The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

European Medicines Agency’s antibody PRIority MEdicines

by

mabs-coverOn 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.

Like this post? Please support the Society by registering here for a membership!

New antibody therapeutics for multiple sclerosis

by

Antibody impressionOn May 27, 2016 the Food and Drug Administration (FDA) approved daclizumab (Zinbryta®) for the treatment of adults with relapsing forms of multiple sclerosis (MS). The product, which targets interleukin-2 receptor alpha chain (CD25), is manufactured using a high-yield process. Daclizumab (Zenapax®) was first approved in 1997 for the prevention of organ transplant rejection. While the two products have the same amino acid sequence, Zinbryta has a different glycosylation pattern and reduced antibody-dependent cytotoxicity compared to Zenapax. Zinbryta’s approval was based in part on the results of the Phase 3 DECIDE study (NCT01064401) of Zinbryta versus interferon β 1a (Avonex®) in patients with relapsing-remitting MS. In this study, patients administered Zinbryta experienced fewer clinical relapses than those who received Avonex (annualized relapse rate 0.22 vs. 0.39; 45% lower rate with Zinbryta; P<0.001). Due to serious safety risks, FDA has included a boxed warning on the product label, and it is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy.

Another antibody therapeutic, ocrelizumab, has been evaluated in a Phase 3 study of patients with primary progressive multiple sclerosis (PPMS). The antibody targets CD20 on B cells, which are implicated in the inflammatory and neurodegenerative processes of MS. Ocrelizumab was granted FDA’s Breakthrough Therapy Designation for PPMS, which is a debilitating form of MS characterized by steadily worsening symptoms. PPMS patients typically do not experience distinct relapses or periods of remission. Currently, no treatments are approved for treatment of the disease. In the pivotal Phase 3 ORATORIO study, treatment with ocrelizumab significantly reduced disability progression and other markers of disease activity compared with placebo. Ocrelizumab is also undergoing evaluation in Phase 3 studies of patients with relapsing-remitting forms of the disease. Genentech plans to submit a marketing application for ocrelizumab as a treatment for MS in 2016. If an application is submitted to FDA by the end of June and receives a priority review, which is a benefit of the Breakthrough Therapy Designation, then ocrelizumab could be approved for marketing in the US by the end of 2016.

Antibody Drug Conjugates – Clinical Progress

by

square logo ADCIn the second half of May several companies reported important progress on their therapeutic ADC products. The Dutch pharmaceutical company Synthon initiated the second phase of the ongoing phase I clinical trial with its investigational anti-HER2 ADC SYD985. During the first part patients with solid tumors of any origin were enrolled. Promising results were obtained in this dose-finding part of the trial in 33 cancer patients who were dosed with between 0.3 and 2.4 mg/kg of SYD985 every three weeks. Very high response rates and durable responses were observed  at doses from 1.2 mg/kg onwards in patients whose cancers were refractory to HER2-targeted agents, including Herceptin® and Kadcyla®. The second part will see 48 additional heavily pre-treated patients with HER2-positive breast cancer enrolled into the Phase I trial. This marked a significant next step in the development of SYD985, the frontrunner of the company’s duocarmycin-based ADC platform.

Additionally, Seattle Genetics announced initiation of a pivotal phase III clinical trial, CASCADE, evaluating vadastuximab talirine (SGN-CD33A) in combination with azacitidine (Vidaza) or decitabine (Dacogen) in older patients with newly diagnosed acute myeloid leukemia (AML). SGN-CD33A is an ADC targeting CD33 comprising an engineered cysteine antibody (EC-mAb) stably linked to a pyrrolobenzodiazepine (PBD) dimer. CD33 is expressed on leukemic blasts in nearly all AML patients and expression is generally consistent regardless of age, cytogenetic abnormalities or underlying mutations. Azacitidine and decitabine are hypomethylating agents (HMAs) commonly used in the treatment of older AML patients. The phase III CASCADE study is a randomized, double-blinded, placebo-controlled, global clinical trial. Patients will be randomized on a 1:1 ratio to be treated with an HMA plus SGN-CD33A or an HMA plus placebo. The secondary endpoints include the comparison of composite complete remission rate, event-free and leukemia-free survival, duration of response, safety, and 30- and 60-day mortality rates. This phase III trial will enroll approximately 500 patients globally.

Atezolizumab: 4th mAb granted a first approval in 2016

by

20150625-example-imageOn May 18, 2016, anti-PD-L1 atezolizumab (Tecentriq®) was approved by the Food and Drug Administration (FDA) as a treatment for patients with locally advanced or metastatic urothelial carcinoma. The marketing application for atezolizumab had received breakthrough therapy designation, priority review status and accelerated approval for this indication. A PD-L1 (SP142) assay complementary diagnostic to detect PD-L1 protein expression levels on the tumor-infiltrating immune cells of patients was also approved. An FDA action on a second application for use of atezolizumab as a treatment for patients with non-small cell lung cancer is expected by October 2016. Atezolizumab is the fourth antibody that inhibits an immune checkpoint to be granted a marketing approval. Two anti-PD1 antibodies, nivolumab (Opdivo®) and pembrolizumab (Keytruda®), were approved in 2014 in the US (2015 in the EU), and one anti-CTLA4 antibody, ipilimumab (Yervoy®), was approved in the US and EU in 2011. Atezolizumab is the fourth antibody product to be granted a first marketing approval in 2016.

Six additional antibody therapeutics (bezlotoxumab, sarilumab, brodalumab, Xilonix, begelomab, olaratumab) are now undergoing their first regulatory review in the European Union and the United States. If these antibodies are approved by the end of the year, the number of first approvals for antibody products in 2016 will set a new record (10 products), exceeding by 1 the previous record set in 2015. The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the European Union and the Unites States. The antibody’s target, format and year of first approval are included. Please log in to access the table, located in the Members Only section.

Not a member? Please join!

Antibody Drug Conjugates – Acquisitions and Partnering

by

 
AbbVie dominated the news in the last weeks of April after announcing the acquisition of Stemcentrx including the company’s late-stage rovalpituzumab tesirine (Rova-T) for $5.8bn. Furthermore, AbbVie partnered up with CytomX to jointly develop and commercialize a probody-drug conjugate (PDC) against CD71.

Stemcentrx’ Rova-T, also known as SC16LD6.5, is addressing small cell lung cancer (SCLC) and other neuroendocrine cancers such as large cell neuroendocrine carcinoma. Rova-T has received orphan drug designation from the FDA for treatment of small cell lung cancer. Rova-T targets delta-like protein 3 (DLL3), which is expressed in >80% SCLC patient tumors and is not present on healthy tissue. Rova-T comprises a D6.5 pyrrolobenzodiazepine (PBD) payload conjugated to cysteine residues on the SC16 antibody, a maleimide-containing linker with an eight-carbon polyethylene glycol spacer, cathepsin B–cleavable valine-alanine dipeptide, and self-immolating group, with an average drug-to-antibody ratio (DAR) of 2. Rova-T represents a multi-billion dollar peak revenue opportunity with expected commercialization in 2018. The acquisition expands AbbVie’s oncology pipeline with four additional early-stage clinical compounds in solid tumor indications and Stemcentrx’ portfolio of preclinical assets.

 

Together with CytomX, AbbVie will co-develop a PDC against CD71. PDCs contain a masking peptide designed to decreasing target binding to healthy tissue and remain inactive until the molecules are activated proteolytically in the tumor microenvironment, thereby minimizing toxicities. The target, transferrin receptor 1 (TfR1), also known as CD71, is ubiquitously expressed on dividing, normal or healthy cells plus a number of hematologic and solid malignant cancer cells. CD71 mediates transferrin-iron complex uptake, an essential process for cell division and therefore also for tumors. CD71 is homogeneously and highly expressed (3+ expression assessed by IHC) in almost all tumor types, including metastatic tumors. The current PDC approach should avoid targeting the many healthy cell types that also express CD71.

 

Additionally, Regeneron Pharmaceuticals and MedImmune (wholly owned subsidiary of  AstraZeneca) entered into a licensing agreement under which Regeneron will use MedImmune’s PBD-based payload and linker technology to develop ADCs against a number of cancer targets. MedImmune will have the option to develop and commercialize certain products created with this technology in territories outside of the United States.