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Updates on sarilumab, erenumab, romosozumab and XBiotech’s candidate antibody

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On May 22, 2017, the Food and Drug Administration (FDA) granted an approval for sarilumab (Kevzara) for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease modifying antirheumatic drugs, such as methotrexate (MTX). Sarilumab is a human monoclonal antibody (mAb) that targets interleukin-6 receptor (IL-6R), and has been shown to inhibit IL-6R-mediated signaling. Sarilumab was first approved on January 12, 2017 for the treatment of adult patients with moderately to severely active RA by Health Canada.

On May 18, 2017, Amgen announced that a biologics license application (BLA) for erenumab was submitted to the FDA. Erenumab is a human mAb targeting calcitonin gene-related peptide receptor. The BLA includes data from pivotal studies investigating the efficacy of erenumab versus placebo in reducing the number of migraine days for patients with episodic and chronic migraine.

On May 21, 2017, Amgen and UCB announced that the Phase 3 ARCH (Active-contRolled FraCture Study in Postmenopausal Women with Osteoporosis at High Risk of Fracture) study of romosozumab in postmenopausal women with osteoporosis at high risk for fracture based on previous fracture history met both primary endpoints and the key secondary endpoint. At the primary analysis, treatment with romosozumab for 12 months followed by alendronate significantly reduced the incidence of new vertebral fractures through 24 months, clinical fractures (primary endpoints) and non-vertebral fractures (key secondary endpoint) in postmenopausal women with osteoporosis at high risk for fracture, compared to alendronate alone. An imbalance in positively adjudicated cardiovascular serious adverse events was observed as a new safety signal (2.5% romosozumab vs 1.9% alendronate at 12 months). Overall adverse events and serious adverse events were generally similar between the treatment groups throughout the ARCH study and also in the initial 12-month romosozumab treatment period. No imbalance in cardiovascular serious adverse events was seen in the 7,180-patient placebo-controlled FRAME (FRActure study in postmenopausal woMen with ostEoporosis) study. Regulatory submissions for romosozumab based on the FRAME study results are currently under review with the FDA, Health Canada and the Pharmaceuticals and Medical Devices Agency in Japan. Amgen has agreed with the FDA that the ARCH data should be considered in the regulatory review prior to the initial marketing authorization, and as a result Amgen does not expect approval of romosozumab in the US to occur in 2017.  Amgen has indicated that engagement with PMDA and Health Canada will occur as part of the ongoing review process, and preparation for the European regulatory submission will continue as planned.

On May 18, 2017, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorization for human IgG1 monoclonal antibody specific for human interleukin-1 alpha XBiotech, intended for treating debilitating symptoms of advanced colorectal cancer. CHMP opinion was based on data from a study in 333 patients that evaluated the effects of the mAb vs placebo on lean body mass and quality of life. The committee noted that the study did not show clear improvements in either lean body mass or quality of life, and there was an increased risk of infection in patients taking the medicine, which was not considered acceptable in vulnerable patients who will be receiving palliative care. There were also inadequate controls of the manufacturing process to ensure the medicine would have the same quality as the product used in clinical trials. Therefore, the CHMP was of the opinion that the benefits of this medicine did not outweigh its risks. The EMA marketing authorization application procedure includes an appeal process. XBiotech Inc. has indicated that they may seek access to this process at the appropriate time.

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First approval for durvalumab

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On May 1, 2017, the US Food and Drug Administration (FDA) granted an approval to the anti-PD-L1 antibody durvalumab (IMFINZI) for the treatment of patients with urothelial carcinoma, and FDA approved a complementary diagnostic, the VENTANA PD-L1 assay, for assessment of PD-L1 protein in suitably prepared urothelial carcinoma tissue. Durvalumab’s license application received accelerated approval, priority review, and Breakthrough Therapy Designation from FDA. The approval was based on one single-arm trial of 182 patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after prior platinum-containing chemotherapy. An ongoing clinical trial to confirm the clinical benefit of durvalumab must be completed to fulfill the conditions of the accelerated approval.
Durvalumab is the sixth antibody therapeutic to be granted a first marketing approval in any country so far in 2017, and the second human IgG1 anti-PD-L1 antibody therapeutic to be approved by FDA in 2017, following the approval of avelumab (Bavencio) for Merkel cell carcinoma in March 2017. It is also the second anti-PD-L1 antibody therapeutic to be granted an approval for urothelial carcinoma, following FDA’s approval of atezolizumab (Tecentriq) in May 2016.
The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of May 1, 2017, marketing applications for a total of 9 antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, marketing applications for sarilumab, which is approved in Canada, and gemtuzumab ozogamicin, which was FDA approved in 2000 and subsequently withdrawn from the US market, are undergoing review in the EU and US.

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First approvals for ocrelizumab and dupilumab

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On March 28, 2017, the US Food and Drug Administration (FDA) granted first approvals for two monoclonal antibody (mAb) therapeutics, ocrelizumab (OCREVUS) and dupilumab (Dupixent®). Ocrelizumab is indicated for relapsing multiple sclerosis (MS) and primary progressive multiple sclerosis (PPMS), while dupilumab is a treatment for adults with moderate-to-severe eczema (atopic dermatitis).

Ocrelizumab (OCREVUS), a humanized IgG1 mAb targeting CD20, is the first drug approved by the FDA for PPMS. Ocrelizumab was granted FDA’s Breakthrough Therapy and Fast Track designations, and its application received priority review. A marketing application for ocrelizumab for the treatment of relapsing multiple sclerosis and primary progressive multiple sclerosis (MS) is being reviewed by the European Medicines Agency. The marketing applications are based on positive results from three Phase 3 studies, OPERA I (NCT01247324), OPERA II (NCT01412333), and ORATORIO (NCT01194570). Identical in their study design, OPERA I and OPERA II evaluated the efficacy and safety of 600 mg ocrelizumab intravenously (IV) administered every six months compared with 44 mg interferon beta-1a (Rebif®) subcutaneously administered 3 times per week in 1,656 people with relapsing forms of MS. Compared with Rebif®, ocrelizumab showed superior efficacy in reducing annualized relapse rates and disability progression sustained for at least three and for at least six months. The ORATORIO study evaluated the efficacy and safety of 600 mg ocrelizumab administered by IV infusion every six months compared with placebo in 732 people with primary progressive MS. Compared to patients who received placebo, patients who received ocrelizumab in this study showed significant reductions in disability progression sustained for at least three and for at least six months, as well as in other measures of progressive disease.

Dupilumab (Dupixent®), an anti-IL-4Ra IgG4 mAb, was granted Breakthrough Therapy designation for moderate-to-severe atopic dermatitis, and the biologics license application was granted a priority review by FDA. The safety and efficacy of Dupixent were established in three placebo-controlled clinical trials with a total of 2,119 adults with moderate-to-severe atopic dermatitis not adequately controlled by topical medication(s). A marketing application for dupilumab is being reviewed by the European Medicines Agency.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of March 28, 2017, marketing applications for a total of 10 antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, marketing applications for sarilumab, which is approved in Canada, and gemtuzumab ozogamicin, which was FDA approved in 2000 and subsequently withdrawn from the US market, are undergoing review in the EU and US.

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Avelumab granted first approval

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On March 23, 2017, avelumab (Bavencio), an anti-PD-L1 human IgG1 mAb, was approved by the Food and Drug Administration (FDA) for treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma, which is a rare form of skin cancer. Avelumab was granted an accelerated approval, which FDA can grant for drugs for serious conditions to fill an unmet medical need using clinical trial data that is thought to predict a clinical benefit to patients. Under such an approval, additional clinical trials are required to confirm the clinical benefit. The biologics license application was granted Priority review and Breakthrough Therapy designation by FDA. Avelumab was granted a US orphan drug designation for Merkel cell carcinoma, which is diagnosed in ~ 1,600 people in the US every year. A marketing application for avelumab is undergoing evaluation by the European Medicines Agency, which also granted avelumab an orphan drug designation. The marketing applications for avelumab are based on data from the Phase 2 JAVELIN Merkel 200 study (NCT02155647), which demonstrated meaningful tumor responses in patients with metastatic disease that progressed after prior chemotherapy. Avelumab is also undergoing evaluation in Phase 3 studies of patients with other types of cancers, including non-small cell lung, renal cell, ovarian, gastric, breast and urothelial cancers.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of March 23, 2017, marketing applications for a total of 11 antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, marketing applications for sarilumab, which is approved in Canada, and gemtuzumab ozogamicin, which was FDA approved in 2000 and subsequently withdrawn from the US market, are undergoing review in the EU and US.

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FDA approves brodalumab

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On February 15, 2017, the US Food and Drug Administration approved brodalumab (Siliq; Valent Pharmaceuticals International, Inc.) to treat adults with moderate-to-severe plaque psoriasis. Brodalumab, an IgG2 monoclonal antibody targeting the interleukin (IL)-17 receptor, inhibits the biological activity of IL-17A, IL-17F and other IL-17s. Labeling for brodalumab includes a Black Box Warning for the risks of suicidal thoughts or behavior. The product was approved with a Risk Evaluation and Mitigation Strategy (REMS) that includes prescriber and pharmacy certifications and informed consent by patients.

Brodalumab was granted its first marketing approval from the Ministry of Health, Labour and Welfare in Japan on July 4, 2016 for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, and psoriatic erythroderma. The product’s brand name in Japan is Lumicef®. A marketing authorization application for brodalumab in psoriasis is undergoing evaluation by the European Medicines Agency.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of February 16, 2017, marketing applications for a total of 12 antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, marketing applications for sarilumab, which is approved in Canada, and gemtuzumab ozogamicin, which was FDA approved in 2000 and subsequently withdrawn from the US market, are undergoing review in the EU and US.

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