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Antibodies new to the market, and exiting

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On February 23, 2018, Kyowa Hakko Kirin Co. Ltd and its partner Ultragenyx Pharmaceutical Inc. announced that a conditional marketing authorization had been granted in the European Union (EU) for burosumab (Crysvita) as a treatment for X-linked hypophosphatemia in children 1 year of age and older, and adolescents with growing skeletons. Burosumab is a human IgG1 monoclonal antibody that binds to and inhibits the activity of fibroblast growth factor 23, thereby reducing loss of phosphate from the kidney and other metabolic abnormalities, and ameliorating bone changes that are a hallmark of the disease. The marketing approval in the EU is the first for burosumab. A biologics license application is undergoing review by the US Food and Drug Administration (FDA), and an action on the application is expected by April 17, 2018.

On February 27, 2018, Roche announced that emicizumab (Hemlibra®) had been approved in the EU for routine prophylaxis of bleeding episodes in people with hemophilia A with factor VIII inhibitors. Emicizumab, a bispecific IgG4 mAb targeting Factors IXa and X that originated at Chugai Pharmaceutical Co. Ltd., was approved by the FDA on November 16, 2017.

On March 2, 2018, Biogen and AbbVie announced the voluntary worldwide withdrawal of marketing authorizations for ZINBRYTA® (daclizumab) for relapsing multiple sclerosis (MS). The withdrawal coincides with an urgent review by the European Medicines Agency (EMA) of inflammatory brain disorder in 8 patients, and follows a 2017 review by EMA of reports of liver injury. Due to the risk of serious liver damage, EMA limited use of Zinbryta to MS patients who had tried at least two other disease modifying treatments and could not be treated with any other such treatments. ZINBRYTA® had been marketed in the EU, US, Switzerland, Canada and Australia.

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Antibody immune checkpoint modulators in the clinic

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The treatment of cancer via antibody therapeutics that modulate immune responses is the focus of substantial research and development by the biopharmaceutical industry. To date, 6 monoclonal antibodies (mAbs) that function by modulating immune checkpoints have been approved in the US: ipilimumab (anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)); pembrolizumab and nivolumab (anti-programmed death receptor 1 (PD-1)); durvalumab, avelumab, and atezolizumab (anti-programmed death ligand 1 (PD-L1)). Cemiplimab, another anti-PD-1 mAb, is currently undergoing regulatory review. Antibody immune checkpoint modulators can be used to treat many types of cancer,[1] which makes them highly attractive for biopharmaceutical development. For example, the approved products, which target only 3 of the many proteins involved in either stimulating or inhibiting immune responses, are used to treat melanoma, non-small-cell lung cancer, head and neck cancer, Hodgkin’s lymphoma, bladder cancer, gastric/gastroesophageal junction adenocarcinoma, renal cell cancer, hepatocellular cancer, Merkel cell carcinoma and colorectal cancer. [2]

More than 80 antibody immune checkpoint modulators sponsored by commercial firms are in clinical development, and they comprise ~ 24% of the clinical pipeline of antibody therapeutics for cancer. Most are in early development, with 50 and 28 antibody immune checkpoint modulators undergoing evaluation in Phase 1 and Phase 2 clinical studies, respectively. Seven (IBI308, BCD-100, PDR001, tislelizumab, camrelizumab, utomilumab, and tremelimumab) are undergoing evaluation in late-stage studies.[3]

Despite the fact that 5 antibodies targeting the PD-1 pathway are already marketed, PD-1 and PD-L1 remain popular as targets for antibodies in development. Of the antibody immune checkpoint modulators currently in the clinic, 21 molecules target PD-1, including five in late-stage clinical studies, and 9 antibodies target PD-L1. Other popular antigens for antibodies in clinical development include glucocorticoid-induced tumor necrosis factor receptor (GITR; target of 7 antibodies); CD40, LAG-3 and OX40 (each the target of 6 antibodies); as well as T-cell immunoglobulin and mucin-domain-containing molecule (TIM-3), T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and CTLA4 (each the target of 4 antibodies). In addition, two bispecific antibodies (anti-PD-1, LAG-3 MGD013; anti-PD-L1, CTLA-4 AK104) targeting these immune checkpoints are in clinical studies; to avoid double counting, these two were excluded from the totals given above.

Over 100 antibody immune checkpoint modulators have entered commercially sponsored clinical studies since 2000, but ~60% of the molecules first entered such studies in the past 3 years. The ultimate fates (approval or termination) for most of the molecules are thus not yet known, but the available data is sufficient to calculate a Phase 1 to 2 transition rate, which is 74%. This rate compares favorably with that for all antibody therapeutics (75%) and anti-cancer antibody therapeutics (69%). The current data suggest that antibody immune checkpoint modulators, as a group, has a notably higher Phase 2 to 3 transition rate compared with all antibody therapeutics. This result, however, is based on outcomes for relatively few molecules. It should be noted that clinical studies may be terminated for business reasons, as well as safety or efficacy issues. For example, although PD-1 and PD-L1 are well-validated targets, the market for anti-PD-1 and anti-PD-L1 antibodies in the future may not be sufficient to justify continued development of all such antibodies in the current pipeline. Termination of molecules at Phase 2 for business reasons would decrease the Phase 2 to 3 transition rate. To date, no antibody immune checkpoint modulators have been terminated during regulatory review; the transition rate at that phase is thus 100%.

The Antibody Society has partnered with Hanson Wade to track trends in the clinical development of innovative cancer therapies, with a focus on immune checkpoint modulators and antibody-drug conjugates. As the date for ICI Boston 2018 (March 19-21) approaches, Hanson Wade has prepared a comprehensive e-book that provides insights into combination strategies involving immune checkpoint inhibitors, which can be downloaded here. Members of The Antibody Society qualify for a 20% discount to ICI Boston 2018. Please contact us at membership@antibodysociety.org for the code.

  1. Torphy RJ, Schulick RD, Zhu Y. Newly Emerging Immune Checkpoints: Promises for Future Cancer Therapy. Int J Mol Sci. 2017; 18(12). pii: E2642. doi: 10.3390/ijms18122642.
  2. Iwai Y, Hamanishi J, Chamoto K, Honjo T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 2017; 24:26. doi.org/10.1186/s12929-017-0329-9.
  3. Kaplon H, Reichert JM. Antibodies to watch in 2018. MAbs. 2018 Jan 4:1-21. doi: 10.1080/19420862.2018.1415671.

The Antibody Society tracks the progress of commercially sponsored antibody therapeutics in clinical development on a continuous basis. We collect information, including molecular composition (e.g., format, isotype, target), phase of development and indications studied, from publicly available sources (e.g., press releases, company websites, meeting abstracts, published literature, clinicaltrials.gov, regulatory agency websites). Our data are cross-checked against databases generously provided by our corporate partners, including Hanson Wade’s Beacon Targeted Therapies and the Therapeutic Antibody Database. It should be noted that companies may not publicly disclose all information for all molecules in the pipeline, especially those in the early stages of development. The numbers of molecules discussed above should thus be considered minimums, as targets have not been disclosed for all the molecules we are tracking. We look forward to reporting additional trends and metrics for antibody therapeutics development in the future.

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Antibodies to watch in 2018

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The pace of antibody therapeutics development accelerated in 2017, and this faster pace is projected to continue through 2018. Notably, the annual number of antibody therapeutics granted a first approval in either the European Union (EU) or United States (US) reached double-digits (total of 10) for the first time in 2017. The 10 antibodies granted approvals are: brodalumab, dupilumab, sarilumab, guselkumab, benralizumab, ocrelizumab, inotuzumab ozogamicin, avelumab, duvalumab, and emicizumab. Brodalumab, however, had already been approved in Japan in 2016.
As of mid-December 2017, 10 antibody therapeutics (ibalizumab, burosumab, tildrakizumab, caplacizumab, erenumab, fremanezumab, galcanezumab, romosozumab, mogamulizumab, cemiplimab) were in regulatory review in the EU or US, and regulatory actions on their marketing applications are expected by the end of 2018.
Based on company announcements and estimated clinical study primary completion dates, and assuming the study results are positive, marketing applications for at least 13 antibody therapeutics that are now being evaluated in late-stage clinical studies may be submitted by the end of 2018. Of the 13 candidates, 8 are for non-cancer indications (lanadelumab, crizanlizumab, ravulizumab, eptinezumab, risankizumab, satralizumab, brolucizumab, PRO140) and 5 are for cancer (sacituzumab govitecan, moxetumomab pasudotox, cemiplimab, ublituximab, isatuximab).
Additional antibody therapeutics to watch in 2018 include 19 mAbs undergoing evaluation in late-stage studies with primary completion dates in late 2017 or during 2018. Of these mAbs, 9 are for non-cancer indications (lampalizumab, roledumab, emapalumab, fasinumab, tanezumab, etrolizumab, NEOD001, gantenerumab, anifrolumab) and 10 are for cancer indications (tremelimumab, isatuximab, BCD-100, carotuximab, camrelizumab, IBI308, glembatumumab vedotin, mirvetuximab soravtansine, oportuzumab monatox, L19IL2/L19TNF). Positive clinical study results may enable marketing application submissions in 2018. Brief summaries of these antibody therapeutics are provided in the ‘Antibodies to watch in 2018’ article, which is now available on the mAbs website. A PDF of this open-access article is available here.

Emicizumab granted FDA approval

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Emicizumab (Hemlibra, emicizumab-kxwh, ACE910, RO5534262), a bispecific IgG4 mAb targeting Factors IXa and X, was approved by the FDA on November 16, 2017. The drug, which is administered once a week, was approved to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed Factor VIII inhibitors. The biologics license application was granted Priority Review and a Breakthrough Therapy designation. Hemlibra was also granted an orphan drug designation by the FDA.

Marketing applications for emicizumab are under review in the European Union and Japan; the European Medicines Agency is reviewing the marketing authorization application under accelerated assessment. Emicizumab was granted an orphan drug designation in Japan for the prevention and reduction of bleeding episodes in patients with congenital factor VIII deficiency with inhibitors. The drug was created by Chugai Pharmaceutical Co., Ltd. and co-developed by Chugai, Roche and Genentech.

The marketing applications for emicizumab include results from the Phase 3 HAVEN 1 (NCT02622321) study and interim analysis of the HAVEN 2 (NCT02795767) study. In the HAVEN 1 study, adult and adolescent patients (12 or older) who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point of the study was the difference in bleeding rates between Group A and Group B. Emicizumab was administered subcutaneously at a dose of 3 milligrams per kilogram per week (mg/kg/week) for 4 weeks followed by 1.5 mg/kg/week up to the end of the study. The annualized bleeding rate in Group A was reduced by 87% compared to Group B (2.9 events vs 23.3 events, P<0.001). [1] The HAVEN 2 study is evaluating the efficacy, safety, and pharmacokinetics of subcutaneous administration of emicizumab in hemophilia A pediatric patients with inhibitors.

1. Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, Santagostino E, Kruse-Jarres R, Negrier C, Kessler C, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809-818. doi: 10.1056/NEJMoa1703068.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of November 16, 2017, a total of 10 mAbs have been granted first approvals in either the US or EU in 2017, and marketing applications for a total of 9 antibody therapeutics that have not yet been approved in either the EU or US are undergoing review in these regions.

Please log in to access the table, located in the Members Only section.

Not a member? Please join! Membership is free for students and employees of the Society’s corporate sponsors.

Benralizumab granted FDA approval

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On November 14, 2017, AstraZeneca announced that benralizumab (Fasenra), an afucosylated IgG1 mab targeting the alpha subunit of IL-5R found on eosinophils, received a US Food and Drug Administration approval for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. The European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a positive opinion on November 10, 2017, recommending the marketing authorization of benralizumab as an add-on maintenance treatment in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus long-acting b-agonists. The European Commission’s decision regarding marketing authorization in the EU is pending. Marketing applications for benralizumab are undergoing review in Japan and other countries. The mAb was in-licensed from BioWa, Inc., a wholly-owned subsidiary of Kyowa Hakko Kirin Co., Ltd. by MedImmune.

The safety and efficacy of benralizumab as a treatment for asthma were evaluated in the WINDWARD program, which included six Phase 3 trials, SIROCCO, CALIMA, ZONDA, BISE, BORA and GREGALE. The randomized, double-blinded, parallel-group, placebo-controlled SIROCCO (NCT01928771) and CALIMA (NCT01914757) trials evaluated the efficacy and safety of a regular, subcutaneous administration of a fixed 30 mg dose of benralizumab for up to 56 weeks in exacerbation-prone adult and adolescent patients 12 years of age and older. Study results were published in 2016. [1, 2] In the 28-week randomized ZONDA study (NCT02075255), the effects of 30 mg benralizumab administered subcutaneously either every 4 weeks or every 8 weeks (with the first three doses administered every 4 weeks) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The study’s primary outcome measure, percentage reduction in final oral steroid dose compared with baseline while maintaining asthma control, was met. The median final oral glucocorticoid doses from baseline were reduced by 75% in patients who received either dose of benralizumab,  compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). [3]

  1. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, Sproule S, Gilmartin G, Aurivillius M, Werkström V, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016; pii: S0140-6736(16)31324-1. doi: 10.1016/S0140-6736(16)31324-1.
  2. FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse WW, Barker P, Sproule S, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; pii: S0140-6736(16)31322-8. doi: 10.1016/S0140-6736(16)31322-8.
  3. Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, Barker P, Sproule S, Ponnarambil S, Goldman M; ZONDA Trial Investigators. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017;376(25):2448-2458. doi: 10.1056/NEJMoa1703501.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of November 15, 2017, a total of 9 mAbs have been granted first approvals in either the US or EU in 2017, and marketing applications for a total of 10 antibody therapeutics that have not yet been approved in either the EU or US are undergoing review in these regions.

Please log in to access the table, located in the Members Only section.

Not a member? Please join! Membership is free for students and employees of the Society’s corporate sponsors.