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Unassigned

New Medicines

CarvyktiRelapsed/refractory multiple myeloma (MM) in adults whose prior regimens included a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody

Information

Carvykti
New molecular entity
Janssen
Johnson & Johnson

Development and Regulatory status

None
Approved (Licensed)
Approved (Licensed)
Yes
Yes
May 22Granted a conditional MA in EU for the treatment of adults with relapsed and refractory multiple myeloma (RRMM) who have received at least three prior therapies, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 antibody, and have demonstrated disease progression on the last therapy [21].
Mar 22Recommended for EU conditional approval by CHMP “for the treatment of adult patients with relapsed and refractory multiple myeloma, 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.” Carvykti will be available as 3.2 x 10⁶ to 1.0 x 10⁸ cells dispersion for infusion [20].
Feb 22FDA approves ciltacabtagene for the treatment of adult patients with relapsed and/or refractory multiple myeloma. The application for cilta-cel was based on findings from, the phase 1b/2 CARTITUDE-1 trial [19].
Nov 21US FDA extend Prescription Drug User Fee Act (PDUFA) target date to February 2022 for ciltacabtagene to treat r/r MM. [16]
Oct 21EMA assessment re-starts after responses received to the Day 120 questions adopted on 10.09.2021 [18].
May 21US FDA accept for priority review the BLA for ciltacabtagene autoleucel for r/r multiple myeloma with a target action date of November 29, 2021. [13]
May 21Filed in EU [12]
Apr 21Janssen announces that rolling submission to FDA is complete. It is anticipated that the biologics license will be accepted within the next two months. If priority review is granted the therapy could be licensed in the US towards the end of 2021 [11].
Feb 21Janssen announces that the CHMP of the EMA will perform an accelerated assessment of the MAA for ciltacabtagene autoleucel (cilta-cel), which it plans to file in H1 2021 and will be supported by the positive results from the Phase Ib/II CARTITUDE-1 study. A rolling submission of the Biologics License Application (BLA) for cilta-cel to the FDA started in December 2020 [10].
Nov 20The company will file for UK MAA when it gets a CHMP opinion under the unilateral procedure [9].
Nov 20JNJ 4528 BCMA CAR-T Therapy has breakthrough therapy status in the US. The FDA granted the special status based on results from the CARTITUDE-1 trial [7].
Apr 20Has orphan drug status for MM (second-line or greater) in the US. Also has orphan drug status in EU [5].
Jan 20EMA granted PRIME desingation in Apr 19. Janssen will file for UK MAA when it gets CHMP opinion under the EU centralised/unilateral procedure [4].
Jan 20First filings planned between 2020-23 [3].

Category

Autologous chimeric antigen receptor (CAR)-T cell therapy. T-lymphocytes are collected from the patient by leukapheresis and modified genetically ex vivo with a lentiviral vector that targets two epitopes on BCMA. Re-infused as a single dose.
Multiple myeloma is the second most common haematological cancer. It is responsible for 15-20% of deaths from haematological cancer and about 2% of all deaths from cancer. The incidence in Europe is 4.5-6.0 per 100,000/year with a mortality rate of 4.1 per 100,000/year [1].
Relapsed/refractory multiple myeloma (MM) in adults whose prior regimens included a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody
Intravenous infusion

Further information

Yes

Trial or other data

May 22After a median follow-up of 27 months, PIb/II Cartitude-1 study, 54.9% of heavily pretreated patients who got a single Carvykti infusion demonstrated no disease progression and 70% were still alive. Detailed data will be presented at the 2022 American Society of Clinical Oncology annual meeting [22].
Dec 21Longer-term results from PIb/II CARTITUDE-1 trial show an ORR of 98% with 83% achieving a stringent Complete Response (sCR) at median 22-month follow-up. At 22 months, median PFS and OS were not reached. Two-year PFS and OS rates were 61% and 74% respectively. No new safety signals were observed with longer follow-up. [17]
Jul 21Single-arm phase Ib/II CARTITUDE-1 study (n=97) found a single cilta-cel infusion was associated with an overall response rate of 97% (67% complete response) in heavily pre-treated patients with multiple myeloma. The data from this study formed the basis of recent regulatory submissions [15].
Jun 21 Single-arm PI/II CARTITUDE-1 study (n=126) is ongoing. New interim data from 97 patients show that OS at 18 months was 81%, ORR was 98% stringent CR was 80% and PFS was 66% (vs. 86% PFS at 9 months). Among MRD evaluable patients (n=61), 92% achieved MRD negative status 1 month post infusion. Improvements in patient-reported HRQoL (n=68) were seen at day 100 for pain (71%), fatigue (62%), physical functioning (72%) and global health status (51%). The study will be completed in April 2022. Rates of Grade ≥3 AEs are neutropenia (96%), thrombocytopenia (79%) , leukopenia (72%) , lymphopenia (53%) and anaemia (81%). There were 2 Grade ≥3 cytokine release syndrome (CRS) events including 1 fatal event at day 99 from sequelae of grade 4 CRS. The rate of Grade ≥3 neurotoxicity was 10%. No cases of severe hypoimmunoglobulinaemia have been reported in association with ciltacabtagene.[14]
Nov 20Janssen announces new data from the PIb/II CARTITUDE-1 study will be presented at ASH. As of the May 20, 2020 clinical cutoff, 97 pts (58.8% male; median age 61.0 y [range 43–78]) with R/R MM received cilta-cel (29 in phase 1b; 68 in phase 2). Median follow-up duration was 8.8 mo (range 1.5–20.4). Pts had received a median of 6 prior lines of therapy (range 3–18); 83.5% were penta-exposed, 87.6% were triple-refractory, 41.2% were penta-refractory, and 97.9% were refractory to last line of therapy. Overall response rate per independent review committee (primary endpoint) was 94.8% (95% CI 88.4–98.3), with a stringent complete response rate of 55.7% (95% CI 45.2–65.8), very good partial response rate of 32.0% (95% CI 22.9–42.2), and partial response rate of 7.2% (95% CI 3.0–14.3). All pts achieved a reduction in M-protein. Median time to first response was 1.0 mo (range 0.9–5.8; 80.4% ≤1.0 mo), and median time to complete response or better was 1.8 mo (range 0.9–12.5; 74.1% ≤3.0 mo); responses deepened over time. Median duration of response was not reached (NR). Of 52 MRD-evaluable pts, 94.2% were MRD-negative at 10-5. The 6-mo progression-free survival (PFS) and overall survival (OS) rates (95% CI) were 87.4% (78.9–92.7) and 93.8% (86.7–97.2), respectively; median PFS and OS were NR. Ten deaths occurred during the study; 8 were due to AEs (both related and unrelated; CRS/hemophagocytic lymphohistiocytosis, neurotoxicity, respiratory failure, sepsis, septic shock, pneumonia, lung abscess, and acute myelogenous leukemia [n=1 each]), and 2 due to progressive disease. AEs reported in >70% of pts were CRS (94.8%; grade [gr] 3/4 4.1%), neutropenia (90.7%; gr 3/4 90.7%), anemia (81.4%; gr 3/4 68.0%), and thrombocytopenia (79.4%; gr 3/4 59.8%). Median time to CRS onset was 7.0 d (range 1–12) and median duration 4.0 d (range 1–27, excluding n=1 with 97 d). CAR-T cell–related neurotoxicity was reported in 20.6% of pts (gr 3/4 10.3%). Cilta-cel CAR+ T cells showed maximum peripheral expansion at 14 d (range 9–43). Among pts with 6 month individual follow-up, 67% had cilta-cel CAR+ T cells below the level of quantification (2 cells/µL) in peripheral blood [8].
Sep 20Ciltacabtagene has been prioritised for potential TA guidance production [6].
Jan 20Johnson & Johnson is anticipating possible data presentation from the CARTITUDE-1 study in 2020 [3].
Jan 20PI/II CARTITUDE-1 study is ongoing but longer recruiting [2].
Jun 18PI/II CARTITUDE-1 study to evaluate the safety and efficacy of JNJ-68284528 starts (MMY2001; NCT03548207). The study will include two phases. In Phase1b the study will enroll adults with multiple myeloma with interval assessments for potential dose escalation or de-escalation in subsequent participants. The dose selected at the completion of phase 1b will be used in Phase 2. Following consent, enrolled participants will undergo an apheresis procedure to collect cells for manufacture of investigational drug product (JNJ-68284528). Following manufacture of the drug product, participants will undergo lymphodepletion prior to infusion of JNJ-68284528. Participants will be followed for at least 2 years after study drug infusion, with long-term 15 year follow-up on a separate study. The study will evaluate safety, biomarkers, pharmacokinetic/pharmacodynamic evaluations and efficacy. 118 adults will be recruited in the US & Japan (no UK study sites). Collection of primary outcome data is due to complete Sep 21 [2].

Evidence based evaluations

CarvyktiRelapsed/refractory multiple myeloma (MM) after 1 to 3 prior therapies

Information

Carvykti
Licence extension / variation
Janssen
Johnson & Johnson

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes
Yes
Apr 20Has orphan drug status for MM (second-line or greater) in the US. Also has orphan drug status in EU [3].

Category

Autologous chimeric antigen receptor (CAR)-T cell therapy. T-lymphocytes are collected from the patient by leukapheresis and modified genetically ex vivo with a lentiviral vector that targets two epitopes on BCMA. Re-infused as a single dose.
Multiple myeloma is the second most common haematological cancer. It is responsible for 15-20% of deaths from haematological cancer and about 2% of all deaths from cancer. The incidence in Europe is 4.5-6.0 per 100,000/year with a mortality rate of 4.1 per 100,000/year [1].
Relapsed/refractory multiple myeloma (MM) after 1 to 3 prior therapies
Intravenous infusion

Further information

Yes

Trial or other data

May 22In CARTITUDE-2, in patients who had received one prior line of therapy and progressed within 12 months, Carvykti shrank tumours in all 19 patients and helped 90% of them reach complete response or better. The data come from cohort B after 13.4 months of median follow-up. Both data points showed improvement from an earlier analysis of 18 patients after a median 4.7 months of follow-up. Back then, the overall response rate was 88.9%, and 27.8% of patients had complete response or stringent complete response. The company previously reported data from cohort A, which enrolled patients who had progressive disease after one to three prior lines of therapy and were refractory to BMS’ Revlimid. There, Carvykti triggered a response in 95% of 20 patients after a median follow-up of 9.7 months. The rate of complete response was 85%, according to data presented at the American Society of Hematology 2021 annual meeting in December 2021 [9].
Apr 22CARTITUDE-4 recruited in the UK at the following sites: Queen Elizabeth Hospital in Birmingham, Bristol Royal Infirmary, University Hospital Wales in Cardiff, University College Hospital in London, King´s College Hospital in London, The Christie Hospital, and the Freeman Hospital in Newcastle [8].
Nov 21CARTITUDE-2 and 4 trials continues to recruit; timelines unchanged [7]
Jun 21First results announced from Cohort A (n=20) in the PII CARTITUDE-2 study. At a median of 5.8 months of follow-up, ORR was 95% with 45% of patients achieving a sCR, 30 percent of patients achieving a CR, 10% of patients achieving a VGPR, and 10% of patients achieving a PR. The overall safety profile, including incidence of CRS and most common hematologic AEs, was consistent with observations in the CARTITUDE clinical development program [6].
Jun 21PII CARTITUDE-2 trial is recruiting. The study started in Nov 2019 and includes 6 cohorts of patients with multiple myeloma. Cohort A patients will have received a minimum of 1 to a maximum of 3 prior lines of therapy including a proteasome inhibitor (PI) and immunomodulatory therapy (IMiD), and lenalidomide refractory per International Myeloma Working Group (IMWG) guidelines. 160 adults will be recruited in countries including the US, Belgium, France, Germany, Netherlands, Israel and Spain. Primary outcome is overall minimal residual disease (MRD) negative rate; collection of these data is due to complete May 22 [5].
Nov 20PIII CARTITUDE-4 study is recruiting [4].
Mar 20PIII CARTITUDE-4 study (NCT04181827) is due to start. It will compare the efficacy of JNJ-68284528 with standard therapy, either pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd). 400 adults will be recruited in the US, Australia, Belgium, France, Germany, Israel, Italy, Netherlands, Spain, Sweden and the UK. Collection of primary outcome data (progression-free survival) is due to complete Apr 26. Participants in the experimental arm will receive one cycle of bridging therapy (PVd or DPd) and a second cycle of PVd or DPd may be administered per communication between the investigator and sponsor along with conditioning regimen (cyclophosphamide 300 milligram [mg]/m^2 intravenous [IV] and fludarabine 30 mg/m^2 IV daily, for 3 days), and JNJ-68284528 infusion 0.75 * 10^6 chimeric antigen receptor (CAR)-positive viable T cells/ kilogram (kg) [2].

Evidence based evaluations

CarvyktiMultiple myeloma (MM) in patients who are ineligible for autologous stem cell transplantation as initial therapy

Information

Carvykti
Licence extension / variation
Janssen
Johnson & Johnson

Development and Regulatory status

None
Phase II Clinical Trials
Phase II Clinical Trials

Category

Autologous chimeric antigen receptor (CAR)-T cell therapy. T-lymphocytes are collected from the patient by leukapheresis and modified genetically ex vivo with a lentiviral vector that targets two epitopes on BCMA. Re-infused as a single dose.
Multiple myeloma is the second most common haematological cancer. It is responsible for 15-20% of deaths from haematological cancer and about 2% of all deaths from cancer. The incidence in Europe is 4.5-6.0 per 100,000/year with a mortality rate of 4.1 per 100,000/year [1].
Multiple myeloma (MM) in patients who are ineligible for autologous stem cell transplantation as initial therapy
Intravenous infusion

Trial or other data

Nov 21PII CARTITUDE-2 study continues to recruit with timescales unchanged. Cohort E of this study included patients in whom transplant is not planned, with high risk disease [3].
Aug 21PIII CARTITUDE-5 study starts (NCT04923893). This will compare the efficacy of Bortezomib, Lenalidomide and Dexamethasone (VRd) induction followed by a single administration of ciltacabtagene autoleucel (cilta-cel) versus VRd induction followed by Lenalidomide and Dexamethasone (Rd) maintenance in newly diagnosed multiple myeloma participants for whom ASCT is not planned as initial therapy in terms of Progression Free Survival (PFS). Patients will be recruited in countries including the US, and Europe (incl UK University Hospitals Birmingham NHS Trust, Bristol Royal Infirmary, Leeds Teaching Hospitals NHS Trust, University College Hospital, King´s College Hospital, Manchester Royal Infirmary, The Royal Marsden). Collection of primary outcome data is due to complete Jun 26 [4].
Jan 21PII CARTITUDE-2 study is recruiting. Cohort D of this study is the same population as that in the proposed PIII CARTITUDE-3 trial [2].
Nov 19PII CARTITUDE-2 study to evaluate the overall minimal residual disease (MRD) negative rate of participants who receive JNJ-68284528 starts (NCT04133636). The study comprises of a Screening Phase (less than or equal to [<=] 28 days prior to apheresis) followed by Apheresis (will occur upon enrollment); a Treatment Phase including a conditioning regimen followed by infusion of JNJ-68284528 and post-infusion assessments from Day 1 to Day 100 (participants who receive an infusion of JNJ-68284528 should continue all subsequent assessments); and a Post-treatment Phase (Day 101 and up to the end of each study cohort). Safety evaluations will include a review of adverse events, laboratory test results, vital sign measurements, physical examination findings (including neurologic examination), assessment of cardiac function, immune effector cell-associated encephalopathy (ICE) score, handwriting assessment, and assessment of Eastern Cooperative Oncology Group (ECOG) performance status grade. Efficacy evaluations will include measurements of tumor burden/residual disease, myeloma proteins, bone marrow examinations, skeletal surveys, extramedullary plasmacytomas, and serum calcium corrected for albumin. For certain participants (those without measurable disease in serum or urine) efficacy will be assessed via imaging: positron emission tomography/ computed tomography (PET/CT) or whole body magnetic resonance imaging (MRI). The overall duration of the study is up to 2.5 years. After lymphodepletion, JNJ-68284528 will be administered as a single infusion to participants in cohort A (Progressive disease after 1-3 prior lines of therapy), cohort B (Early relapse after front-line), cohort C (Relapsed/refractory multiple myeloma after proteasome inhibitor [PI], immunomodulatory [IMiD], anti-CD38, and anti-B-cell maturation antigen [BCMA] therapy) and cohort D (Less than CR after autologous stem cell transplantation [ASCT] front-line therapy; some participants will be administered JNJ-68284528 followed by lenalidomide). 120 adults will be recruited in countries including the US and Europe (no UK sites). Collection of primary outcome data (percentage of participants who achieve MRD negative status by evaluation of bone marrow aspirate as defined by the International Myeloma Working Group criteria) is due to complete Apr 22 [2].