Featured Image: Doctor explaining clinical trial to patient. Courtesy: © 2019. Fotolia Used with permission.

Earlier this year, in April, Celldex Therapeutics reported that the randomized, Phase IIb METRIC Study of glembatumumab vedotin, also known as CDX-011, a targeted antibody-drug conjugate or ADC, compared to capecitabine (Xeloda®; Genentech/Roche) in patients with metastatic triple-negative breast cancers that overexpress gpNMB failed to meet its primary endpoint, progression-free survival (PFS) as assessed by an independent, central reading of patient scans. [1][2]

As a consequence, the company announced that, based on these results, the decision was made to discontinue the glembatumumab vedotin development program across all indications.

NCT01997333 (CLINICAL TRIAL / GLEMBATUMUMAB VEDOTIN / CDX-011 / CR011-VCMMAE)
Schematic 1.0: The main purpose of the Phase II METRIC study was to see whether Glembatumumab Vedotin, an antibody-drug conjugate also known as CDX-011, is effective in treating patients who have advanced Triple-Negative Breast Cancer (TNBC), and whose tumor cells make a protein called glycoprotein NMB (gpNMB), which glembatumumab vedotin binds to. The study was also designed to further characterize the safety of CDX-011 treatment in this patient population.

Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate targeting glycoprotein NMB (gpNMB). This protein is overexpressed by multiple tumor types, including breast cancer, melanoma, lung cancer, uveal melanoma and osteosarcoma.

MabPlex
 

The gpNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream but to release MMAE upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect.

Strategic prioritization
“Celldex has made considerable progress on an important strategic prioritization of our pipeline, following announcement in April of the METRIC study results in triple-negative breast cancer and discontinuation of the glembatumumab vedotin program across all indications,” commented Anthony Marucci, Co-founder, President and Chief Executive Officer of Celldex Therapeutics.

Following the discontinuation of the glembatumumab vedotin development program, the company announced that it will also cancel the ongoing development of CDX-014.  This ADC, which targets TIM-1, is currently in early Phase I development in renal cell and clear cell ovarian carcinomas.[2]

The investigational agent is designed to target the extracellular domain of the T cell immunoglobulin mucin domain 1 (TIM-1),  a type I transmembrane protein that was originally described as kidney injury molecule 1 (KIM-1) due to its elevated expression in kidney and urine after renal injury.

NCT02837991 (Clinical Trial/ CDX-014)
Schematic 2.0: The NCT02837991 study was designed to determine the safety and effectiveness of CDX-014. The study enrolled patients with advanced or metastatic renal cell carcinoma and ovarian clear cell carcinoma. This study included a Dose-Escalation Phase followed by a Cohort Expansion Phase All patients enrolled in the study were closely monitored to determine if there is a response to the treatment as well as for any side effects that may occur.

In this agent, the anti-TIM-1 antibody covalently linked via via a valine-citrulline (vc) peptide linker, to a potent cytotoxin, monomethyl auristatin E (MMAE) using Seattle Genetics’ proprietary technology and designated as CDX-014.

In pre-clinical trials CDX-014 was shown to exhibit in vitro cytostatic or cytotoxic activity against a variety of TIM-1 expressing cell lines, but not on TIM-1 negative cell lines.[3]

Focus
The company is expected to focus clinical development on two company-sponsored programs—CDX-1140, a promising CD40 agonist, and CDX-3379, which blocks ErbB3, a receptor thought to play an important role in regulating cancer cell growth and survival.

“[The] development of varlilumab and CDX-301 will also continue externally through investigator-sponsored initiatives and internally through inclusion in combination studies,” Marucci added.

ADC-Development programs
With a number of other announcements made by various companies developing antibody-drug conjugates,  it is noteworthy to see that the majority of ADC-development programs being discontinued are in early phase I development (69%) and phase II (16%) development.[4]

While there there  is a relatively high number of ADC-development programs being cancelled, it is also noteworthy that there are nine new ADC-development programs that enter clinical trials this year.