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Is R&D of antibody therapeutics for non-cancer diseases in decline?

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Although cancer is often the focus of attention, antibody-based drugs are developed and approved for many other indications, such as immune-mediated, neurological, ophthalmic and skeletal disorders, as well as cardiovascular/hemostasis, respiratory and infectious diseases. Antibody therapeutics for diseases other than cancer comprise slightly over half (58%) of all  antibody products granted their first approval in either the US or European Union (EU), and they comprise approximately half (48%) of the late-stage commercial pipeline. [1]

The number of first approvals of antibodies for non-cancer diseases is expected to be especially high in 2018, with 3 already approved in either the US or EU (burosomab, ibalizumab, tildrakizumab) and another 7 that may be approved by the end of the year. Burosumab (burosumab-twza; Crysvita), which targets fibroblast growth factor 23, was approved in the EU and US in February and April 2018, respectively, for X-linked hypophosphatemia. The anti-CD4 product ibalizumab-uiyk (Trogarzo) was first approved in the US in March 2018 for treatment of patients with multi-drug resistant HIV infection. Tildrakizumab-asmn (Ilumya), which targets interleukin-23p19, was approved in the US in March for treatment of moderate-to-severe plaque psoriasis. Antibodies for non-cancer indications that may be approved by the end of the year include three for the prevention of migraine (erenumab, fremanezumab, galcanezumab), two for cardiovascular/hemostasis indications (caplacizumab for the treatment of acquired thrombotic thrombocytopenic purpura; lanadelumab for prevention of hereditary angioedema attacks) and one (emapalumab) for treatment of  primary hemophagocytic lymphohistiocytosis, which is a clinical syndrome of hyperinflammation that is lethal if untreated. In addition, romosozumab, which targets sclerostin, is in review in the EU and US as a treatment for osteoporosis, but the US Food and Drug Administration has requested additional clinical data from Phase 3 studies.

Despite the success of antibodies for non-cancer diseases, the percentage of these molecules entering first-in-human studies has recently declined [Figure 1].

Whereas during 2010-2014 antibodies for non-cancer diseases comprised 46-60% of all antibodies entering clinical study each year, they have comprised a declining percentage in all subsequent years (44%, 37% and 22% in 2015, 2016 and 2017, respectively). It must be noted that there was a substantial increase in the total number of antibody therapeutics entering clinical studies during the 2015-17 (ave. 106/year) compared to 2010-2014 (ave. 64/year). Nevertheless, the number of antibodies for non-cancer diseases that entered studies in 2017 was the lowest (so far) in this decade. One reason for this decline may be the current focus of research on antibodies that modulate immune checkpoints or redirect T cells and on immunoconjugates such as antibody-drug conjugates, which are almost exclusively developed as treatments for cancer. While the number of antibodies for non-cancer diseases in Phase 2 studies (~130) is likely sufficient to replenish the number in Phase 3 studies and regulatory review in the short term,  early-stage studies of more will be needed to sustain the flow of these therapeutics onto the market well into the future.

[1] Kaplon H, Reichert JM. Antibodies to watch in 2018. MAbs. 2018 Feb/Mar;10(2):183-203.

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First approval for tildrakizumab-asmn

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On March 20, 2018, the US Food and Drug Administration (FDA) approved tildrakizumab-asmn (Ilumya) for treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Tildrakizumab, a humanized IgG1 kappa monoclonal antibody, targets IL-23p19 and blocks the interaction of IL-23 with its receptor, thereby inhibiting release of pro-inflammatory cytokines and chemokines.

FDA approval was supported by results from two Phase 3 trials (reSURFACE 1 and 2) in which patients were randomized to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo (2:2:1; reSURFACE 1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2; reSURFACE 2). In these trials, the tildrakizumab 200 mg and 100 mg doses were well tolerated and found to be efficacious compared with placebo and etanercept in the treatment of patients with moderate-to-severe chronic plaque psoriasis. The results of both studies were published in The Lancet in July 2017.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. As of March 23, a total of 3 antibody therapeutics had been granted first approvals in either the US or EU in 2018, and marketing applications for another 8 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.

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First approval for ibalizumab-uiyk

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On March 6, 2018, the US Food and Drug Administration (FDA) approved ibalizumab-uiyk (Trogarzo) for adult patients infected with human immunodeficiency virus (HIV) who were previously treated with multiple HIV medications and whose HIV infections are resistant currently available therapies. Ibalizumab-uiyk, a humanized IgG4 monoclonal antibody, is a CD4 domain 2-directed post-attachment HIV-1 inhibitor. The marketing application was granted Breakthrough Therapy, Fast Track and Priority Review designations, and ibalizumab was granted an orphan drug designation by FDA. Theratechnologies Inc. and TaiMed Biologics, Inc. have an agreement to market and distribute Trogarzo in the US and Canada.

The product is administered intravenously (IV) as a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks after dilution in 250 mL of 0.9% sodium chloride. The safety and efficacy of ibalizumab-uiyk were evaluated in the Phase 3 TMB-301 study (NCT02475629), which was a single arm, multicenter clinical trial conducted in 40 heavily treatment-experienced HIV-infected patients with multidrug resistant HIV-1. At Week 25, viral load <50 was achieved in 43% of patients, while 55% and 48% of patients had a ≥ 1 log10 reduction in viral load and a ≥ 2 log10 reduction in viral load, respectively. The most common adverse reactions reported in at least 5% of subjects were diarrhea, dizziness, nausea, and rash. In total, 292 patients with HIV-1 infection were exposed to ibalizumab-uiyk IV infusion during clinical studies. Additional prescribing information for the drug can be found here.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of March 7, 2018, a total of 2 mAbs have been granted first approvals in either the US or EU in 2018, 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.

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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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