Since 2010, the “Antibodies to watch” article series has documented annually the number and identities of commercially sponsored antibody therapeutics in Phase 3 studies, regulatory review and those recently approved in the US and EU. Taken together, the articles have captured the extraordinary doubling of the number of antibody therapeutics in Phase 3 studies from 26 to 53, as identified in the “Antibodies to watch in 2010” and “Antibodies to watch in 2016” articles, respectively. Due to the highly dynamic nature of antibody therapeutics development, numerous transitions have occurred during 2016, and the Society offers here a mid-year update to data reported in the “Antibodies to watch in 2016” article.

As described in our previous posts, 4 antibody therapeutics (atezolizumab, reslizumab, ixekizumab, obiltoxaximab) were granted first marketing authorizations in either the US or EU during January to June 2016. As of mid-2016, marketing applications for 8 antibody therapeutics are being considered for first approvals in the US or EU. Of these, 5 applications (olaratuzumab, bezlotoxumab, sarilumab, brodalumab, ocrelizumab) have Food and Drug Administration action dates during September -December 2016. Recommendations by the European Medicines Agency on applications for Xilonix and inotuzumab ozogamicin could be made in 2016, but additional time would be needed for the European Commission’s decision regarding whether to grant the marketing authorization. It thus remains to be seen whether the number of antibody therapeutics approved in the US or EU during 2016 will match or exceed the record of 9 approvals granted in a single year set in 2015.

As of mid-2016, 53 unique antibody therapeutics were in Phase 3 studies. This is the same total number noted in the “Antibodies to watch in 2016” article, but the antibodies included in the totals are not all the same. The tables included in this mid-year update result from the addition of antibodies that started a first Phase 3 study in late 2015 to mid-2016, and deletion of antibodies that transitioned to regulatory review, reverted to an earlier clinical phase or had their development suspended or terminated. Compared to the totals included in the “Antibodies to watch in 2016” article, the number of antibodies in Phase 3 studies for cancer indications as of mid-2016 decreased slightly (from 17 to 15, respectively), while those for non-cancer indications increased slightly (from 36 to 38, respectively).

Antibodies for cancer represent only 28% of the current commercial Phase 3 pipeline, although they are ~55% of the overall clinical pipeline of therapeutic antibodies. The 15 antibody therapeutics in Phase 3 studies for cancer indications are notable for the diversity in their composition. Of the 15, 6 (40%) are non-canonical antibodies (1 radiolabeled antibody, 1 scFv-containing liposome, 2 immunotoxins, 2 antibody-drug conjugates (ADCs)), and a majority of the canonical antibodies (i.e., full-length IgG1, 2 or 4) are Fc- or glyco-engineered to enhance functionality. The 2 ADCs now in Phase 3 studies represent a vanguard, as this type of antibody therapeutic has entered clinical studies in large numbers only recently. Of the ADCs currently in clinical studies, most (44/56, 79%) are in either Phase 1 or Phase 1/2 studies, and most (55/56) are for cancer indications. ADCs now comprise ~20% of the clinical pipeline of antibodies for cancer, but ~11% of all antibodies in clinical development. There is substantial diversity of the targets, drugs, linkers, and drug-to-antibody ratios of the ADCs in the clinic. For example, of the ADCs in the clinic, targets for 51 have been disclosed, and 39 of these 51 targets are unique, i.e., only one ADC in clinical studies is known to target that particular antigen. Antigens known to be the target of more than one ADC in clinical studies include CD19, CD37, EGFR, HER2 and mesothelin. The diversity of the molecules may initially serve as a hindrance, but knowledge gained by the development of this class of molecules should increase overall as more ADCs enter clinical studies, transition through the phases and join the two ADCs currently on the market, brentuximab vedotin (Adcetris®) and ado-trastuzumab vedotin (Kadcyla®).

Antibodies for non-cancer indications dominate the current commercial Phase 3 pipeline. Unlike the antibodies for cancer, the 38 antibodies in Phase 3 studies for non-cancer indications are mostly canonical full-length IgG1, 2 or 4 molecules. Only 4 of the 38 (~11%) are non-canonical molecules: 1 bispecific antibody and 3 antibody ‘fragments’ (scFv, Fab, nanobody). Like ADCs, bispecific antibodies are expected to comprise a larger percentage of the Phase 3 pipeline in the next ~6-8 years. Bispecific antibodies now comprise ~9% of the entire commercial pipeline of antibody therapeutics, but most (32/45, 71%) of those are currently in early clinical studies (either Phase 1 or Phase 1/2). Compared to ADCs, bispecific antibodies are undergoing evaluation in a broader range of indications, although the majority of bispecifics (30/45, 67%) are for cancer and they comprise ~11% of the clinical pipeline of antibodies for cancer. The two bispecific antibodies now on the market, catumaxomab (Removab®) and blinatumomab (BLINCYTO®), are both for cancer. Nevertheless, the one bispecific antibody now in Phase 3 studies, emicizumab, is for a non-cancer indication (hemophilia A).

The clinical pipeline of antibody therapeutics, including at Phase 3, is highly dynamic. The Antibody Society will continue to track antibodies in the clinic, and report progress to its members.

Acknowledgements: The Antibody Society thanks Hanson Wade for access to the Beacon ADC database.

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