On December 11, 2023 Johnson & Johnson reported an analysis from the Phase 1/2 MonumenTAL-1 study of TALVEY (talquetamab-tgvs) in patients with relapsed or refractory multiple myeloma (RRMM) showed that patients treated with TALVEY were subsequently treated effectively with several classes of therapy, including anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy as well as BCMA and anti-Fc receptor-like protein 5 (FcRH5) bispecific antibodies, after TALVEY treatment (Press release, Johnson & Johnson, DEC 11, 2023, View Source [SID1234638450]). These data, featured in a poster presentation at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #2007), highlight the versatility of TALVEY when used before or after BCMA-directed CAR-T and bispecifics in triple-class exposed patients with RRMM.1 Additional results from the MonumenTAL-1 study, also featured in a poster presentation, support the overall versatility of TALVEY by showing continued strong efficacy among patients with prior exposure to T-cell redirection therapy (TCR) (Abstract #3377).2

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In MonumenTAL-1, 297 patients with no prior exposure to TCR received TALVEY at the recommended Phase 2 dose (RP2D) of 0.8 mg/kg biweekly (Q2W) [n=154] or 0.4 mg/kg weekly (QW) [n=143].1 Patients in the study received a median of five prior lines of therapy; 75 percent of patients were triple-class refractory; 29 percent were penta-drug refractory; and 12 percent had prior belantamab mafodotin exposure.1 Overall, 162 patients received at least one subsequent antimyeloma therapy (SAT) after TALVEY discontinuation, including chemotherapy-based regimens (n=48); a proteasome inhibitor- (PI), an immunomodulatory drug- (IMiD), or other anti-neoplastic–containing regimen (n=44); anti-CD38 mAb-containing regimens (n=27); bispecific antibodies (n=23; n=19 anti–BCMA; n=4 anti–FcRH5); CAR-T therapy (n=17; including n=9 anti–BCMA-targeting CAR-T); or anti-BCMA antibody-drug conjugates (n=9).1

Results show that patients who discontinued TALVEY were able to achieve a response with SATs, including 65 percent (11/17) of patients who received subsequent CAR-T cell therapy, of whom 35 percent achieved a complete response (CR) or better.1 Patients treated with anti-BCMA bispecific antibodies as the first SAT achieved an overall response rate (ORR) of 58 percent (11/19), and 75 percent (3/4) responded to anti-FcRH5 bispecific antibody therapy as the first SAT.1

A separate updated analysis of the MonumenTAL-1 study, focused on safety and efficacy of TALVEY in patients with RRMM after prior TCRs (n=70), showed continued strong efficacy of TALVEY across populations exposed to TCR (predominantly anti-BCMA), with an ORR of 73 percent and median duration of response (mDOR) of more than 1 year in the post–CAR-T cell therapy setting.2 More than 56 percent of patients exposed to prior bispecific antibody responded.2

"Results from the MonumenTAL-1 analyses support the versatility of talquetamab either before or after BCMA-directed CAR-T and bispecifics in patients with triple-class exposed relapsed or refractory multiple myeloma," said Ajai Chari, M.D., Director of Multiple Myeloma Program, Professor of Clinical Medicine at the University of California, San Francisco.‡ "Talquetamab presents a new treatment option for patients and physicians who want to save BCMA-directed for later lines of therapy."

Data from the Pivotal Phase 1/2 MonumenTAL-1 Study Highlight Reported Continued Efficacy of TALVEY with Reduced Intensity Dosing

An oral presentation at ASH (Free ASH Whitepaper) 2023 highlighted results from 50 patients in the Phase 1/2 MonumenTAL-1 study who were switched to reduced intensity dosing based on meeting specific response criteria or to mitigate treatment-emergent adverse events (TEAEs) such as oral-, nail- and/or skin-related TEAEs, which may be related to expression of GPRC5D (Abstract #1010).3 Patients whose dose was reduced maintained durable responses to TALVEY treatment.3 Two additional cohorts, which were conducted to examine the impact of prospective reduction in dosing intensity after response was achieved, included 24 patients with a median follow-up of 13.2 months.3 In total, 79 percent (19/24) of patients achieved a partial response (PR) or better and switched from 0.8 mg/kg Q2W to either 0.4 mg/kg Q2W or 0.8 mg/kg Q4W.3 Following the change in dosing, at six months, mDOR was not reached.3

Patients who prospectively switched to reduced dosing intensity trended towards improved resolution of GPRC5D-related TEAEs, except for weight loss (prospective: 12.5 percent resolved and without dose reduction: 18.9 percent resolved).3 Resolution of TEAEs occurred for oral-toxicities (33.3 percent and 26.9 percent); nail-toxicities (11.1 percent and 12.0 percent) and non-rash skin-toxicities (50.0 percent and 15.3 percent), in the prospective and without dose reduction cohorts, respectivly.3 Thus, improvement or resolution of oral-, nail-, and skin-related TEAEs was observed over time in some patients in the prospective reduced and less frequent dosing cohorts.3

These results show the potential of modifying the TALVEY dose, after a response is achieved, as a strategy to manage oral-, nail-, and skin-related TEAEs and improve patient experience without compromising efficacy.3

First-ever Results from Study of TALVEY and IMiD Combination Show Promising Overall Response Rate in Patients with RRMM

Results from the Phase 1b MonumenTAL-2 study of TALVEY and pomalidomide for the treatment of patients with RRMM highlight the potential to combine TALVEY with other anti-myeloma therapies.4 These data, from the first-ever study of a regimen combining a GPRC5D-targeted therapy and an immunomodulatory agent, were featured as an oral presentation at the 2023 ASH (Free ASH Whitepaper) Annual Meeting (Abstract #1014).4

Patients in the Phase 1b MonumenTAL-2 study (n=35) were treated with subcutaneous (SC) TALVEY at the RP2D of 0.8 mg/kg Q2W (n=19) or 0.4 mg/kg QW (n=16) with step-up doses, plus two milligrams of oral pomalidomide daily.4 With a median follow-up of 15 months in the QW cohort (n=16), the overall response rate was 94 percent among response-evaluable patients, 63 percent achieved a CR or better, and 88 percent of responders achieved a very good partial response (VGPR) or better.4 With a median follow-up of 11.1 months in the Q2W cohort (n=19), the ORR was 84 percent in response-evaluable patients, with 37 percent achieving a CR or better and 68 percent achieving a VGPR or better.4 Overall response rates were consistent across patient subgroups, including patients treated with prior pomalidomide or CAR-T cell therapy.4

Responses in both patient cohorts were rapid, with a median time to first response of 1.7 months (range, 0.9–3.3) in the QW cohort and 1.2 months (range, 0–4.8) in the Q2W cohort.4 At nine months, 100 percent of responders maintained their response in the QW cohort and 84 percent maintained response in the Q2W cohort.4 mDOR and progression-free survival (PFS) were not reached, and 9-month PFS rates observed in the QW and Q2W cohorts were 94 percent and 76 percent, respectively.4

"Findings from the MonumenTAL-2 and MonumenTAL-1 studies demonstrate the versatility of TALVEY across patient subgroups, showing the efficacy, manageable safety profile and effect of TALVEY on B-cell preservation," said Christoph Heuck, M.D., Vice President, Hematology Clinical Development, Johnson & Johnson Innovative Medicine. "The promising early results observed with the combination of TALVEY and pomalidomide, even in patients who had previously received pomalidomide or CAR-T cell therapy, reinforce our scientific strategy in focusing on improving upon and deepening responses through combination regimens."

The most common adverse events across both cohorts were oral related (86 percent); cytokine release syndrome (CRS; 74 percent; 3 percent Grade 3/4); neutropenia (63 percent).4 Most common grade 3/4 hematologic AEs were neutropenia (54 percent), anemia (26 percent), and thrombocytopenia (20 percent).4 Nail, skin, and rash toxicities occurred in 69 percent, 74 percent, and 20 percent of patients, respectively; the majority were Grade 1/2 with no discontinuations.4 Grade 1 immune effector cell-associated neurotoxicity syndrome occurred in three patients.4 Infections occurred in 80 percent of patients (23 percent Grade 3/4); most common were pneumonia (23 percent) and upper respiratory tract infection (23 percent).4 Adverse events led to TALVEY dose reduction or schedule change in 34 percent of patients and dose reduction of pomalidomide in 46 percent of patients.4 In total, four patients discontinued treatment. One patient died due to pulmonary embolism.4

About TALVEY
TALVEY (talquetamab-tgvs) received approval from the U.S. FDA in August 2023 as a first-in-class GPRC5D-targeting bispecific antibody for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.5 The European Commission (EC) granted conditional marketing authorization (CMA) of TALVEY ▼ (talquetamab) in August 2023 as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma (RRMM) who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.6

TALVEY is a bispecific T-cell engaging antibody that binds to the CD3 receptor expressed on the surface of T-cells and G protein-coupled receptor class C group 5 member D (GPRC5D), a novel multiple myeloma target which is highly expressed on the surface of multiple myeloma cells and non-malignant plasma cells, as well as some healthy tissues such as epithelial cells of the skin and tongue.

For more information, visit www.TALVEY.com.

About MonumenTAL-1

MonumenTAL-1 (Phase 1: NCT03399799, Phase 2: NCT04634552) is a Phase 1/2 single-arm, open-label, multicohort, multicenter dose-escalation study involving more than 300 patients.7,8 Phase 1 evaluated the safety and efficacy of TALVEY in adults with relapsed or refractory multiple myeloma who received three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.1,2 The study excluded patients who experienced T-cell redirection therapy within 3 months, prior Grade 3 or higher CRS related to any T-cell redirection therapy, an autologous stem cell transplant within the 12 weeks, an allogenic stem cell transplant within the 6 months, Eastern Cooperative Oncology Group (ECOG) performance score of 3 or higher, stroke or seizure within 6 months, CNS involvement or clinical signs of meningeal involvement of multiple myeloma, plasma cell leukemia, or active or documented history of autoimmune disease (exception of vitiligo, resolved childhood atopic dermatitis or resolved Grave’s Disease that is euthyroid based on clinical and laboratory testing).7,8

Phase 2 of the study evaluated the efficacy of TALVEY in participants with relapsed or refractory multiple myeloma at the recommended Phase 2 dose(s) (RP2Ds), established as SC 0.4 mg/kg weekly and 0.8 mg/kg every two weeks, respectively. Efficacy was based on overall response rate (ORR) and duration of response (DOR) as assessed by an Independent Review Committee using the International Myeloma Working Group (IMWG) criteria.3

About MonumenTAL-2

The MonumenTAL-2 (NCT05050097) study is an ongoing Phase 1 study of subcutaneous talquetamab in combination with carfilzomib, daratumumab SC, lenalidomide or pomalidomide for the treatment of patients with multiple myeloma. The primary objective of the MonumenTAL-2 study is to identify and characterize the safety of the treatment combinations. Secondary objectives of the MonumenTAL-2 study include overall response rates, duration of response and time to response.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.9 In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumors.10 Multiple myeloma is the third most common blood cancer and remains an incurable disease.11 In 2023, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 people will die from the disease.12 People living with multiple myeloma have a five-year relative survival rate of 59.8 percent.13 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels and kidney problems or infections.14,15

TALVEY IMPORTANT SAFETY INFORMATION

INDICATION AND USAGE

TALVEY (talquetamab-tgvs) is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

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

IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY, including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME

Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TALVEY. Initiate TALVEY treatment with step-up dosing to reduce the risk of CRS. Withhold TALVEY until CRS resolves or permanently discontinue based on severity.

Neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), and serious and life-threatening or fatal reactions, can occur with TALVEY. Monitor patients for signs and symptoms of neurologic toxicity including ICANS during treatment. Withhold or discontinue TALVEY based on severity.

Because of the risk of CRS and neurologic toxicity, including ICANS, TALVEY is available only through a restricted program called the TECVAYLI and TALVEY Risk Evaluation and Mitigation Strategy (REMS).

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS

Cytokine Release Syndrome (CRS): TALVEY can cause cytokine release syndrome, including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 76% of patients who received TALVEY at the recommended dosages, with Grade 1 CRS occurring in 57% of patients, Grade 2 in 17%, and Grade 3 in 1.5%. Recurrent CRS occurred in 30% of patients. CRS occurred in 33% of patients with step-up dose 3 in the biweekly dosing schedule (N=153). CRS occurred in 30% of patients with the first 0.4 mg/kg treatment dose and in 12% of patients treated with the first 0.8 mg/kg treatment dose. The CRS rate for both dosing schedules combined was less than 3% for each of the remaining doses in Cycle 1 and less than 3% cumulatively from Cycle 2 onward. The median time to onset of CRS was 27 (range: 0.1 to 167) hours from the last dose, and the median duration was 17 (range: 0 to 622) hours. Clinical signs and symptoms of CRS include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, and tachycardia. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

Initiate therapy with step-up dosing and administer pre-treatment medications (corticosteroids, antihistamine, and antipyretics) prior to each dose of TALVEY in the step-up dosing schedule to reduce the risk of CRS. Monitor patients following administration accordingly. In patients who experience CRS, pre-treatment medications should be administered prior to the next TALVEY dose.

Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care based on severity, and consider further management per current practice guidelines. Withhold TALVEY until CRS resolves or permanently discontinue based on severity.

Neurologic Toxicity including ICANS: TALVEY can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), including fatal reactions. In the clinical trial, neurologic toxicity occurred in 55% of patients who received the recommended dosages, with Grade 3 or 4 neurologic toxicity occurring in 6% of patients. The most frequent neurologic toxicities were headache (20%), encephalopathy (15%), sensory neuropathy (14%), and motor dysfunction (10%).

ICANS was reported in 9% of 265 patients where ICANS was collected and who received the recommended dosages. Recurrent ICANS occurred in 3% of patients. Most patients experienced ICANS following step-up dose 1 (3%), step-up dose 2 (3%), step-up dose 3 of the biweekly dosing schedule (1.8%), or the initial treatment dose of the weekly dosing schedule (2.6%) (N=156) or the biweekly dosing schedule (3.7%) (N=109). The median time to onset of ICANS was 2.5 (range: 1 to 16) days after the most recent dose with a median duration of 2 (range: 1 to 22) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient and provide supportive care based on severity; withhold or permanently discontinue TALVEY based on severity and consider further management per current practice guidelines. [see Dosage and Administration (2.5)].

Due to the potential for neurologic toxicity, patients receiving TALVEY are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during the step-up dosing schedule and for 48 hours after completion of the step-up dosing schedule, and in the event of new onset of any neurological symptoms, until symptoms resolve.

TECVAYLI and TALVEY REMS: TALVEY is available only through a restricted program under a REMS, called the TECVAYLI and TALVEY REMS because of the risks of CRS and neurologic toxicity, including ICANS.

Further information about the TECVAYLI and TALVEY REMS program is available at www.TEC-TALREMS.com or by telephone at 1-855-810-8064.

Oral Toxicity and Weight Loss: TALVEY can cause oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis. In the clinical trial, 80% of patients had oral toxicity, with Grade 3 occurring in 2.1% of patients who received the recommended dosages. The most frequent oral toxicities were dysgeusia (49%), dry mouth (34%), dysphagia (23%), and ageusia (18%). The median time to onset of oral toxicity was 15 (range: 1 to 634) days, and the median time to resolution to baseline was 43 (1 to 530) days. Oral toxicity did not resolve to baseline in 65% of patients.

TALVEY can cause weight loss. In the clinical trial, 62% of patients experienced weight loss of 5% or greater, regardless of having an oral toxicity, including 28% of patients with Grade 2 (10% or greater) weight loss and 2.7% of patients with Grade 3 (20% or greater) weight loss. The median time to onset of Grade 2 or higher weight loss was 67 (range: 6 to 407) days, and the median time to resolution was 50 (range: 1 to 403) days. Weight loss did not resolve in 57% of patients who reported weight loss.

Monitor patients for signs and symptoms of oral toxicity. Counsel patients to seek medical attention should signs or symptoms of oral toxicity occur and provide supportive care as per current clinical practice, including consultation with a nutritionist. Monitor weight regularly during therapy. Evaluate clinically significant weight loss further. Withhold TALVEY or permanently discontinue based on severity.

Infections: TALVEY can cause infections, including life-threatening or fatal infections. Serious infections occurred in 16% of patients, with fatal infections in 1.5% of patients. Grade 3 or 4 infections occurred in 17% of patients. The most common serious infections reported were bacterial infection (8%), which included sepsis and COVID-19 (2.7%).

Monitor patients for signs and symptoms of infection prior to and during treatment with TALVEY and treat appropriately. Administer prophylactic antimicrobials according to local guidelines. Withhold or consider permanently discontinue TALVEY as recommended, based on severity.

Cytopenias: TALVEY can cause cytopenias, including neutropenia and thrombocytopenia. In the clinical trial, Grade 3 or 4 decreased neutrophils occurred in 35% of patients, and Grade 3 or 4 decreased platelets occurred in 22% of patients who received TALVEY. The median time to onset for Grade 3 or 4 neutropenia was 22 (range: 1 to 312) days, and the median time to resolution to Grade 2 or lower was 8 (range: 1 to 79) days. The median time to onset for Grade 3 or 4 thrombocytopenia was 12 (range: 2 to 183) days, and the median time to resolution to Grade 2 or lower was 10 (range: 1 to 64) days. Monitor complete blood counts during treatment and withhold TALVEY as recommended, based on severity.

Skin Toxicity: TALVEY can cause serious skin reactions, including rash, maculo-papular rash, erythema, and erythematous rash. In the clinical trial, skin reactions occurred in 62% of patients, with grade 3 skin reactions in 0.3%. The median time to onset was 25 (range: 1 to 630) days. The median time to improvement to grade 1 or less was 33 days.

Monitor for skin toxicity, including rash progression. Consider early intervention and treatment to manage skin toxicity. Withhold TALVEY as recommended based on severity.

Hepatotoxicity: TALVEY can cause hepatotoxicity. Elevated ALT occurred in 33% of patients, with grade 3 or 4 ALT elevation occurring in 2.7%; elevated AST occurred in 31% of patients, with grade 3 or 4 AST elevation occurring in 3.3%. Grade 3 or 4 elevations of total bilirubin occurred in 0.3% of patients. Liver enzyme elevation can occur with or without concurrent CRS.

Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TALVEY or consider permanent discontinuation of TALVEY, based on severity [see Dosage and Administration (2.5)].

Embryo-Fetal Toxicity: Based on its mechanism of action, TALVEY may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TALVEY and for 3 months after the last dose.

Adverse Reactions: The most common adverse reactions (≥20%) are pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, weight decreased, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhea, hypotension, and headache.

The most common Grade 3 or 4 laboratory abnormalities (≥30%) are lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, and hemoglobin decreased.

Please read full Prescribing Information, including Boxed Warning, for TALVEY.

On December 11, 2023 Cimeio Therapeutics, the leading biotechnology company in the field of epitope shielding, reported data for its CD45 and CD33 programs during this weekend’s American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in San Diego (Press release, Cimeio Therapeutics, DEC 11, 2023, View Source [SID1234638466]). The two studies provide further evidence that epitope editing allows for the development of powerful immunotherapies that would not be safe to administer without first protecting healthy cells.

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The first abstract, titled "Hematopoietic Stem Cells Expressing Engineered CD45 Enable a Near Universal Targeted Therapy for Hematologic Diseases," demonstrated the efficacy of Cimeio’s proprietary CD45 targeting ADC (CIM053-ADC) at depleting an aggressive AML cancer cell line in vivo, while the CD45 engineered HSCs were fully protected, engrafted and reconstituted the hematopoietic system in humanized mice. After just two doses of CIM053-ADC, all mice were cancer-free while the healthy hematopoietic cells were unaffected. This study demonstrates the potential of CD45-targeted ADC therapy for patients with hematologic malignancies.

The second abstract, titled "Base Edited HSPCs Are Shielded From CD33 Therapy but Preserve CD33 Expression," showed how Cimeio’s CD33 shielding variant effectively protected cells from a CD33 antibody, while maintaining CD33 expression. CD33 is a useful target for AML and other diseases of HSCs.

Collectively, these studies further underscore the potential for Cimeio’s therapies, when coupled with its shielding technology, to transform the treatment of hematologic malignancies, genetic, and autoimmune diseases.

"AML patients who have residual disease at the time of a bone marrow transplant have a high risk for relapse," said Corey Cutler, M.D., M.P.H., Medical Director of the Stem Cell Transplantation Program at the Dana Farber Cancer Institute and Professor of Medicine at Harvard Medical School. "An effective therapy that could be given post-transplant to treat residual disease and prevent relapse, but would not affect the newly transplanted cells, would be a real advancement in the way we treat AML. Bone marrow transplant has the potential to cure patients of their leukemia, and improving upon this approach through epitope shielding and novel post-transplant therapies is an exciting possibility."

On December 11, 2023 Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, reported presentations of data from its IMerge Phase 3 clinical trial evaluating first-in-class investigational telomerase inhibitor imetelstat in patients with lower risk myelodysplastic syndromes (MDS), as well as population analysis of claims data in lower risk MDS (Press release, Geron, DEC 11, 2023, View Source [SID1234638418]). The data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place from December 9-12, 2023, in San Diego, CA and virtually as well as published online in Blood.

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"These latest analyses from IMerge Phase 3 presented at ASH (Free ASH Whitepaper) contribute to a growing body of data from the trial, including a recent publication in The Lancet,which continue to give us confidence in what we believe is a meaningful clinical benefit with imetelstat in these lower risk MDS patients," said Faye Feller, M.D., Executive Vice President, Geron’s Chief Medical Officer. "If approved, we believe that the significant improvement in red blood cell transfusion independence possible with imetelstat could provide an important new treatment option for many lower risk MDS patients who suffer from iron overload and low quality of life associated with transfusion dependence."

"As we continue to see additional analyses from IMerge Phase 3, such as these latest presentations at ASH (Free ASH Whitepaper), the clinical attributes of imetelstat continue to be differentiated, particularly high RBC-TI response rate, durability of response and the consistency of effect across MDS subgroups that have historically been very difficult to treat," said Amer Methqal Zeidan, MBBS MHS, Associate Professor of Internal Medicine (Hematology) and director of hematology Early Therapy Research at Yale School of Medicine and Yale Cancer Center, who is an IMerge lead investigator. "Additionally, the safety profile was well-characterized, with Grade 3/4 neutropenia and thrombocytopenia that were generally transient, reversible to Grade 2 or less, and clinically manageable, and most importantly, had few clinical consequences and did not affect the efficacy of imetelstat."

Below are the highlights of the 6 company-sponsored abstracts:

"Efficacy of Imetelstat in Achieving Red Blood Cell Transfusion Independence Across Different Risk Subgroups in Patients With Lower-Risk Myelodysplastic Syndromes Relapsed/Refractory to Erythropoiesis-Stimulating Agents in IMerge Phase 3 Study"

This oral presentation provides a subgroup analysis from IMerge Phase 3 evaluating RBC-transfusion independence (RBC-TI) rates in patients treated with imetelstat vs. placebo across different risk subgroups as defined by International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) or IPSS molecular (IPSS-M) risk profiles. The results showed that imetelstat consistently had higher RBC-TI response rates than placebo across these different risk subgroups. Overall, durable 24-week and 1-year RBC-TI responses were observed with imetelstat in all lower- and higher-risk subgroups. Reclassifying patients by IPSS-M revealed that one-third of the patients (4/12) identified as higher-risk IPSS-M derived 8-week RBC-TI benefit whereas higher-risk subgroups receiving placebo failed to achieve long-term RBC-TI, regardless of the risk classification scheme used.

"Impact of Mutational Status on Clinical Response to Imetelstat in Patients with Lower Risk Myelodysplastic Syndromes in the IMerge Phase 3 Study"

This poster evaluates the impact of MDS-associated mutations on clinical efficacy of imetelstat for the 165 of 178 patients for whom mutation data were available. Results showed that in patients who had more than one mutation detected at baseline and more than two mutations at baseline, imetelstat significantly improved the 8-week and 24-week RBC-TI response rates compared with placebo. A significantly higher percentage of imetelstat-treated than placebo-treated patients with baseline mutations in SF3B1, a gene commonly mutated in MDS, achieved 8- and 24-week RBC-TI. RBC-TI responses in patients receiving imetelstat occurred regardless of the presence of mutations associated with poor prognosis or the number of mutations. This analysis suggests clinical benefit of imetelstat across different molecularly defined subgroups and independent of the underlying molecular mutation pattern.

"Durable Continuous Transfusion Independence With Imetelstat in IMerge Phase 3 for Patients With Heavily Transfused Non-Del(5q) Lower-Risk Myelodysplastic Syndromes Relapsed/Refractory to or Ineligible for Erythropoiesis-Stimulating Agents"

This poster reports on the patients enrolled in IMerge Phase 3 who achieved one-year or greater continuous RBC-TI response, which included 17.8% of imetelstat-treated patients (21/118; 95% CI, 11.4-25.9) and 1.7% of patients on placebo (1/60; 95% CI, 0-8.9). One-year RBC-TIs were achieved by 44.7% of 8-week RBC-TI responders and 63.6% of 24-week RBC-TI responders. During the one-year or greater RBC-transfusion-free interval, RBC transfusion burden was reduced from a baseline range of 4-9 units and hemoglobin improved a median of 5.2 g/dL. Imetelstat 1-year RBC-TI responders had a median duration of RBC-TI of 123 weeks (95% CI, 80.4-NE) and no patients progressed to acute myeloid leukemia (AML). At the time of data cutoff (May 10, 2023), 13 1-year RBC-TI responders receiving imetelstat and one patient receiving placebo were ongoing on treatment. Of the 18 imetelstat one-year responders for whom mutational data were available, complete elimination of certain mutational clones was observed in 10 of 18 patients (55.5%) for whom mutational data were available and 13 (72.2%) achieved greater than or equal to 50% SF3B1 variant allele frequency (VAF) reduction, including 7 patients with complete elimination of VAF. For these one-year RBC-TI responders and consistent with the overall safety profile for patients on IMerge Phase 3, Grade 3-4 thrombocytopenia and neutropenia occurred in 14 (67%) and 20 (95%) patients, with a mean duration of 1.78 (1.58) and 2.25 (2.48) weeks, respectively. 81% of Grade 3-4 neutropenia and 89% of Grade 3-4 thrombocytopenia were reversible to Grade 2 or below within 4 weeks.

"Improvement of Patient-Reported Outcomes Among Heavily Pretreated Patients With Lower-Risk Myelodysplastic Syndromes and High Transfusion Burden Treated With Imetelstat on the IMerge Phase 3 Trial"

This abstract published in Blood describes exploratory results from patient-reported outcomes (PROs) questionnaires used in IMerge Phase 3. Functional Assessment of Cancer Therapy-Anemia (FACT-An; 55 items) and Quality of Life in Myelodysplasia Scale (QUALMS; 38 items) were the main questionnaires used. Findings consistently showed that imetelstat-treated patients reported improved fatigue, dyspnea, and QUALMS composite scores (total and physical burden) compared to those on placebo. Further, patients treated with imetelstat did not experience greater deterioration in systemic symptoms, pain, physical function or bleeding than those on placebo. These data indicate that, in addition to improving RBC transfusion burden in patients with LR MDS, imetelstat targets multiple core symptoms of LR MDS simultaneously, also improving those respective PROs.

"Characterization and Management of Cytopenias after Imetelstat Treatment in the IMerge Phase 3 Trial of Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS)"

This abstract published in Blooddescribes treatment-emergent adverse events (TEAEs) of grade 3 or 4 thrombocytopenia and neutropenia, which were more prevalent in cycles 1-3 (68.6% and 62.7% respectively), and their frequency decreased over time. In the imetelstat group, cytopenias were managed with protocol-specified treatment delays and dose adjustments. Dose reductions due to neutropenia and thrombocytopenia occurred in 33.1% and 22.9% of patients, respectively. Thrombocytopenia and neutropenia were also managed by cycle delays in 46.6% and 50.8% of patients, by platelet transfusions in 17.8% of patients, and by concomitant therapy with growth factor support (mostly during cycles 2-4) in 34.7% of patients. Among 47 patients who achieved the primary endpoint of 8-week RBC-TI with imetelstat, 72.3% and 59.6% of patients had grade 3 or4 neutropenia and thrombocytopenia, respectively. This analysis shows that these Grade 3or 4 thrombocytopenia and neutropenia were generally transient, reversible and manageable through treatment delays and dose adjustments, and suggests that these TEAEs do not affect the efficacy of imetelstat.

A Geron-sponsored population analysis of claims data also were presented in poster format.

"Durable Transfusion Independence in Lower Risk Myelodysplastic Syndrome (LR MDS) Is Associated with Better Survival: A Population Level Analysis Based on a Large US Health Insurance Claims Database"

This poster describes a population level analysis of 5,662 lower risk MDS patients identified through Optum Clinformatics between October 2015 and June 2022. In these patients, real-world progression-free survival (rwPFS) from the start of first- and second- line therapy respectively, was significantly longer in patients who achieved 16-week RBC-TI after treatments than in patients who did not (p < .0001). RBC-TI responders also had significantly greater improvement in median overall survival (OS) from first and second line than non-responders (p < .0001 for both). This analysis indicates that achievement of RBC-TI was associated with improved survival, suggesting that transfusion dependence is a modifiable predictor of clinical outcomes in lower risk MDS.

The presentation and posters are available on the Publications Section of Geron’s corporate website and the abstracts are available online in Blood.

About IMerge Phase 3

The Phase 3 portion of the IMerge Phase 2/3 study is a double-blind, 2:1 randomized, placebo-controlled clinical trial to evaluate imetelstat in patients with IPSS Low or Intermediate-1 risk (lower risk) transfusion dependent MDS who were relapsed after, refractory to, or ineligible for, erythropoiesis stimulating agent (ESA) treatment, had not received prior treatment with either a HMA or lenalidomide and were non-del(5q). To be eligible for IMerge Phase 3, patients were required to be transfusion dependent, defined as requiring at least four units of packed red blood cells (RBCs), over an eight-week period during the 16 weeks prior to entry into the trial. The primary efficacy endpoint of IMerge Phase 3 is the rate of red blood cell transfusion independence (RBC-TI) lasting at least eight weeks, defined as the proportion of patients without any RBC transfusion for at least eight consecutive weeks since entry to the trial (8-week RBC-TI). Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks (24-week RBC-TI), the duration of RBC-TI and the rate of hematologic improvement erythroid (HI-E), which is defined under 2006 IWG criteria as a rise in hemoglobin of at least 1.5 g/dL above the pretreatment level for at least eight weeks or a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden. A total of 178 patients were enrolled in IMerge Phase 3 across North America, Europe, Middle East and Asia.

About Imetelstat

Imetelstat is a novel, first-in-class investigational telomerase inhibitor exclusively owned by Geron and being developed in hematologic malignancies. Data from non-clinical studies and clinical trials of imetelstat provide strong evidence that imetelstat targets telomerase to inhibit the uncontrolled proliferation of malignant stem and progenitor cells in myeloid hematologic malignancies resulting in malignant cell apoptosis and potential disease-modifying activity. Imetelstat has been granted Fast Track designation by the U.S. Food and Drug Administration for both the treatment of adult patients with transfusion dependent anemia due to Low or Intermediate-1 risk MDS that is not associated with del(5q) who are refractory or resistant to an erythropoiesis stimulating agent, and for adult patients with Intermediate-2 or High-risk myelofibrosis (MF) whose disease has relapsed after or is refractory to janus associated kinase (JAK) inhibitor treatment. Imetelstat is currently not approved by any regulatory authority.

On December 11, 2023 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported initial data from the ongoing ORIC-533 Phase 1 dose escalation trial in patients with relapsed/refractory multiple myeloma at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (poster here) (Press release, ORIC Pharmaceuticals, DEC 11, 2023, View Source [SID1234638434]).

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"ORIC-533 demonstrated an exceptionally well-tolerated safety profile and preliminary evidence of clinical antimyeloma activity in heavily pretreated relapsed/refractory multiple myeloma patients, which to our knowledge is the first reported single agent activity for a CD73 inhibitor in any oncology indication," said Pratik Multani, MD, chief medical officer. "We believe the Phase 1 data presented today position ORIC-533 as an ideal candidate for combinations with other immune-based antimyeloma therapies, including bispecific anti-BCMA-CD3 antibodies, CAR-T therapies, and anti-CD38 antibodies."

"We’re excited that multiple ORIC programs have achieved preliminary proof of concept that justify advancement into later stage studies. Given our desire to advance both ORIC-114, our EGFR/HER2 exon 20 inhibitor for lung cancer, and ORIC-944, our PRC2 inhibitor for prostate cancer, into Phase 2 and beyond, those two programs will require a level of focus from our team that necessitates the prioritization of our clinical pipeline," said Jacob M. Chacko, MD, chief executive officer. "As such, we intend to complete the single agent dose escalation for ORIC-533 in the coming months, and then combination studies will only be pursued with the operational and financial backing of a future partner for that program. This prioritization extends our projected cash runway into 2026, even with the increased expenses associated with moving ORIC-114 and -944 towards registrational studies."

ORIC-533 Phase 1 Study Design

ORIC-533 is being evaluated in a Phase 1 dose escalation trial in patients with relapsed/refractory multiple myeloma. The primary objectives of the trial are safety and determination of the recommended Phase 2 dose (RP2D). Additional objectives include characterization of the pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.

ORIC-533 Phase 1 Dose Escalation Data

As of November 28, 2023, a total of 23 patients with multiple myeloma received doses ranging from 400 mg to 2400 mg once daily. The study included a heavily pretreated patient population where 100% of patients were triple-class refractory, 91% were penta-refractory, and 57% also received prior anti-BCMA bispecific antibody and/or CAR-T therapy.

ORIC-533 demonstrated a favorable pharmacokinetic profile with an estimated plasma half-life of ~24 hours, which supports QD dosing. ORIC-533 clinical exposures achieved concentrations associated with efficacy in ex vivo models. ORIC-533 also demonstrated strong inhibition of soluble CD73 enzymatic activity across all dose levels, highlighting good target engagement, including in the bone marrow.

ORIC-533 was well tolerated with only Grade 1 and 2 treatment-related adverse events (TRAEs), without any specific recurrent toxicity. There were no dose limiting toxicities, dose reductions or treatment-related serious adverse events.

ORIC-533 exhibited clear evidence of immune activation in the majority of patients dosed at ≥ 1200 mg, as evidenced by an increased abundance and fraction of activated CD8+ T cells and NK cells. At the 1600 mg dose, there were notable reductions in soluble BCMA levels in serum, indicating that ORIC-533 was having a measurable antimyeloma effect. Soluble BCMA levels have been reported to correlate with clinical response on treatment and predict progression free survival of various therapies. Finally, there were multiple examples of clinical activity, including a confirmed minor response in a patient with penta-refractory myeloma who had progressed on an anti-BCMA bispecific antibody 3 months before study entry.

Next Steps

The company intends to complete dose escalation for ORIC-533 in the first quarter of 2024. Given the overall profile of ORIC-533, it is an ideal candidate for development in combination with other immune-based antimyeloma therapies, and the company intends to evaluate strategic partnerships to enable such development.

Conference Call and Webcast Details

To join the conference call via phone and participate in the live Q&A session, please pre-register online here to receive a telephone number and unique passcode required to enter the call. A live webcast and audio archive of the conference call will be available through the investor section of the company’s website at www.oricpharma.com. The webcast will be available for replay for 90 days following the presentation.

About ORIC-533

ORIC-533 is a highly potent, orally bioavailable small molecule inhibitor of CD73, a key node in the adenosine pathway believed to play a central role in resistance to chemotherapy and immunotherapy-based treatment regimens. ORIC-533 has demonstrated greater potency in preclinical studies compared to an antibody approach, as well as other small molecule inhibitors of CD73 and adenosine receptor antagonists. Preclinical data demonstrated that ORIC-533 binds CD73 with high affinity and effectively blocks adenosine-driven immunosuppression in a high AMP environment, reflective of AMP levels observed in tumors. In preclinical studies, nanomolar concentrations of ORIC-533 efficiently rescued cytotoxic T-cell function in the presence of high AMP concentrations, as well as in ex vivo bone marrow aspirates from relapsed or refractory multiple myeloma patients.

On December 11, 2023 Johnson & Johnson reported new patient-reported outcomes (PRO) from the Phase 3 CARTITUDE-4 study of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) demonstrated clinically meaningful improvements in health-related quality of life and meaningful reductions in disease-specific symptoms according to multiple PRO measures in the treatment of adult patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy (LOT) (Press release, Johnson & Johnson, DEC 11, 2023, View Source [SID1234638451]). These data were featured as an oral presentation at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #1063).

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"These results from the CARTITUDE-4 study showed the potential of cilta-cel to significantly improve health-related quality of life measures for patients, including pain, fatigue and emotional functioning," said Roberto Mina, Assistant Professor, Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy.‡ "Cilta-cel has demonstrated deep and durable responses in later lines of therapy, and these results show the potential of cilta-cel for patients with lenalidomide-refractory multiple myeloma as early as after first relapse."

In this analysis of the Phase 3 CARTITUDE-4 study, patients in the CARVYKTI arm reported improved functioning and symptom reduction from baseline, while PRO scores in the standard of care (SOC) regimens, pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) arm trended toward worsening or lower degrees of improvement from baseline for most domains and symptoms.1 CARVYKTI exceeded clinically meaningful thresholds for average improvement in global health status (10.1 points), pain (–10.2 points) and the visual analogue scale (8.0 points) from baseline to month 12; improvements in fatigue (–9.1 points) and emotional functioning (9.5 points) neared clinically meaningful thresholds.1 Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; 100-point scale), a 30-item instrument designed to measure quality of life in all cancer patients, the analysis showed that results numerically favored CARVYKTI for all other domains.1,2 The median time until multiple myeloma symptom worsening in the CARVYKTI arm was 23.7 months compared to 18.9 months in the SOC arm (Hazard Ratio [HR]= 0.42; 95 percent Confidence Interval [CI], 0.26–0.68; p value p0.003), measured with the Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q; 5-point scale).1

The CARTITUDE-4 study enrolled 419 patients with lenalidomide-refractory multiple myeloma and one to three prior LOT.1 At clinical cut-off, 99 patients in the CARVYKTI arm and 66 in the SOC arm had both baseline and 12-month PRO assessments, representing data prior to progression.1 PRO compliance was 100 percent at baseline and decreased with subsequent visits to 74 percent in the CARVYKTI and 81 percent in the SOC arm at month 12.1 Patients were administered EORTC QLQ-C30, EuroQoL 5-Dimension 5-Level (EQ-5D-5L; 100-point scale) and MySIm-Q questionnaires throughout the course of the study.1 In the primary analysis of CARTITUDE-4 presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, CARVYKTI reduced the risk of disease progression or death by 74 percent (Hazard Ratio [HR]=0.26; 95 percent Confidence Interval [CI], 0.18–0.38; p value p<0.0001) compared to two SOC regimens, PVd or DPd, in adults with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior LOT.3

CARTITUDE-2: Updated CARVYKTI Results in Earlier Lines of Treatment

Longer-term efficacy and safety data from CARTITUDE-2 cohorts A and B were also presented in an oral presentation at ASH (Free ASH Whitepaper) (Abstract #1021). At a median follow-up of approximately 29 months, patients treated with CARVYKTI in earlier LOT, both those with lenalidomide-refractory multiple myeloma after one to three LOT (cohort A) and those with early relapse (cohort B), experienced deep and durable responses.4 In the 20 patients in cohort A and 19 in cohort B, treatment with CARVYKTI resulted in overall response rates of 95 percent (complete response or better [≥CR], 90 percent) and 100 percent (≥CR, 90 percent), respectively. Median progression-free survival (PFS) was not reached in either cohort, and 24-month PFS rates were 75 percent in cohort A and 73 percent in cohort B; respective 24-month overall survival rates were 75 percent and 84 percent.

No new CAR-T-related safety signals were observed; one additional CAR-T cell neurotoxicity of sensory loss (grade 2) which resolved was reported in cohort B.3 Cohort A provides insight into potential longer-term survival outcomes that may be expected in the Phase 3 CARTITUDE-4 study, which enrolled the same patient population.

"The data presented at ASH (Free ASH Whitepaper) highlight our commitment to pursue the development of cutting-edge therapies with the intent of providing clinically meaningful real-life benefits for patients, in addition to robust efficacy and safety data," said Jordan Schecter, M.D., Vice President, Clinical Development Cellular Therapy Program, Johnson & Johnson Innovative Medicine. "These analyses add to the continued evidence from the CARTITUDE-4 study and build our confidence in the profile of CARVYKTI as a potential and promising treatment option for patients with multiple myeloma whose disease recurs early."

About CARTITUDE-4

CARTITUDE-4 (NCT04181827) is the first international, randomized, open-label Phase 3 study evaluating the efficacy and safety of cilta-cel versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in adult patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy.

About CARTITUDE-2

CARTITUDE-2 (NCT04133636) is an ongoing, multi-cohort Phase 2 study evaluating the safety and efficacy of cilta-cel in patients with multiple myeloma. Cohort B evaluates patients who received one line of prior therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and had disease progression per IMWG criteria within 12 months after treatment with autologous stem cell transplantation (ASCT) or from the start of anti-myeloma therapy for participants who have not had an ASCT. Cohort A evaluates patients who had progressive multiple myeloma after 1–3 prior lines of therapy including a PI and an IMiD, were lenalidomide refractory, and had no prior exposure to BCMA-targeting agents.

About CARVYKTI (ciltacabtagene autoleucel; cilta-cel)

CARVYKTI received U.S. Food and Drug Administration approval in February 2022 for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a PI, an IMiD agent, and an anti-CD38 monoclonal antibody.5 In May 2022, the European Commission granted conditional marketing authorization of CARVYKTI for the treatment of adults with relapsed and refractory multiple myeloma who have received at least three prior therapies, including an IMiD agent, a PI and an anti-CD38 antibody, and have demonstrated disease progression on the last therapy.

CARVYKTI is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding chimeric antigen receptor (CAR) that directs the CAR positive T-cells to eliminate cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. The CARVYKTI CAR protein features two BCMA-targeting single domains designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.

In December 2017, Janssen Biotech, Inc. entered into an exclusive worldwide license and collaboration agreement with Legend Biotech USA, Inc. to develop and commercialize CARVYKTI.

For more information, visit www.CARVYKTI.com.

About multiple myeloma

Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.6 In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumors.7 Multiple myeloma is the third most common blood cancer and remains an incurable disease.8,9 In 2023, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 people will die from the disease.10 People living with multiple myeloma have a 5-year relative survival rate of 59.8 percent.11 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels and kidney problems or infections.12,13

CARVYKTI IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, and PROLONGED and RECURRENT CYTOPENIA

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI. Do not administer CARVYKTI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI. Provide supportive care and/or corticosteroids as needed.

Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI.

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI. HLH/MAS can occur with CRS or neurologic toxicities.

Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI.

CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.

WARNINGS AND PRECAUTIONS

Cytokine Release Syndrome (CRS) including fatal or life-threatening reactions, occurred following treatment with CARVYKTI in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS (2019 ASTCT grade) occurred in 5% (5/97) of patients, with Grade 5 CRS reported in 1 patient. The median time to onset of CRS was 7 days (range: 112 days). The most common manifestations of CRS included pyrexia (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (ALT) (14%) and sinus tachycardia (11%). Grade 3 or higher events associated with CRS included increased AST and ALT, hyperbilirubinemia, hypotension, pyrexia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation and hemorrhage, HLH/MAS, angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, increased C-reactive protein, ferritin, blood alkaline phosphatase and gamma-glutamyl transferase.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. One patient with CRS and suspected HLH/MAS developed a fatal retroperitoneal hemorrhage in the setting of thrombocytopenia, coagulopathy and anticoagulation.

Sixty-nine of 97 (71%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four (45%) patients received only tocilizumab, of whom 33 (34%) received a single dose and 11 (11%) received more than one dose; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids. Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic toxicities, which may be severe, life-threatening or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, Guillain-Barré Syndrome, immune mediated myelitis, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Overall, one or more subtypes of neurologic toxicity described below occurred following ciltacabtagene autoleucel in 26% (25/97) of patients, of which 11% (11/97) of patients experienced Grade 3 or higher events. These subtypes of neurologic toxicities were also observed in two ongoing studies.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Patients may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. ICANS occurred in 23% (22/97) of patients receiving ciltacabtagene autoleucel including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). The median time to onset of ICANS was 8 days (range 1-28 days). All 22 patients with ICANS had CRS. The most frequent (≥5%) manifestation of ICANS included encephalopathy (23%), aphasia (8%) and headache (6%).

Monitor patients at least daily for 10 days following CARVYKTI infusion at the REMS certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Parkinsonism: Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome (ICANS). Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe release signs. The median onset of parkinsonism in the 5 patients in CARTITUDE-1 was 43 days (range 15-108) from infusion of ciltacabtagene autoleucel.

Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease, for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment.

Guillain-Barré Syndrome: A fatal outcome following Guillain-Barré Syndrome (GBS) has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulin (IVIG). Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulin and plasma exchange, depending on severity of GBS.

Immune Mediated Myelitis: Grade 3 myelitis has occurred 25 days following treatment in another ongoing study. Symptoms reported included hypoesthesia of the lower extremities and the lower abdomen with impaired sphincter control. Symptoms improved with the use of corticosteroids and intravenous immunoglobulin. Myelitis was ongoing at the time of death from other cause.

Peripheral Neuropathy: Six patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor or sensorimotor neuropathies. Median time of onset of symptoms was 62 days (range 4-136 days), median duration of peripheral neuropathies was 256 days (range 2-465 days) including those with ongoing neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of peripheral neuropathies.

Cranial Nerve Palsies: Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE-1. All three patients had 7th cranial nerve palsy; one patient had 5th cranial nerve palsy as well. Median time to onset was 26 days (range 21-101 days) following infusion of ciltacabtagene autoleucel. Occurrence of 3rd and 6th cranial nerve palsy, bilateral 7th cranial nerve palsy, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): Fatal HLH occurred in one patient (1%), 99 days after ciltacabtagene autoleucel. The HLH event was preceded by prolonged CRS lasting 97 days. The manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction.

One patient with Grade 4 HLH/MAS developed fatal intracerebral and gastrointestinal hemorrhage in the setting of coagulopathy and thrombocytopenia 12 days after treatment in another ongoing study. Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematological parameters in patients with HLH/MAS and transfuse per institutional guidelines.

HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

CARVYKTI REMS: Because of the risk of CRS and neurologic toxicities, CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS.

Further information is available at View Source or 1-844-672-0067.

Prolonged and Recurrent Cytopenias: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion. One patient underwent autologous stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia.

In CARTITUDE-1, 30% (29/97) of patients experienced prolonged Grade 3 or 4 neutropenia and 41% (40/97) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion.

Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia and anemia were seen in 63% (61/97), 18% (17/97), 60% (58/97), and 37% (36/97) after recovery from initial Grade 3 or 4 cytopenia following infusion. After Day 60 following ciltacabtagene autoleucel infusion, 31%, 12% and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia. Eighty-seven percent (84/97) of patients had one, two, or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Six and 11 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.

Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

Infections: CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening or fatal infections occurred in patients after CARVYKTI infusion.

Infections (all grades) occurred in 57 (59%) patients. Grade 3 or 4 infections occurred in 23% (22/97) of patients; Grade 3 or 4 infections with an unspecified pathogen occurred in 17%, viral infections in 7%, bacterial infections in 1%, and fungal infections in 1% of patients. Overall, four patients had Grade 5 infections: lung abscess (n=1), sepsis (n=2) and pneumonia (n=1).

Grade 5 infections reported in other studies include bronchopulmonary aspergillosis, pneumocystis jirovecii pneumonia, and CMV colitis (with HSV-1 hepatitis). Another patient developed mycotic aneurysm due to cerebral aspergillosis and died of subarachnoid hemorrhage.

Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 10% of patients after ciltacabtagene autoleucel infusion, 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 a randomized controlled study of relapsed or refractory multiple myeloma (CARTITUDE-4), patients treated with ciltacabtagene autoleucel had an increased rate of fatal COVID-19 infections compared to the standard therapy arm. Counsel patients on the importance of prevention measures. Follow institutional guidelines for the vaccination and management of immunocompromised patients with COVID-19.

Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV), or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

Hypogammaglobulinemia was reported as an adverse event in 12% (12/97) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients. Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Use of Live Vaccines: The safety of immunization with live viral vaccines during or following CARVYKTI 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 CARVYKTI treatment, and until immune recovery following treatment with CARVYKTI.

Hypersensitivity Reactions have occurred in 5% (5/97) of patients following ciltacabtagene autoleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage appropriately according to the severity of the hypersensitivity reaction.

Secondary Malignancies: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc., at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline, or neuropathy, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI 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, and in the event of new onset of any neurologic toxicities.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common laboratory adverse reactions (incidence greater than or equal to 50%) include thrombocytopenia, neutropenia, anemia, aminotransferase elevation, and hypoalbuminemia.

Please read full Prescribing Information, including Boxed Warning, for CARVYKTI.