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Mogamulizumab enters EU regulatory review

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Mogamulizumab (KW-0761, Poteligeo®), is an IgG1 afucosylated humanized monoclonal antibody targeting CC chemokine receptor 4 (CCR4) expressed on tumor cells of patients with cutaneous T-cell leukemia lymphoma (CTCL), including mycosis fungoides and Sézary syndrome. Afucosylation enhances the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of the mAb. Mogamulizumab was initially approved in Japan in March 2012 for the treatment of patients with relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma (ATL), and then granted marketing authorization in Japan for the treatment of patients with relapsed or refractory CCR4-positive, peripheral T-cell lymphoma (PTCL) and CTCL in March 2014, and with chemotherapy-naive CCR4-positive ATL in December 2014.

In October 2017, Kyowa Hakko Kirin announced that a marketing authorization application (MAA) for mogamulizumab, for the treatment of CTCL in adults who have received at least one prior systemic therapy, is under review at the European Medicines Agency. The MAA includes data from the randomized, open-label, multi-center Phase 3 MAVORIC study (NCT01728805), which evaluated the effects of mogamulizumab versus vorinostat (Zolinza®) in patients with refractory cutaneous T cell lymphoma who failed previous treatment. The study included 372 patients who were randomized to receive either mogamulizumab (1.0 mg/kg weekly x 4 in cycle 1, then every other week until progression) or vorinostat (400 mg orally daily). The primary outcome measure of the study was progression-free survival (PFS), with the target being a 50% improvement over the reference median PFS for vorinostat (median PFS of 254 days for the mogamulizumab arm versus 169 days for the vorinostat arm). In April 2017, Kyowa Hakko Kirin announced top-line results from the MAVORIC study indicating the primary endpoint of PFS had been met. In August 2017, mogamulizumab received breakthrough therapy designation in the US for mycosis fungoides and Sézary syndrome based on results from the MAVORIC study.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of November 10, 2017, marketing applications for a total of 11 antibody therapeutics that have not yet been approved in either the EU or US are undergoing review in these regions.

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Back in business: gemtuzumab ozogamicin

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Roughly 17 years ago gemtuzumab ozogamicin was first approved by the FDA for the treatment of patients over the age of 60 with CD33-positive relapsed acute myelogenous leukemia (AML), and who were not considered candidates for other cytotoxic chemotherapy.

The drug, also known as Mylotarg, was the result of a long-lasting collaboration between Wyeth (acquired by Pfizer in 2009) and CellTech (acquired by UCB in 2004), dating all the way back to 1991. Nine years later it was approved as a single agent under an “accelerated” approval based on the surrogate response rate endpoint that was observed in 142 patients with AML across 3 clinical trials. The approval made Mylotarg the first ADC to hit the US market at the time.

However, things turned quickly for the product. One year into its approval it required a black box packaging warning related to the increased risk of veno-occlusive disease. Initially, the warning was aimed at patients who did not receive bone marrow transplantation, but later the increased frequency of veno-occlusive disease was also observed in Gemtuzumab-treated patients after bone marrow transplantation.

A confirmatory, post-approval clinical trial commenced in 2004, per FDA guidelines for accelerated approval. Results of the randomized Phase 3 SWOG S0106 trial showed a significantly higher fatal induction toxicity rate in gemtuzumab combination therapy group versus the control group receiving only chemotherapy (16/283 = 5.7% versus 4/281 = 1.4%; p =  0.01).

Following the results of SWOG S0106 and the post-marketing experience with the drug, Pfizer decided to withdraw Mylotarg from the market in 2010 at the request of the FDA. The discontinuation was an upset in the ADC field. Upon the withdrawal brentuximab vedotin and trastuzumab emtansine were the only two approved ADCs for years to come. However, the potential of ADC therapeutics has seen a revival and around 60-70 products are in clinical trials at the moment.

Not only the ADC field itself bounced back after this blow, but also gemtuzumab ozogamicin made a recent comeback. Early this year Pfizer resubmitted Mylotarg for regulatory review and both the FDA and the EMA accepted to review the application based on added data from the Phase 3 randomized, open-label ALFA-0701 trial. In this study Mylotarg was evaluated as an addition to the standard induction chemotherapy using an alternative fractionated dosing schedule in 280 adult, de novo, AML patients between 50 and 70 years old. Additionally, a meta-analysis of patient-level data from over 3000 patients in five randomized Phase 3 trials were evaluated.

Now, seven years after discontinuation, gemtuzumab ozogamicin is back in business in the US. The FDA has approved the lower recommended dosage range and the alternative treatment schedule. The authorization now covers single uses or in combination with chemotherapy in a patient population that now also includes adults with newly diagnosed CD33-positive AML, and adults and children 2 years and older with relapsed or refractory CD33-positive AML.

First approval for guselkumab

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On July 13, 2017, the Food and Drug Administration (FDA) approved the biologics license application for guselkumab (TREMFYA). The product, a human IgG1 monoclonal antibody targeting interleukin-23, is indicated for the treatment of patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Approval was based on results from a clinical development program that included more than 2,000 patients in the Phase 3 VOYAGE 1, VOYAGE 2 and NAVIGATE studies. Guselkumab was generated using MorphoSys’ Human Combinatorial Antibody Library technology.

As of July 13, guselkumab is the eighth antibody therapeutic to be granted a first marketing approval in any country in 2017, following the approvals of brodalumab, avelumab, ocrelizumab, dupilumab, durvalumab, sarilumab and inotuzumab ozogamicin. The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of July 13, 2017, marketing applications for a total of nine antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, a marketing application for the antibody-drug conjugate gemtuzumab ozogamicin, which was approved in 2000 by the US FDA and subsequently withdrawn from the US market, is undergoing review in the EU and US.

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The source infix is out!

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The World Health Organization (WHO) issues International Nonproprietary Names (INN) for therapeutic antibodies. These INNs contain the suffix –mab preceded by a source (or species) infix such as -xi- for chimeric, -zu- for humanized and -u- for human antibodies. Changes in definitions and procedures, which WHO implemented in 2014, resulted in INN with inconsistent source designations for an array of chimeric and humanized antibodies. Discussions spearheaded by The Antibody Society have now led to a resolution of the issue. At the 64th Consultation on INN held in April 2017, the WHO INN expert group decided to eliminate the source infix. Although the change was officially announced today, WHO implemented the changes promptly and applicants have already received INN issued under the new naming scheme, i.e., without an INN source infix. The Antibody Society board members Paul W.H.I. Parren, Paul J. Carter and Andreas Plückthun provide analysis and more information in a Perspective article that will be published in the upcoming August/September 2017 issue of mAbs. Society members will be alerted by email when this article is available for downloading from the ‘Latest Articles’ section of the mAbs website.

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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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