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Four new antibody therapeutics enter regulatory review

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Marketing applications for four antibody therapeutics (crizanlizumab, enfortumab vedotin, teprotumumab, isatuximab) were recently submitted to the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

On July 16, 2019, Novartis announced the FDA accepted the company’s Biologics License Application (BLA) and has granted Priority Review for crizanlizumab (SEG101). Novartis submitted the application for crizanlizumab for the prevention of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). The FDA submission is supported by results from the Phase 2 SUSTAIN study, which showed that crizanlizumab (5 mg/kg) reduced the median annual rate of VOCs leading to health care visits by 45.3% compared with placebo (1.63 vs 2.98, P=0.010) in patients with or without hydroxyurea. Clinically significant reductions in the frequency of VOCs were observed among patients regardless of sickle cell disease genotype or hydroxyurea use. A marketing authorization application for crizanlizumab is undergoing evaluation by EMA.

  • Crizanlizumab, humanized IgG2 targeting P-selectin, was granted Breakthrough Therapy designation in December 2018

On July 16, 2019, Seattle Genetics, Inc. and Astellas Pharma Inc. announced submission of a BLA for accelerated approval to the FDA for enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial cancer who have received a PD-1/L1 inhibitor and who have received a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. The submission is based on results from the first cohort of patients in the EV-201 pivotal Phase 2 clinical trial that were presented as a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology (ASCO) in June.

  • Enfortumab vedotin is a human IgG1 antibody-drug conjugate that targets Nectin-4, a protein that is highly expressed in urothelial cancers.

On July 10, 2019, Horizon Therapeutics plc announced that it has submitted a BLA to FDA for teprotumumab for the treatment of active thyroid eye disease. Teprotumumab has Breakthrough Therapy, Orphan Drug and Fast Track designations from the FDA. Horizon requested priority review for the application, which, if granted, could result in a six-month review process. The FDA has a 60-day filing review period to determine whether the BLA is complete and acceptable for filing.

  • Teprotumumab is a human IgG1 antibody that targets insulin-like growth factor 1 receptor.

On July 10, 2019, Sanofi announced that the FDA has accepted for review the BLA for isatuximab (SAR650984) for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). The target action date for the FDA decision is April 30, 2020. Isatuximab received orphan designation for relapsed/refractory multiple myeloma from both the FDA and the EMA, and in the second quarter of 2019 the EMA accepted a marketing authorization application for evaluation.

  • Isatuximab is a novel IgG1 antibody that binds selectively to a specific epitope on CD38.

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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. Located in the ‘Web Resources’ section of our website, the list is updated regularly and can be downloaded in Excel format. Information about antibody therapeutics that may enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.

New antibody-drug conjugate approved in the US

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On June 10, 2019, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Polivy (polatuzumab vedotin-piiq), in combination with the chemotherapy bendamustine and a rituximab product (BR), to treat adult patients with diffuse large B-cell lymphoma (DLBCL) that has progressed or returned after at least two prior therapies. Polivy is composed of a humanized anti-CD79b IgG1 antibody conjugated to the antimitotic agent monomethyl auristatin E (MMAE). The antibody’s target is highly expressed on B cells of patients with lymphoma. The biologics license application for Polivy was granted FDA’s Breakthrough Therapy and priority review designations. The drug also has European Medicines Agency (EMA)’s PRIME designation, and US and EU Orphan Drug designations for DLBCL. EMA is reviewing a marketing authorization application for Polivy.

The drug’s efficacy was evaluated in a study of 80 patients with relapsed or refractory DLBCL who were randomized to receive Polivy with BR or BR alone. Efficacy was based on complete response rate and duration of response (DOR), defined as the time the disease stays in remission. At the end of treatment, the complete response rate was 40% with Polivy plus BR compared to 18% with BR alone. Of the 25 patients who achieved a partial or complete response to Polivy plus BR, 16 (64%) had a DOR of at least six months and 12 (48%) had a DOR of at least 12 months.

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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. Located in the ‘Web Resources’ section of our website, the list is updated regularly 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’.

 

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’.