The US Food and Drug Administration has approved Amjevita® (adalimumab-atto) as a biosimilar to Humira® (adalimumab). In adult patients, Amjevita® is approved for moderately to severely active rheumatoid arthritis; active psoriatic arthritis; active ankylosing spondylitis (an arthritis that affects the spine); moderately to severely active Crohn’s disease; moderately to severely active ulcerative colitis; and moderate to severe plaque psoriasis. Amjevita® is also indicated for moderately to severely active polyarticular juvenile idiopathic arthritis in patients four years of age and older.
Amjevita® is the third antibody-based drug to gain approval as a biosimilar in the US this year. Inflectra® (infliximab-dyyb), a biosimilar to Remicade® (infliximab), was approved in April 2016 and Erelzi® (etanercept-szzs) , a biosimilar to Enbrel® (etanercept), was approved in August 2016.
Antibody-based biosimilar products approved in the EU or US
The number of antibody-based biosimilar therapeutics approved in the European Union or United States is poised to grow substantially in 2016 and 2017. The originator products that target tumor necrosis factor (TNF) have been of particular interest to the biosimilar industry due to the expiration of key patents and the large global markets for the products. In 2013, the three top-selling originator anti-TNF products were infliximab (Remicade®), etanercept (Enbrel®) and adalimumab (Humira®), which combined had global sales of nearly $18 billion that year. The first biosimilar anti-TNF products approved in either the EU or US were Inflectra® and Remsima®, both of which are versions of infliximab. Inflectra® and Remsima® were approved in the EU in September 2013 for rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.
While no antibody-based biosimilar products were approved in either the EU or US in 2014 or 2015, two products have been approved in each of these regions so far in 2016, and more may be approved soon. In the EU, the biosimilar etanercept BENEPALI® was approved in January 2016 for moderate to severe rheumatoid arthritis, psoriatic arthritis, severe ankylosing spondylitis, severe non-radiographic axial spondyloarthritis, and plaque psoriasis, and the biosimilar infliximab Flixabi® was approved in May 2016 for rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. In the US, Inflectra® was approved in April 2016 for the treatment of moderately to moderately to severely active rheumatoid arthritis, severely active Crohn’s disease, moderately to severely active ulcerative colitis, active ankylosing spondylitis, active psoriatic arthritis, chronic severe plaque psoriasis, and the biosimilar etanercept Erelzi® was approved in August 2016 for moderate to severe rheumatoid arthritis, moderate to severe polyarticular juvenile idiopathic arthritis, active psoriatic arthritis, active ankylosing spondylitis, and chronic moderate to severe plaque psoriasis. A biosimilar adalimumab (ABP-501) may be approved soon, as the Food and Drug Administration’s (FDA) Arthritis Advisory Committee voted unanimously to support approval of it in July 2016. The product was recommended for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis in patients aged 4 years and older, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, and plaque psoriasis.
Although the FDA does not release comprehensive lists of products in review, the European Medicines Agency (EMA) does provide limited information on applications for centralized marketing authorization under evaluation. As of August 3, 2016, a total of 6 applications for biosimilar adalimumab (3 applications), etanercept (1 application), and the anti-CD20 rituximab (2 applications) were under evaluation. In late August, EMA also accepted for review a marketing authorization application for a proposed biosimilar trastuzumab, which is used to treat certain HER2-positive breast and gastric cancers. Thus, there may soon be as many as 11 biosimilar antibody-based therapeutics on the market in the EU, and many of these could also gain approval in the US.
Antibodies to watch in 2016: Mid-year update
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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Update on antibodies in regulatory review
A biologics license application (BLA) for romosozumab, an IgG2 monoclonal antibody targeting sclerostin, was recently submitted to the US Food and Drug Administration (FDA). The application includes data from the randomized, double-blind, placebo-controlled Phase 3 FRAME study (NCT01575834) of ~7,200 postmenopausal women with osteoporosis, defined as low bone mineral density at the total hip or femoral neck. The study met the primary endpoint of reduction of the incidence of new vertebral fracture through 12 months in postmenopausal women with osteoporosis treated with romosozumab. The study also evaluated whether romosozumab treatment for 12 months followed by denosumab (Prolia®) treatment for 12 months, compared with placebo followed by denosumab treatment, reduced the risk of new vertebral fractures through 24 months; this endpoint was also met. The effects of romosozumab were compared to teriparatide (FORTEO®), a recombinant form of parathyroid hormone, in the randomized, open-label Phase 3 STRUCTURE study (NCT01796301). In this study, postmenopausal women with osteoporosis transitioning from bisphosphonate treatment who were administered romosozumab demonstrated a statistically significant increase in hip bone mineral density and strength compared with those who received teriparatide.
In other news, the FDA requested the submission of new data and analyses from the MODIFY I (NCT01241552) and MODIFY II (NCT01513239) clinical trials of bezlotoxumab, which has extended the review time on bezlotoxumab by three months, to October 23, 2016. Bezlotoxumab, a human IgG1 mAb that targets Clostridium difficile (C. difficile) toxin B, was evaluated for prevention of C. difficile infection recurrence. MODIFY I was a Phase 3, randomized, double-blind, placebo-controlled, adaptive design study of a single infusion of bezlotoxumab, an anti-C. difficile toxin A human monoclonal antibody (MK-3415, and the combination of bezlotoxumab + MK-3415 in patients receiving antibiotic therapy for C. difficile infection. The Phase 3 MODIFY II study compared only bezlotoxumab and the combination of bezlotoxumab + MK-3415 to placebo in patients receiving antibiotic therapy for C. difficile infection. The primary endpoint, the rate of C. difficile infection recurrence through week 12 compared to placebo, was met in both studies.
The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the European Union and United States. Of the 8 mAbs currently in regulatory review in these regions, 4 have FDA action dates known to occur in late October-December 2016. One additional mAb is likely to have an FDA action date by the end of 2016, based on the date of BLA submission and review status. Please log in to access the table, located in the Members Only section.
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European Medicines Agency’s antibody PRIority MEdicines
On June 1, the European Medicines Agency (EMA) announced that four medicines in development were accepted under their new PRIority MEdicines (PRIME) scheme, which focuses on medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options. In this voluntary scheme, EMA offers early, proactive and enhanced support to developers to optimize the generation of robust data on a medicine’s benefits and risks, and enable accelerated assessment of medicine applications. Early clinical data that shows a medicine has the potential to benefit patients with unmet medical needs must be provided for it to be accepted for PRIME access.
Of the four medicines given PRIME access to date, two, aducanumab and NI-0501, are antibody therapeutics. Aducanumab, which targets amyloid beta, has PRIME access as a treatment of Alzheimer’s disease. The antibody is currently being evaluated in two Phase 3 studies of patients with early Alzheimer’s disease. The primary objective of the studies is to evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment. An estimated 1350 patients will be enrolled in each study. Both studies were initiated in 2015, and have primary completion dates in February 2020.
NI-0501, a human mAb targeting interferon gamma, has PRIME access as a treatment of primary hemophagocytic lymphohistiocytosis (PHL). A Phase 2, open-label, single arm study to explore the safety, tolerability, pharmacokinetics and efficacy of intravenous multiple administrations of NI-0501 in children with PHL is currently recruiting patients. The study was initiated in 2013 and has an estimated enrollment of 10 patients. The primary completion date of the study is December 2016. NI-0501 has orphan drug designations in the European Union and United States. It also has the US Food and Drug Administration’s Breakthrough Therapy Designation, which, like the PRIME scheme, is intended to expedite the development and review of new therapies for serious or life threatening conditions that have shown encouraging early clinical results over available therapies.
Find information about the four medicines accepted under the PRIME scheme here.
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