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You are here: Home / Archives for ADC

First approval for inotuzumab ozogamicin in the European Union

July 5, 2017 by Janice Reichert

The European Commission has granted a marketing approval for the antibody-drug conjugate (ADC) inotuzumab ozogamicin (BESPONSA) as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin is a CD22-targeting humanized IgG4 antibody conjugated to the drug calicheamicin via an acetyl butyrate linker. The approval of BESPONSA was supported by results from the Phase 3 INO-VATE ALL trial (ClinicalTrials.gov number NCT01564784), which compared the effects of either inotuzumab ozogamicin or standard intensive chemotherapy in adults with relapsed or refractory ALL Results of this study were published in The New England Journal of Medicine in 2016. A biologics license application for inotuzumab ozogamicin for the treatment of adult patients with relapsed or refractory B-cell precursor ALL is undergoing a priority review by the US Food and Drug Administration (FDA); the goal date for their decision is in August 2017.

As of July 1, inotuzumab ozogamicin is the seventh antibody therapeutic to be granted a first marketing approval in any country in 2017, following the approvals of brodalumab, avelumab, ocrelizumab, dupilumab, durvalumab, and sarilumab. The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of July 1, 2017, marketing applications for a total of 10 antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, a marketing application for the ADC gemtuzumab ozogamicin, which was approved in 2000 by the US FDA and subsequently withdrawn from the US market, is undergoing review in the EU and US.

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Filed Under: ADC, Approvals

Increased clinical pipeline of Antibody Drug Conjugates in 2016

January 25, 2017 by Joost Melis

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.

Filed Under: ADC, Clinical pipeline, Development metrics, European Medicines Agency, Food and Drug Administration

Phase I Data for Enfortumab Vedotin and the World ADC Awards

October 22, 2016 by Joost Melis

During the annual congress of the European Society of Medical Oncology (ESMO) in Copenhagen, interim clinical data for enfortumab vedotin (ASG-22ME) and ASG-15ME (Seattle Genetics and Agensys/Astellas) in patients with metastatic urothelial cancer were presented. Both enfortumab vedotin and ASG-15ME are investigational ADCs making use of the microtubule-disrupting toxin MMAE conjugated to anti-Nectin-4 and a SLITRK6-targeting antibody respectively. Nectin-4 and SLITRK6 are highly expressed in urothelial cancers, particularly bladder cancer but also include carcinomas of the ureter and renal pelvis.

There is a high unmet need for patients with metastatic urothelial cancer. In 2016 approximately 77,000 people will be diagnosed and more than 16,000 will die from urothelial bladder cancer. For patients diagnosed with locally advanced or metastatic the average five-year survival is only approximately 15%.

The clinical trial data showed that each agent demonstrated anti-tumor activity in patients previously treated with platinum-based chemotherapy, checkpoint inhibitors, taxanes and those with liver metastases and were generally well-tolerated.

Of the 49 patients evaluable for response to enfortumab vedotin treatment, 18 patients (37%) had an objective response, including one patient (2%) achieving a complete response and 17 patients (35%) who achieved a partial response. The preliminary estimate of median progression-free survival is 16.6 weeks. The recommended phase II dose is 1.25 mg/kg.

Of the 48 patients evaluable for response upon ASG-15ME treatment, 18 patients (38%) showed an objective response, including one patient (2%) who achieved a complete response and 17 patients (35%) achieving a partial response. The preliminary estimate of median progression-free survival is 16.1 weeks.

Both agents demonstrated encouraging anti-tumor activity and safety in these patient groups, and these data support the scheduled advancement to later stage development.


 

In other ADC-related news this month, during the 7th World ADC conference in San Diego the winners of the 3rd World ADC Awards were announced. The World ADC Awards showcase excellence within antibody drug conjugate research and reward the innovation, leadership, and devotion shown by the best companies, teams, and individuals in the industry. Across eight categories winners were awarded which in full can be viewed here (http://worldadc-awards.com/awards-2016/winners/).

The award for Best ADC Platform Technology was won by the Fleximer platform developed by Mersana Therapeutics. Winner of the Most Promising Clinical Candidate
was the ADC Rovalpituzumab tesirine (developed by Abbvie-Stemcentrx). BSP Pharmaceuticals took the prize for Best Contract Manufacturing Provider and ADC Therapeutics won Best New Drug Developer. John Lambert was awarded for his Long Standing Contribution to the field.

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Filed Under: ADC, Clinical pipeline, Meetings

Antibody-drug conjugates in the spotlight

October 14, 2016 by Janice Reichert

square logo ADCAntibody-drug conjugates (ADCs) are designed to deliver cytotoxic agents into targeted cells, and they are typically developed as treatments for cancer. Due to the need for new cancer drugs, the development of ADCs is the focus of substantial efforts by the biopharmaceutical industry. Nearly 60 ADCs are currently in clinical studies, one ADC, inotuzumab ozogamicin, is undergoing regulatory review, and three ADCs have been granted approvals, although the first to be approved, gemtuzumab ozogamicin (Mylotarg®) was withdrawn from the market in 2010.

Two ADCs, brentuximab vedotin (Adcetris®) and ado-trastuzumab emtansine (Kadcyla®), are currently marketed in the United States (US) and European Union (EU), as well as other countries. These two ADCs are disparate in their composition, and are used as treatments for different indications. Brentuximab vedotin is composed of an anti-CD30 monoclonal antibody (mAb) conjugated to the tubulin inhibitor monomethyl auristatin E via a valine-citruline dipeptide linkage designed for conditional cleavage inside cells. In contrast, ado-trastuzimab emtansine comprises an anti-human epidermal growth factor receptor-2 (HER2) mAb coupled to the tubulin-disrupting maytansinoid DM1 drug via a non-reducible thioether linkage. Brentuximab vedotin was granted its first approval in 2011 for two indications: 1) classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates; and 2) systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. The first approval for ado-trastuzumab emtansine was granted in 2013; the product is indicated for the treatment of HER2-positive metastatic breast cancer in patients who previously received trastuzumab and a taxane separately or in combination.

Of the nearly 60 ADCs in the clinic, only two (depatuxizumab mafodotin, vadastuximab talirane) are currently in late-stage (Phase 2/3 or 3) clinical studies, but two additional ADCs (sacituzumab govitecan, mirvetuximab soravtansine) may transition to Phase 3 soon. Depatuxizumab mafodotin (ABT-414) is composed of an anti-epidermal growth factor receptor (EGFR) mAb conjugated to the tubulin inhibitor monomethyl auristatin F via a stable maleimidocaproyl linker. The Phase 2b/3 Intellance 1 study (NCT02573324) of the ADC with concurrent chemoradiation and adjuvant temozolomide in adult patients with newly diagnosed glioblastoma multiforme (GBM) with EGFR amplification was initiated in late 2015. Depatuxizumab mafodotin has orphan drug designations for GBM in the US and glioma in the EU, and it was granted a US Rare Pediatric Disease Designation for pediatric EGFR-amplified diffuse intrinsic pontine glioma, a brainstem tumor that is highly aggressive and difficult to treat. Vadastuximab talirane (SGN-33A) is an anti-CD33 mAb with 2 engineered cysteine residues through which DNA cross-linking pyrrolobenzodiazepine dimer drug moieties are conjugated via a protease-cleavable valine-alanine dipeptide linker. The Phase 3 CASCADE clinical trial (NCT02785900) of vadastuximab talirine in combination with azacitidine (Vidaza) or decitabine (Dacogen) in older patients with newly diagnosed acute myeloid leukemia (AML) was initiated in May 2016.  Results from a Phase 1 study indicated that the ADC in combination with hypomethylating agents was a well-tolerated regimen with a high remission rate in older patients with AML.

The transitions of sacituzumab govitecan (IMMU-132) and mirvetuximab soravtansine (IMGN853) to Phase 3 may occur by the end of 2016. The start of a Phase 3 study (NCT02574455) that will evaluate the safety and efficacy of sacituzumab govitecan in refractory/relapsed triple-negative breast cancer (TNBC) patients is scheduled for December 2016. This ADC has received US Breakthrough Therapy and Fast Track designations for the treatment of patients with TNBC. Sacituzumab govitecan comprises an anti-TROP-2 mAb conjugated via a pH-sensitive linker to SN-38, the active metabolite of the chemotherapeutic irinotecan, in a site-specific manner. Mirvetuximab soravtansine is being assessed as a single-agent therapy in the FORWARD I trial (NCT02631876) of the ADC versus investigator’s choice of chemotherapy in adults with folate receptor (FR)-α positive advanced epithelial ovarian cancer, primary peritoneal cancer or primary fallopian tube cancer, which is being changed from a Phase 2 to a Phase 3 trial. Mirvetuximab soravtansine is composed of an anti-FRα mAb linked to the tubulin-disrupting maytansinoid DM4 via a cleavable linker.

It should be noted that, despite the increased complexity of the molecules, ADCs are also the focus of companies developing biosimilar products. As discussed in previous Society posts, biosimilars of antibody-based drugs that have lost patent protection, including adalimumab (Humira®), rituximab (Rituxan®, Mabthera®), trastuzumab (Herceptin®) and etanercept (Enbrel®), are already approved or undergoing regulatory review in the US and EU, as well as other countries.

The Antibody Society thanks Hanson Wade for access to Beacon, the World ADC database.

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Filed Under: ADC, Clinical pipeline, Phase 3 pipeline Tagged With: Antibody drug conjugates, antibody therapeutics

Antibody Drug Conjugates – News

July 10, 2016 by Joost Melis

square logo ADCImmunomedics announced the issuance of a novel patent (U.S. Patent 9,375,489) related to the company’s lead cancer therapeutic, sacituzumab govitecan, also known as IMMU-132. This antibody-drug conjugate (ADC) comprises a humanized antibody to the cancer target Trop-2 and is conjugated with SN-38, an active metabolite of the anti-cancer drug irinotecan. The patent entitled “Antibody-SN-38 Immunoconjugates with a CL2A Linker.” is the 28th issued U.S. patent covering the uses and composition of sacituzumab govitecan.

The ADC is in development for the treatment of patients with many diverse solid cancers. The most advanced indication in development is triple-negative breast cancer (TNBC). Phase II are also studies ongoing in patients with metastatic non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC) and in patients with metastatic urothelial cancers. According to Immunomedics’ updated clinical development plan for sacituzumab govitecan, in Q3 of 2016 the company plans to complete enrollment of additional patients into the ongoing single-arm Phase II study for patients with relapsed/refractory metastatic TNBC who received at least 2 prior therapies, including taxane. Immunomedics is collaborating with the FDA for completion of the ongoing Phase II trial and for submitting an Accelerated Approval registration application. Also discussions with the European Medicine Agency (EMA) have been initialized, and EMA has provided the company with advice on the scheduled Phase III trial.

 

In other news, AbbVie announced safety and preliminary efficacy data from a Phase I study of ABT-414. ABT-414 is an investigational ADC for treatment of epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM). Glioblastoma is the most common and most aggressive type of malignant primary brain tumor and in most cases a fatal disease. Amplified EGFR is the most common genetic mutation associated (~50% are EGFR mutations) with malignant GBM. With standard of care therapy, patients with GBM have a median survival of 15 months after diagnosis and two-year survival is 30%, demonstrating the urgent unmet need for new treatment options.

Published data showed no dose-limiting toxicities and frequent, reversible ocular toxicities. Furthermore, an estimated 30% (n=44) of patients treated with ABT-414 as monotherapy were progression free at six months [95% CI=17, 44] (secondary endpoint). Best Response Assessment in Neuro-Oncology (RANO) Criteria identified two partial responses, 18 patients with stable disease, and 24 with progressive disease for a total of 44 patients with complete data.

The most common serious adverse event (>1 patient) (n=48) was seizure (8%) as of January 7, 2016. Grade 3/4 treatment emergent adverse events (TEAEs) (>1 patient) were keratitis (15%), corneal epithelial microcysts (8%), hemiparesis (6%), hyperglycemia (6%), muscular weakness (6%), seizure (6%), blurred vision (4%) and ulcerative keratitis (4%).The most common TEAEs (≥25% patients) in this study arm were blurred vision (60%), headache (29%), photophobia (29%), dry eye (27%), eye pain (27%), and fatigue (27%).

 

Filed Under: Ab news, ADC, Clinical pipeline Tagged With: ADC, Antibody drug conjugates, antibody therapeutics, cancer, clinical pipeline, GBM, NSCLC, SCLC, TNBC

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