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Biologics license application submitted for eptinezumab, an anti-CGRP antibody for migraine prevention

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Alder BioPharmaceuticals has submitted a biologics license application (BLA) for eptinezumab, a humanized IgG1 monoclonal antibody that targets calcitonin gene-related peptide (CGRP), for migraine prevention. If the US Food and Drug Administration grants approval, Alder will be on track to launch the drug in Q1 2020. The BLA included data from the PROMISE 1 and PROMISE 2 studies, which evaluated the effects of eptinezumab in episodic migraine patients (n=888) or chronic migraine patients (n=1,072), respectively.  In PROMISE 1, the primary and key secondary endpoints were met, and the safety and tolerability were similar to placebo, while in PROMISE 2, the primary and all key secondary endpoints were met, and the safety and tolerability was consistent with earlier eptinezumab studies.

Alder announced one-year results from the PROMISE 1 study in June 2018, which indicated that, following the first quarterly infusion, episodic migraine patients treated with 300 mg eptinezumab experienced 4.3 fewer monthly migraine days (MMDs) from a baseline of 8 MMDs, compared to 3.2 fewer MMDs for placebo from baseline (p= 0.0001). At one year after the third and fourth quarterly infusions, patients treated with 300 mg eptinezumab experienced further gains in efficacy, with a reduction of 5.2 fewer MMDs compared to 4.0 fewer MMDs for placebo-treated patients.  In addition, ~31% of episodic migraine patients achieved, on average per month, 100% reduction of migraine days from baseline compared to ~ 21% for placebo. New 6-month results from the PROMISE 2 study were also released in June 2018.  These results indicated that, after the first quarterly infusion, chronic migraine patients dosed with 300 mg of eptinezumab experienced 8.2 fewer MMDs, from a baseline of 16 MMDs, compared to 5.6 fewer MMDs for placebo from baseline (p <.0001). A further reduction in MMDs was seen following a second infusion; 8.8 fewer MMDs for patients dosed with 300 mg compared to 6.2 fewer MMDs for those with placebo. In addition, ~ 21% of chronic migraine patients achieved, on average, 100% reduction of MMDs from baseline compared to 9% for placebo after two quarterly infusions of 300 mg of eptinezumab.

If approved, eptinezumab would become the fourth antibody therapeutic for migraine prevention on the US market, following the approval of erenumab-aooe (Aimovig; Novartis), galcanezumab-gnlm (Emgality; Eli Lilly & Company) and fremanezumab-vfrm (Ajovy; Teva Pharmaceuticals) in 2018.

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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.

New antibody-drug conjugate, polatuzumab vedotin, enters FDA review

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Roche’s biologics license application (BLA) for polatuzumab vedotin in combination with bendamustine plus Rituxan® (rituximab) (BR) for the treatment of people with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) has been accepted and granted a priority review by the US Food and Drug Administration. A decision on approval of the BLA is expected by August 19, 2019. Developed in collaboration with Seattle Genetics, polatuzumab vedotin is composed of a humanized anti-CD79b IgG1 antibody conjugated to the antimitotic agent monomethyl auristatin E. The antibody’s target is highly expressed on B cells of patients with lymphoma. Polatuzumab vedotin was granted FDA’s Breakthrough Therapy designation,  the European Medicines Agency (EMA)’s PRIME designation, and US and EU Orphan Drug designations for DLBCL. A marketing application for polatuzumab vedotin is undergoing review by EMA.

The BLA is based on positive clinical data from a randomized Phase 1/2 study (NCT02257567/GO29365),  which evaluated polatuzumab vedotin administered by IV infusion in combination with standard doses of BR or obinutuzumab in patients with R/R follicular lymphoma (FL) or DLBCL. Study results indicated that median overall survival was over one year in people with R/R DLBCL not eligible for a hematopoietic stem cell transplant who received the combination of polatuzumab vedotin and BR, and less than 5 month for those in the BR arm of the study (12.4 vs. 4.7 months, hazard ratio (HR)=0.42; 95% CI 0.24-0.75). In addition, polatuzumab vedotin plus BR increased median progression-free survival (PFS) and led to a 66% reduction in risk of disease worsening or death compared to BR alone (median PFS: 7.6 months vs. 2.0 months; HR=0.34; 95% CI 0.20-0.57), and patients treated with polatuzumab vedotin plus BR showed a longer time between first response to treatment and disease worsening than those receiving BR alone (investigator assessed median duration of response: 10.3 months vs. 4.1 months; HR=0.44).

The combination of polatuzumab vedotin with R-CHP protocol (rituximab, cyclophosphamide, doxorubicin and prednisone) versus R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone) in DLBCL patients is currently being investigated in the Phase 3 POLARIX (NCT03274492) study. The primary endpoint is PFS. Secondary outcome measures include PFS, compete response and overall survival. The estimated primary completion date of the study is December 2019.

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FDA approval for caplacizumab-yhdp

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On February 6, 2019, the US Food and Drug Administration approved caplacizumab-yhdp (Cablivi), in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP). During episodes of this rare, life-threatening blood clotting disorder, microclots can form, leading to low platelet counts, ischemia and organ dysfunction in aTTP patients.  Approval was based on positive results from a study of 145 patients with an acute episode of aTTP who were randomized 1:1 to receive either caplacizumab or placebo in addition to standard-of-care treatment, which was daily plasma exchange and immunosuppression. Caplacizumab was granted its first approved in the European Union (EU) on August 31, 2018. The mAb was granted Fast Track designation in the US and Orphan Drug designations in the US and EU for the treatment of aTTP.

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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.

“Antibodies to watch in 2019”

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The latest “Antibodies to watch” article is now freely accessible at mAbs! 

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, the scope of the data presented was expanded 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).

As of November 2018, a record number of antibodies (erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), burosumab (Crysvita), lanadelumab (Takhzyro), caplacizumab (Cablivi), mogamulizumab (Poteligeo), moxetumomab pasudodox (Lumoxiti), cemiplimab (Libtayo), ibalizumab (Trogarzo), tildrakizumab (Ilumetri, Ilumya), emapalumab (Gamifant)) that treat a wide variety of diseases were granted a first approval in either the European Union (EU) or United States (US). Also as of November 2018, 4 antibody therapeutics (sacituzumab govitecan, ravulizumab, risankizumab, romosozumab) were being considered for their first marketing approval in the EU or US, and an additional 3 antibody therapeutics developed by Chinese companies (tislelizumab, sintilimab, camrelizumab) were in regulatory review in China. In addition, the data show that 3 product candidates (leronlimab, brolucizumab, polatuzumab vedotin) may enter regulatory review by the end of 2018, and at least 12 (eptinezumab, teprotumumab, crizanlizumab, satralizumab, tanezumab, isatuximab, spartalizumab, MOR208, oportuzumab monatox, TSR-042, enfortumab vedotin, ublituximab) may enter regulatory review in 2019. Notably, approximately half (18 of 33) of the late-stage pipeline of antibody therapeutics for cancer are immune checkpoint modulators or antibody-drug conjugates. Of these, 7 (tremelimumab, spartalizumab, BCD-100, omburtamab, mirvetuximab soravtansine, trastuzumab duocarmazine, and depatuxizumab mafodotin) are being evaluated in clinical studies with primary completion dates in late 2018 and in 2019, and are thus ‘antibodies to watch’. The Antibody Society looks forward to documenting progress made with these and other ‘antibodies to watch’ in the next installment of this article series.

Update: Data in “Antibodies to watch in 2019” is as of November 2018. As noted in the post below, risankizumab was approved by FDA on December 21, 2018, bringing the total number of antibody therapeutics approved in the EU or US during 2018 to 13.

First approval for ravulizumab

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On December 21, 2018, the US Food and Drug Administration approved Ultomiris (ravulizumab) injection for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare and life-threatening blood disease characterized by hemolysis of red blood cells mediated by the complement system. Developed by Alexion Pharmaceuticals, ravulizumab is a humanized mAb that inhibits complement component 5 (C5). The biologics license application for ravulizumab received a Priority Review designation. In a Phase 3 study, ravulizumab demonstrated non-inferiority to Soliris® (anti-C5 eculizumab) in complement-inhibitor treatment-naïve patients with PNH. Also developed by Alexion Pharmaceuticals, Soliris® was first approved for PNH in 2007. Ravulizumab is also undergoing regulatory review in the EU. It was granted Orphan Drug designation in both the US and EU for the treatment of patients with PNH.

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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. As of December 21, a total of 13 antibody therapeutics had been granted first approvals in either the US or EU in 2018, and marketing applications for another 3 that have not yet been approved in either the EU or US are undergoing review in these regions. Please log in to access the table in Excel format, located in the Members Only section.