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.
Mogamulizumab enters EU regulatory review
Mogamulizumab (KW-0761, Poteligeo®), is an IgG1 afucosylated humanized monoclonal antibody targeting CC chemokine receptor 4 (CCR4) expressed on tumor cells of patients with cutaneous T-cell leukemia lymphoma (CTCL), including mycosis fungoides and Sézary syndrome. Afucosylation enhances the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of the mAb. Mogamulizumab was initially approved in Japan in March 2012 for the treatment of patients with relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma (ATL), and then granted marketing authorization in Japan for the treatment of patients with relapsed or refractory CCR4-positive, peripheral T-cell lymphoma (PTCL) and CTCL in March 2014, and with chemotherapy-naive CCR4-positive ATL in December 2014.
In October 2017, Kyowa Hakko Kirin announced that a marketing authorization application (MAA) for mogamulizumab, for the treatment of CTCL in adults who have received at least one prior systemic therapy, is under review at the European Medicines Agency. The MAA includes data from the randomized, open-label, multi-center Phase 3 MAVORIC study (NCT01728805), which evaluated the effects of mogamulizumab versus vorinostat (Zolinza®) in patients with refractory cutaneous T cell lymphoma who failed previous treatment. The study included 372 patients who were randomized to receive either mogamulizumab (1.0 mg/kg weekly x 4 in cycle 1, then every other week until progression) or vorinostat (400 mg orally daily). The primary outcome measure of the study was progression-free survival (PFS), with the target being a 50% improvement over the reference median PFS for vorinostat (median PFS of 254 days for the mogamulizumab arm versus 169 days for the vorinostat arm). In April 2017, Kyowa Hakko Kirin announced top-line results from the MAVORIC study indicating the primary endpoint of PFS had been met. In August 2017, mogamulizumab received breakthrough therapy designation in the US for mycosis fungoides and Sézary syndrome based on results from the MAVORIC study.
The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of November 10, 2017, marketing applications for a total of 11 antibody therapeutics that have not yet been approved in either the EU or US are undergoing review in these regions.
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Back in business: gemtuzumab ozogamicin
Roughly 17 years ago gemtuzumab ozogamicin was first approved by the FDA for the treatment of patients over the age of 60 with CD33-positive relapsed acute myelogenous leukemia (AML), and who were not considered candidates for other cytotoxic chemotherapy.
The drug, also known as Mylotarg, was the result of a long-lasting collaboration between Wyeth (acquired by Pfizer in 2009) and CellTech (acquired by UCB in 2004), dating all the way back to 1991. Nine years later it was approved as a single agent under an “accelerated” approval based on the surrogate response rate endpoint that was observed in 142 patients with AML across 3 clinical trials. The approval made Mylotarg the first ADC to hit the US market at the time.
However, things turned quickly for the product. One year into its approval it required a black box packaging warning related to the increased risk of veno-occlusive disease. Initially, the warning was aimed at patients who did not receive bone marrow transplantation, but later the increased frequency of veno-occlusive disease was also observed in Gemtuzumab-treated patients after bone marrow transplantation.
A confirmatory, post-approval clinical trial commenced in 2004, per FDA guidelines for accelerated approval. Results of the randomized Phase 3 SWOG S0106 trial showed a significantly higher fatal induction toxicity rate in gemtuzumab combination therapy group versus the control group receiving only chemotherapy (16/283 = 5.7% versus 4/281 = 1.4%; p = 0.01).
Following the results of SWOG S0106 and the post-marketing experience with the drug, Pfizer decided to withdraw Mylotarg from the market in 2010 at the request of the FDA. The discontinuation was an upset in the ADC field. Upon the withdrawal brentuximab vedotin and trastuzumab emtansine were the only two approved ADCs for years to come. However, the potential of ADC therapeutics has seen a revival and around 60-70 products are in clinical trials at the moment.
Not only the ADC field itself bounced back after this blow, but also gemtuzumab ozogamicin made a recent comeback. Early this year Pfizer resubmitted Mylotarg for regulatory review and both the FDA and the EMA accepted to review the application based on added data from the Phase 3 randomized, open-label ALFA-0701 trial. In this study Mylotarg was evaluated as an addition to the standard induction chemotherapy using an alternative fractionated dosing schedule in 280 adult, de novo, AML patients between 50 and 70 years old. Additionally, a meta-analysis of patient-level data from over 3000 patients in five randomized Phase 3 trials were evaluated.
Now, seven years after discontinuation, gemtuzumab ozogamicin is back in business in the US. The FDA has approved the lower recommended dosage range and the alternative treatment schedule. The authorization now covers single uses or in combination with chemotherapy in a patient population that now also includes adults with newly diagnosed CD33-positive AML, and adults and children 2 years and older with relapsed or refractory CD33-positive AML.
Increased clinical pipeline of Antibody Drug Conjugates in 2016
The antibody-drug conjugate (ADC) clinical pipeline has continued to grow in 2016. Last month two ADCs entered the clinic: Genmab’s MMAE-conjugated HuMax-AXL-ADC is now in Phase 1/2 development for five different types of solid tumors (ovary, cervix, endometrium, lung and thyroid). Additionally, a PBD-conjugated ADC for multiple myeloma (SGN-CD352A), was added to Seattle Genetics’ clinical pipeline.
In total, 32 clinical trials involving ADCs were initiated in 2016 and a significant progression of the pipeline into Phase 2 and 3 clinical trial was observed that year. During last year, 14 novel ADCs entered Phase 1, now totaling 37 Phase 1 ADCs. Three ADCs initiated Phase 1/2 development in 2016, increasing the total number of ADCs in this stage to 8. Four ADCs (AGS-16C3F, Anetumab Ravtansine, SAR566658, Rova-T) progressed towards Phase 2 (11 ADCs are now in Phase 2) and two drugs (IMGN853, SGN-CD33A) entered Phase 3 trials, doubling the number of ADCs in this clinical phase.
This year, a market approval could become a reality for inotuzumab ozogamicin. Currently, a marketing authorization application for acute lymphocytic leukemia (ALL) is being reviewed by EMA. Another possible approval is the re-approval for Mylotarg using a different dosing regimen.
Antibody therapeutics for immune-mediated disorders
Patients’ choice in antibody therapeutics for common immune-mediated disorders such as psoriasis and rheumatoid arthritis (RA) is set to substantially increase in 2017. As of December 1, 2016, marketing applications for 10 antibody therapeutics are being evaluated by either the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) for possible first approvals in the US or EU, respectively. Of these, five (brodalumab, dupilumab, sirukumab, sarilumab, and guselkumab) are being considered as treatments for immune-mediated disorders.
Brodalumab (LUMICEF®) is a human anti-IL-17 receptor A mAb that inhibits biological activity of IL-17A, IL-17F and other IL-17s. The product was granted a first marketing approval from the Ministry of Health, Labour and Welfare in Japan on July 4, 2016 for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, and psoriatic erythroderma. The FDA’s action date for the biologics license application (BLA) is February 16, 2017. A marketing authorization application for brodalumab in psoriasis is undergoing evaluation by EMA. Guselkumab, an IgG1 mAb that targets the IL-23 p19 subunit, is undergoing review by FDA and EMA as a treatment for plaque psoriasis. Dupilumab (Dupixent®), an anti-IL-4Ra IgG4 mAb, is undergoing review by FDA for atopic dermatitis. The mAb has Breakthrough Therapy designation for this indication, and the BLA was granted a priority review. FDA’s action date for the application is March 29, 2017. Sirukumab is a human anti-IL-6 mAb being evaluated by EMA, FDA and the Ministry of Health, Labour and Welfare for the treatment of adult patients with moderately to severely active RA. Sarilumab, a human IgG1 targeting IL-6R, is undergoing review by EMA, FDA and the Ministry of Health, Labour and Welfare in Japan for the treatment of adult patients with moderately to severely active RA. The BLA submitted to FDA has undergone a first review; deficiencies identified were detailed in a complete response letter.
The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the US or EU. Please log in to access the table, located in the Members Only section.
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