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Risankizumab-rzaa granted FDA approval

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On April 23, 2019, the US Food and Drug Administration approved risankizumab-rzaa (SKYRIZI™) for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Risankizumab is a humanized IgG1 monoclonal antibody that inhibits interleukin (IL)-23, a cytokine involved in inflammatory processes, by binding to its p19 subunit. SKYRIZI is part of a collaboration between Boehringer Ingelheim and AbbVie, with AbbVie leading development and commercialization of SKYRIZI globally.

The product’s approval is supported by data from four randomized, placebo and/or active-controlled pivotal studies, ultIMMA-1, ultIMMa-2, IMMhance and IMMvent, that evaluated the safety and efficacy of risankizumab in more than 2,000 patients with moderate-to-severe chronic plaque psoriasis. The co-primary endpoints of the studies were Psoriasis Area and Severity Index and static Physician Global Assessment [sPGA] score of clear or almost clear [sPGA 0/1] at 16 weeks versus placebo. In these four studies, all co-primary and ranked secondary outcome measures were met and no new safety signals were observed. Results of the UltIMMa-1 (NCT02684370) and UltIMMa-2 (NCT02684357) studies were reported in The Lancet. Risankizumab was previously approved in Japan and Canada, and a marketing authorization application for risankizumab is currently undergoing regulatory review in the European Union.

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The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US. Please log in to access the table, which is located in the Members Only section and can be downloaded in Excel format. Information about other antibody therapeutics that may enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.

Romosozumab-aqqg granted FDA approval

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On April 9, 2019, the US Food and Drug Administration approved romosozumab-aqqg (Evenity) to treat osteoporosis in postmenopausal women at high risk of bone fractures. Developed by Amgen and UCB, romosozumab is a humanized IgG2 monoclonal antibody that targets sclerostin. This is the second global approval of romosozumab, following its approval in Japan.

FDA’s approval was based the results of the Phase 3 placebo-controlled FRAME and active-controlled ARCH studies. As reported by Amgen, treatment with EVENITY resulted in a significant reduction of new vertebral fracture at 12 months compared to placebo in the FRAME study. This significant reduction in fracture risk persisted through the second year in women who received EVENITY during the first year and transitioned to denosumab compared to those who transitioned from placebo to denosumab. In addition, EVENITY significantly increased bone mineral density (BMD) at the lumbar spine, total hip and femoral neck compared to placebo at 12 months. Following the transition from EVENITY to denosumab at month 12, BMD continued to increase through month 24.

In the ARCH study, treatment with EVENITY for 12 months followed by 12 months of alendronate significantly reduced the incidence of new vertebral fracture at 24 months. EVENITY followed by alendronate significantly reduced the risk of clinical fracture (defined as a composite of symptomatic vertebral fracture and nonvertebral fracture) after a median follow-up of 33 months. EVENITY significantly increased BMD at the lumbar spine, total hip and femoral neck at 12 months compared to alendronate. Twelve months of treatment with EVENITY followed by 12 months of treatment with alendronate significantly increased BMD compared with alendronate alone.

The European Medicines Agency is reviewing a marketing application for romosozumab.

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The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US. Please log in to access the table, which is located in the Members Only section and can be downloaded in Excel format. Information about other antibody therapeutics that may enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.

BLA submission started for leronlimab as part of combination therapy for patients with HIV

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CytoDyn Inc. has submitted the non-clinical portion of a biologics license application (BLA) for leronlimab (700 mg dose) in combination with highly active antiretroviral therapy for treatment of patients with human immunodeficientcy virus (HIV).  ‘Rolling’ BLA submission is a benefit of leronlimab’s Fast Track drug designation, which was granted by the US Food and Drug Administration for this indication. CytoDyn is working to complete the clinical, and chemistry, manufacturing and controls sections of the BLA. Leronlimab, a humanized IgG4 monoclonal antibody, blocks CCR5. The chemokine receptor CCR5 is the principal HIV co-receptor, but it has potential as a drug target for other diseases, such as cancer and immune-mediated disorders.

As recently announced by CytoDyn, clinical study data has shown that a weekly dose of 525 mg and 700 mg of leronlimab yielded approximately a 90% response rate for HIV-infected patients who pass the first 10 weeks of monotherapy without virologic failure. Approximately 30% of patients fail within the first 10 weeks of monotherapy on a 525 mg dosage and 17% at a dosage of 700 mg. Patients who pass the first 10 weeks of monotherapy on a 525 mg dose have reached an average total of 32 weeks with sustained viral load suppression.

CytoDyn is also developing leronlimab as a treatment for graft-vs.-host disease (GVHD) and triple-negative breast cancer. A Phase 2 study (NCT02737306 ) of the safety and efficacy of leronlimab for prophylaxis of acute GVHD in patients undergoing reduced intensity conditioning allogeneic stem-cell transplantation has an estimated primary completion date of December 2019.  A Phase 1b/2 study (NCT03838367) of leronlimab combined with carboplatin in patients with CCR5+ metastatic triple negative breast cancer is not yet recruiting patients.

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The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US. Please log in to access the table, which is located in the Members Only section and can be downloaded in Excel format. Information about other antibody therapeutics that may enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.

Antibody therapeutics in early-stage clinical studies

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The popular “Antibodies to watch” articles aim to update members of The Antibody Society, as well as the broader scientific community, on progress in the late-stage clinical development of innovative antibody therapeutics. Data for these molecules (60 as of March 22, 2019) are made available in the Members Only area of The Antibody Society’s website. We are pleased to announce that we are expanding our coverage of the commercial clinical pipeline to include data for antibody therapeutics that have recently entered clinical study. Two factors motivated us: 1) the remarkable increase in the number entering clinical study annually (to ~120 in 2018); and 2) the remarkable focus on antibodies developed for cancer (~80% of the total in 2018). Data for antibody therapeutics that entered clinical study recently, in Excel format, may be downloaded from the Members Only area.

The biopharmaceutical industry’s intense focus on the development of antibody therapeutics, and particularly those for cancer, is unabated in 2019, according to the data available by mid-March. We have identified 17 antibody therapeutics for which an application to start clinical study was filed or a Phase 1 study was started in 2019, and an additional 11 antibody therapeutics with clinical studies not yet recruiting patients, as listed on clinicaltrials.gov. The rate of clinical entry for antibody therapeutics so far in 2019 is thus similar to that observed in 2018 (~10 per month). The trend toward development of antibodies as treatments for cancer is also quite similar. Of the 2019 cohort so far identified, 22 of 28 (79%) are for cancer.

The commercial clinical pipeline of cancer therapies has become increasingly dominated by 3 categories of antibodies: 1) immune checkpoint modulators; 2) antibody-drug conjugates (ADCs); and 3) bispecific antibodies (see figure for details).

Our data so far suggests that this trend will continue in 2019, as nearly three-quarters of the antibody therapeutics currently in the 2019 cohort fit in one (or more) of the 3 categories. Examples of antibodies that fit more than 1 category include TG-1801 (TG Therapeutics, Inc., Novimmune SA), a bispecific antibody targeting the immune checkpoint CD47 as well as CD19, and  INBRX-105 (Inhibrx, Inc.), a bispecific antibody targeting the immune checkpoints PD-L1 and 4-1BB. TG-1801, a human IgG1 designed to target and deplete B-cells, is undergoing evaluation in a Phase 1 study (NCT03804996) of patients with B-cell lymphoma. INBRX-105 is undergoing evaluation as a treatment for hematological and solid tumors in a Phase 1 study (NCT03809624).

More to come! Throughout 2019, we will track and report on the development of all antibody therapeutics that enter clinical study during the year.

Attention members! Please log in to access our data for all antibody therapeutics that entered clinical study during 2018 or so far in 2019. After logging in, click on ‘Antibodies in early-stage studies’ in the Members Only dropdown menu. Data will be updated throughout 2019.

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Most read from mAbs, Feb/March 2019

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The Antibody Society is pleased and proud to be affiliated with mAbs, a multi-disciplinary journal dedicated to advancing the art and science of antibody research and development. We hope you enjoy these summaries based on the abstracts of the most read papers published in a recent issue. All the articles are open access; PDFs can be freely downloaded by following the links below.

Issue 11.2 (February/March 2019)

Antibodies to watch in 2019.
For the past 10 years, the annual ‘Antibodies to watch’ articles have provided updates on key events in the late-stage development of antibody therapeutics, such as first regulatory review or approval, that occurred in the year before publication or were anticipated to occur during the year of publication. To commemorate the 10th anniversary of the article series and to celebrate the 2018 Nobel Prizes in Chemistry and in Physiology or Medicine, which were given for work that is highly relevant to antibody therapeutics research and development, Kaplon and Reichert expanded the scope of the data presented to include an overview of all commercial clinical development of antibody therapeutics and approval success rates for this class of molecules. The data indicate that:
1) antibody therapeutics are entering clinical study, and being approved, in record numbers;
2) the commercial pipeline is robust, with over 570 antibody therapeutics at various clinical phases, including 62 in late-stage clinical studies; and
3) Phase 1 to approval success rates are favorable, ranging from 17–25%, depending on the therapeutic area (cancer vs. non-cancer).

Ion channels as therapeutic antibody targets.
In this review, Hutchings et al evaluate the technical challenges of raising antibodies to membrane-spanning proteins together with enabling technologies that may facilitate the discovery of antibody therapeutics to ion channels. They also discuss the potential targeting opportunities in the anti-ion channel antibody landscape, along with a number of case studies where functional antibodies that target ion channels have been reported. Antibodies currently in development and progressing towards the clinic are highlighted.

Influence of N-glycosylation on effector functions and thermal stability of glycoengineered IgG1 monoclonal antibody with homogeneous glycoforms.
The separation of various glycoforms to investigate the biological and functional relevance of glycosylation is a major challenge, and the individual contributions of each glycoform is usually not considered when evaluating mAbs with highly heterogeneous distributions. In this study, Wada et al used chemoenzymatic glycoengineering incorporating an endo-β-N-acetylglucosaminidase (ENGase) EndoS2 and its mutant with transglycosylation activity to generate mAb glycoforms with highly homogeneous and well-defined N-glycans to better understand and precisely evaluate the effect of each N-glycan structure on Fc effector functions and protein stability. They demonstrated that the core fucosylation, non-reducing terminal galactosylation, sialylation, and mannosylation of IgG1 mAb N-glycans impact not only on FcγRIIIa binding, antibody-dependent cell-mediated cytotoxicity, and C1q binding, but also FcRn binding, thermal stability and propensity for protein aggregation.

Co-engaging CD47 and CD19 with a bispecific antibody abrogates B-cell receptor/CD19 association leading to impaired B-cell proliferation.
In this report, Hatterer et al describes the generation of a CD47xCD19 bispecific antibody (biAb) to target and deplete B cells via multiple antibody-mediated mechanisms. Interestingly, the biAb, constructed of a CD19 binding arm and a CD47 binding arm, inhibited BCR-mediated B-cell proliferation with an effect even more potent than a CD19 monoclonal antibody (mAb). The inhibitory effect of the biAb was not attributable to CD47 binding because a monovalent or bivalent anti-CD47 mAb had no effect on B cell proliferation. Fluorescence resonance energy transfer analysis demonstrated that co-engaging CD19 and CD47 prevented CD19 clustering and its migration to BCR clusters, while only engaging CD19 (with a mAb) showed no impact on either CD19 clustering or migration. The lack of association between CD19 and the BCR resulted in decreased phosphorylation of CD19 upon BCR activation. Furthermore, the biAb differentially modulated BCR-induced gene expression compared to a CD19 mAb. Taken together, this unexpected role of CD47xCD19 co-ligation in inhibiting B cell proliferation illuminates a novel approach in which two B cell surface molecules can be tethered, to one another in order, which may provide a therapeutic benefit in settings of autoimmunity and B cell malignancies.

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