FDA Approves Eli Lilly’s Jaypirca for Relapsed Mantle Cell Lymphoma
Eli Lilly has received FDA approval for Jaypirca, a non-covalent BTK inhibitor, in relapsed mantle cell lymphoma (MCL) patients who have relapsed after treatment with other drugs in the class. Adult MCL patients who have previously received at least two lines of systemic therapy, including a covalent BTK inhibitor, are eligible for accelerated approval.
Jaypirca (pirtobrutinib) was developed specifically for patients who develop resistance mutations to currently available BTK inhibitors for MCL, such as AbbVie/Johnson & Johnson’s Imbruvica (ibrutinib), AstraZeneca’s Calquence (acalabrutinib), and BeiGene’s Brukinsa (zanubrutinib). It is the first non-covalent or reversible BTK drug to be approved by the FDA, and its mechanism of action involves targeting a different binding site on the BTK protein.
Jaypirca had an objective response rate of 50%, including 13% complete responses, and a median duration of response of more than eight months in the open-label, phase I/II BRUIN clinical trial, which included 120 patients with MCL as well as patients with other types of blood cancer. The patients in the study had previously received a median of three lines of therapy, including at least one covalent BTK inhibitor.
Meanwhile, continued approval in MCL is likely to be contingent on the results of confirmatory clinical trials. BRUIN MCL-321 is a phase III trial being conducted by Lilly that compares Jaypirca to a physician’s choice of BTK inhibitors in MCL patients who have received one or more prior lines of therapy and are BTK inhibitor naive.
Jaypirca is set to be available in the United States “in the coming weeks,” according to Lilly, with a list price of $21,000 for a 30-day supply, a premium over covalent BTK drugs, which typically cost between $13,000 and $16,000 per month.
EMA Reviewing Novartis’ Adakveo After Phase III Trial Failure
The European Medicines Agency’s (EMA) human medicines committee has begun reviewing Novartis’ Adakveo, a sickle cell disease (SCD) therapy that failed to show efficacy in a phase III trial. Novartis announced on Friday that the phase III STAND trial of Adakveo (crizanlizumab) found no statistically significant difference between the drug and placebo in annualized rates of vaso-occlusive crises (VOCs), which are excruciatingly painful attacks that affect patients with SCD on an intermittent basis.
The Committee for Medicinal Products for Human Use (CHMP) of the European Union’s Medicines and Healthcare Products Regulatory Agency (EMA) said it would “assess the impact of these findings on the balance of benefits and risks of Adakveo,” as well as the impact on its conditional approval, which was granted in 2020.
STAND found no benefit over placebo for both Adakveo doses tested – 5 mg/kg and 7.5 mg/kg given as a 30-minute infusion once a month – which Novartis described as “inconsistent with previous trial results” with the drug. Adakveo, an anti-P-selectin antibody, became the first new treatment for VOCs in SCD patients in decades when it was approved for marketing in the EU, just months after the FDA approved it in the US based on the SUSTAIN trial results.
That study found that Adakveo reduced the median annual VOC rate to 1.63 compared to 2.98 for placebo, a 45% reduction regardless of sickle cell disease genotype or whether they were receiving hydroxyurea, a decades-old treatment for SCD. It was also discovered that Adakveo reduced the number of days patients stayed in the hospital by 42%, with 36% of those taking the drug experiencing no VOCs compared to 17% of placebo-treated patients.
Janssen Announces Unblinding of Phase 3 CARTITUDE-4 Study of CARVYKTI
The Janssen Pharmaceutical Companies of Johnson & Johnson announced that the Phase III CARTITUDE-4 study comparing CARVYKTI® (ciltacabtagene autoleucel; cilta-cel) versus pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd) for the treatment of patients with relapsed and lenalidomide-refractory multiple myeloma met its primary endpoint of significant improvement in progression-free survival (PFS) at the first pre-specified interim analysis. As a result of meeting the primary endpoint, the Independent Data Monitoring Committee recommended that the study be unblinded.
“The CARTITUDE-4 study represents the first Phase III program in our comprehensive clinical development strategy for CARVYKTI, and further demonstrates our commitment to advance the treatment of patients with relapsed/refractory multiple myeloma,” said Jordan Schecter, M.D., Vice President, Clinical Development Cellular Therapy Program, Janssen Research & Development, LLC. “We look forward to the presentation of the data from the CARTITUDE-4 study at a future medical meeting.”
CARTITUDE-4 (NCT04181827) is the first randomized Phase III study of CARVYKTI® efficacy and safety. In the study, CARVYKTI® is compared to standard-of-care treatments PVd or DPd in adult patients with relapsed or lenalidomide-refractory multiple myeloma who have received one to three prior lines of therapy. The primary endpoint of the study is PFS; secondary endpoints include safety, overall survival, minimal residual disease negative rate, and overall response rate. Patients enrolled in the CARTITUDE-4 study will be followed for the duration of the study for primary, secondary, and exploratory endpoints. The CARTITUDE-4 study’s findings will be presented at a future scientific conference and shared with health authorities in planned submission applications.
EU Advisors Delivers Negative Opinion on Ipsen’s Rare Disease Drug Palovarotene
Ipsen has suffered a setback in its marathon effort to bring palovarotene to market for the extremely rare disease fibrodysplasia ossificans progressiva (FOP) after EU advisors advised against approval. The European Medicines Agency’s human medicines committee issued a negative opinion on palovarotene, making it very unlikely that the drug will be approved by the European Commission, though Ipsen has stated that it will request a re-examination of the marketing application.
The decision comes after Ipsen was forced to withdraw its marketing application for palovarotene in the United States in 2021, delaying regulatory filings elsewhere, although the French pharmaceutical company has received approval for the drug in Canada, where it is marketed as Sohonos. It refiled in the United States but received a complete response from the FDA in December with a request for more clinical information, further delaying the program, and the CHMP’s decision will further erode confidence in the drug’s prospects.
Palovarotene was acquired by Ipsen as part of its $1 billion upfront acquisition of Clementia Pharma in 2019, but it ran into trouble almost immediately. It failed a futility test in a pivotal trial, and the FDA placed it on a partial clinical hold in 2020 while it investigated a safety signal. Currently, the only treatment available to patients with FOP – a disorder in which bony lesions form in muscles, tendons, and ligaments – is medication to treat symptoms such as pain.
Even if Ipsen eventually gets palovarotene approved in the EU and the US, its advantage over rival FOP therapy developers is dwindling. Among them is Regeneron, whose garetosmab candidate has had its own setbacks, including an FDA clinical hold, but has now advanced to phase III testing. Meanwhile, Ipsen has another FOP candidate in its portfolio thanks to a $535 million agreement signed in 2019 with Blueprint for BLU-782, an ALK2 inhibitor.
NICE Recommends Gilead Sciences and Kite’s Yescarta on NHS in England
Gilead Sciences and Kite, a Gilead company, announced that the National Institute for Health and Care Excellence (NICE) had recommended Yescarta (axicabtagene ciloleucel; axi-cel) for routine NHS commissioning in England for the treatment of some adults with certain types of lymphoma. Yescarta, a CD19-directed genetically modified autologous T-cell immunotherapy investigated in the ZUMA-1 trial, is the first chimeric antigen receptor (CAR) T-cell therapy recommended for routine use on the NHS in England, which means that eligible patients will be able to access CAR-T cell therapy in the long term for the first time.
All adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) who have received two or more systemic therapies will be eligible for the treatment in the third-line setting. DLBCL and PMBCL are both aggressive types of non-Hodgkin lymphoma. Each year, approximately 14K cases of non-Hodgkin lymphoma are diagnosed in the United Kingdom, with approximately 5K cases being DLBCL and 330 being PMBCL. DLBCL has a lower overall survival rate than other blood cancers, with 60% of patients surviving for five years compared to 70% for all blood cancers.
Following initial chemotherapy, up to 45% of DLBCL patients will require a second-line treatment, which frequently includes high-dose chemotherapy and a stem cell transplant. Approximately half of all transplant recipients will eventually relapse. NICE’s most recent decision ensures that patients in the third-line setting will continue to have access to CAR-T cell therapy.
European Commission Approves Daiichi Sankyo and AstraZeneca’s Enhertu for HER2-low Breast Cancer
The European Commission has approved Daiichi Sankyo and AstraZeneca’s Enhertu as the first targeted therapy for HER2-low breast cancer, potentially opening the door to treatment for many patients. With the EU approval, a subset of breast cancer patients who would previously have been deemed to have HER2-negative tumors and thus be excluded from HER2-directed therapy will now have a treatment option.
In Europe, approximately 531K breast cancer patients are diagnosed each year, with approximately 141K deaths, and approximately half of all cases would be classified as HER2-low, with patients having both hormone receptor (HR)-positive and HR-negative disease.
Along with a large patient population, Enhertu (trastuzumab deruxtecan) showed promising results in the DESTINY-Breast04 study, which enrolled patients with HER2-low unresectable, metastatic breast cancer who had received multiple lines of prior treatment and was highlighted at last year’s ASCO congress. Enhertu reduced the risk of disease progression or death by 50% in the 557-patient study while improving overall survival by 36% compared to chemotherapy – translating to an extra half year of life for patients, extending from a median of 16.8 months to 23.4 months.
Last summer, AstraZeneca and Daiichi Sankyo claimed FDA approval for the HER2-low indication in the US, adding to Enhertu’s growing list of indications, including second- and third-line therapy for HER2+ metastatic breast cancer and a second-line therapy for HER2+ metastatic gastric cancer.
The approval is “a significant clinical advance for patients in Europe with both HR-positive and HR-negative disease who previously had limited treatment options in the late-line setting,” according to Daiichi Sankyo’s head of oncology, Ken Keller. “This milestone also supports our vision of bringing Enhertu to more patients across the HER2 spectrum,” he further added.