Joost Melis, Author at The Antibody Society

Back in business: gemtuzumab ozogamicin

September 23, 2017 by Joost Melis

Roughly 17 years ago gemtuzumab ozogamicin was first approved by the FDA for the treatment of patients over the age of 60 with CD33-positive relapsed acute myelogenous leukemia (AML), and who were not considered candidates for other cytotoxic chemotherapy.

The drug, also known as Mylotarg, was the result of a long-lasting collaboration between Wyeth (acquired by Pfizer in 2009) and CellTech (acquired by UCB in 2004), dating all the way back to 1991. Nine years later it was approved as a single agent under an “accelerated” approval based on the surrogate response rate endpoint that was observed in 142 patients with AML across 3 clinical trials. The approval made Mylotarg the first ADC to hit the US market at the time.

However, things turned quickly for the product. One year into its approval it required a black box packaging warning related to the increased risk of veno-occlusive disease. Initially, the warning was aimed at patients who did not receive bone marrow transplantation, but later the increased frequency of veno-occlusive disease was also observed in Gemtuzumab-treated patients after bone marrow transplantation.

A confirmatory, post-approval clinical trial commenced in 2004, per FDA guidelines for accelerated approval. Results of the randomized Phase 3 SWOG S0106 trial showed a significantly higher fatal induction toxicity rate in gemtuzumab combination therapy group versus the control group receiving only chemotherapy (16/283 = 5.7% versus 4/281 = 1.4%; p = 0.01).

Following the results of SWOG S0106 and the post-marketing experience with the drug, Pfizer decided to withdraw Mylotarg from the market in 2010 at the request of the FDA. The discontinuation was an upset in the ADC field. Upon the withdrawal brentuximab vedotin and trastuzumab emtansine were the only two approved ADCs for years to come. However, the potential of ADC therapeutics has seen a revival and around 60-70 products are in clinical trials at the moment.

Not only the ADC field itself bounced back after this blow, but also gemtuzumab ozogamicin made a recent comeback. Early this year Pfizer resubmitted Mylotarg for regulatory review and both the FDA and the EMA accepted to review the application based on added data from the Phase 3 randomized, open-label ALFA-0701 trial. In this study Mylotarg was evaluated as an addition to the standard induction chemotherapy using an alternative fractionated dosing schedule in 280 adult, de novo, AML patients between 50 and 70 years old. Additionally, a meta-analysis of patient-level data from over 3000 patients in five randomized Phase 3 trials were evaluated.

Now, seven years after discontinuation, gemtuzumab ozogamicin is back in business in the US. The FDA has approved the lower recommended dosage range and the alternative treatment schedule. The authorization now covers single uses or in combination with chemotherapy in a patient population that now also includes adults with newly diagnosed CD33-positive AML, and adults and children 2 years and older with relapsed or refractory CD33-positive AML.

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.

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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Antibody Drug Conjugates – News

July 10, 2016 by Joost Melis

Immunomedics 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%).

Antibody Drug Conjugates – Clinical Progress

June 1, 2016 by Joost Melis

In 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.