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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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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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Update on antibody therapeutics in late-stage clinical studies

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Five monoclonal antibody (mAb) therapeutics have recently transitioned into late-stage clinical studies. Three (utomilumab, isatuximab, SHR-1210) are being evaluated as treatments for cancer, and the effects of two (crizanlizumab, olokizumab) are being studied in patients with other disorders.  Utomilumab (PF-05082566) is a human IgG2 antibody agonist that targets the extracellular domain of 4-1BB (CD137), which is a co-stimulatory receptor expressed on activated T cells. In preclinical studies, Fisher et al (1) demonstrated that utomilumab can activate NF-κB and induce downstream cytokine production, promote leukocyte proliferation, and inhibit tumor growth in a xenograft tumor model. Utomilumab is included in a multi-center, international, randomized, open label, 2-component (Phase 1b followed by Phase 3), parallel-arm study (Javelin DLBCL; NCT02951156) of avelumab in combination with various agents for the treatment of relapsed/refractory diffuse large B-cell lymphoma. The study includes a total of 5 arms (A: avelumab/utomilumab/rituximab; B: avelumab/utomilumab/azacitidine; C: avelumab/rituximab/bendamustine; D: selected regimen from Phase 1b component, which may be the agents investigated in study arms A or B or C; E: investigator’s choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin). Progression-free survival is the primary outcome measure of the Phase 3 component of the study, which has an estimated primary completion date of February 2021.

Isatuximab (SAR650984), a humanized anti-CD38 IgG1 mAb, is undergoing evaluation in a Phase 3 randomized, open-label, multicenter study (ICARIA-MM; NCT02990338) comparing the mAb in combination with pomalidomide and low-dose dexamethasone vs. pomalidomide and low-dose dexamethasone in patients with refractory or relapsed and refractory multiple myeloma. Jiang et al (2) demonstrated that isatuximab utilizes multiple mechanisms of action in mediating multiple myeloma cell cytotoxicity, and that pomalidomide augments this cytotoxicity. Progression-free survival is the primary outcome measure of the Phase 3 study, which has an estimated primary completion date of May 2018.

SHR-1210 is a humanized IgG4 antibody targeting programmed death-1. A randomized controlled multi-center Phase 2/3 study (NCT02989922) to evaluate SHR-1210 in patients with advanced hepatocellular carcinoma who failed or intolerable to prior systemic treatment is currently recruiting patients. The study will assess whether SHR-1210 treatment improves objective response rate and overall survival compared with the standard of care. The estimated primary completion date of the study is December 2018.

Crizanlizumab (SEG101, SelG1) is a humanized IgG2 P-selectin (CD62) inhibitor undergoing evaluation for prevention or reduction of the occurrence of pain crises in patients with sickle cell disease. Results from the Phase 2 SUSTAIN study (NCT01895361) showed that crizanlizumab administered at 5.0 mg/kg intravenously 14 times over a period of 52 weeks reduced the median annual rate of sickle cell-related pain crises by 45.3% compared to placebo (1.63 vs 2.98, p=0.010) (3). The median time to the first crisis was significantly longer in patients who received crizanlizumab compared with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). Crizanlizumab is listed as in Phase 3, with a planned filing date of 2020, in the Novartis Annual Report 2016.

Olokizumab, an anti-interleukin-6 humanized IgG4 mAb (4), is undergoing evaluation in three Phase 3 studies evaluating two doses of olokizumab (64 mg subcutaneous every 2 or 4 weeks) in patients with rheumatoid arthritis (RA). The primary outcome measures are the ACR20 response at Week 14. The Phase 3 NCT02760368 study (CREDO 1) will determine how safe and effective olokizumab is compared to placebo in RA patients who are already receiving, but not fully responding to, treatment with methotrexate. The study’s estimated primary completion date is May 2018. In study NCT02760407 (CREDO 2), the effectiveness and safety of olokizumab is being compared to placebo and adalimumab in RA patients who are taking methotrexate but have active disease. The study’s estimated primary completion date is January 2019. In study NCT02760433 (CREDO 3), the effects of olokizumab are being compared to placebo in patients with RA who are already receiving, but not fully responding to treatment with a tumor necrosis factor inhibitor (CREDO 3). The study’s estimated primary completion date is February 2019. Olokizumab, formerly known as CDP-6038, is under development by R-Pharm under a worldwide exclusive license from UCB Pharma S.A.

The Antibody Society maintains comprehensive tables that list mAbs in late-stage clinical studies (i.e., pivotal Phase 2, Phase 2/3 or Phase 3) for cancer and non-cancer indications. These tables are updated versions of Tables 3 and 4 in the article ‘Antibodies to watch in 2017’.  The tables will be updated with new information about antibody therapeutics that enter late-stage studies as the information is made available during the year. Information in bold was added during 2017. Antibody therapeutics that transition from late-stage studies to regulatory review are listed with the ‘Approved antibodies’ in the Members Only section of The Antibody Society’s website.

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1.       Fisher TS, et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol Immunother. 2012; 61(10):1721-33.

2.       Jiang H, et al. SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia. 2016; 30(2):399-408.

3.       Ataga KI, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017; 376(5):429-439.

4.       Shaw S, et al. Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling. MAbs. 2014; 6(3):774-82.