials of CASGEVY will be given into a vein (intravenous infusion) over a short period of time.

After the CASGEVY infusion, you will stay in hospital so that your healthcare provider can closely monitor your recovery. This can take 4-6 weeks, but times can vary. Your healthcare provider will decide when you can go home.

What should I avoid after receiving CASGEVY?

Do not donate blood, organs, tissues, or cells at any time in the future
What are the possible or reasonably likely side effects of CASGEVY?

The most common side effects of CASGEVY include:

Low levels of platelet cells, which may reduce the ability of blood to clot and may cause bleeding
Low levels of white blood cells, which may make you more susceptible to infection
Your healthcare provider will test your blood to check for low levels of blood cells (including platelets and white blood cells). Tell your healthcare provider right away if you get any of the following symptoms:

fever
chills
infections
severe headache
abnormal bruising
prolonged bleeding
bleeding without injury such as nosebleeds; bleeding from gums; blood in your urine, stool, or vomit; or coughing up blood
These are not all the possible side effects of CASGEVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of CASGEVY

Talk to your healthcare provider about any health concerns.

Please see full Prescribing Information including Patient Information for CASGEVY.