The U.S. Food and Drug Administration (FDA) has accepted the Biologics License Application (BLA) for loncastuximab tesirine, previously known as ADCT-402.

The investigational agent is an antibody-drug conjugate (ADC) composed of a humanized monoclonal antibody directed against human CD19 and conjugated through a linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin.

Pyrrolobenzodiazepine (PBD) dimers produce highly cytotoxic DNA cross-links, and, in comparison to other ADC payloads such as the auristatin and maytansinoid tubulin inhibitor classes, they exploit a different cellular target.  They also exploit a different mode of DNA damage to other DNA interacting warheads such as calicheamicin. [1]

Loncastuximab tesirine is being developed by Swiss-based ADC Therapeutics for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and granted priority review status. The FDA has set a Prescription Drug User Fee Act or PDUFA target date of May 21, 2021.

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“The FDA’s acceptance of our Biologics License Application and granting of priority review for loncastuximab tesirine is a tremendous accomplishment that brings ADC Therapeutics one step closer to being able to offer patients with relapsed or refractory DLBCL a greatly needed new treatment option in 2021,” said Chris Martin, Chief Executive Officer of ADC Therapeutics.

“We look forward to working with the FDA during its review of our BLA submission for loncastuximab tesirine. Our organization remains focused on robust planning for a successful launch next year.”

Mechanism of Action
Once bound to a CD19-expressing cell, loncastuximab tesirine is designed to be internalized by the cell, following which the warhead is released. The warhead is designed to bind irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thus disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell death.

CD19 is an immunoglobulin superfamily (IgSF) surface glycoprotein of 95 kDa. It is expressed from the earliest stages of B cell development until plasma cell terminal differentiation when its expression is lost.[2]

CD19 is a clinically validated target for the treatment of B-cell malignancies because it is expressed on most B-cell malignancies and in the B-cell lineage at an early stage, even before the expression of CD20; it internalizes efficiently in lymphoma tumor models and it is possibly involved in the development of B-cell cancers.  Research has shown that CD19 can upregulate the expression and phosphorylation of c-Myc which is a proto-oncogene found mutated and/or overexpressed in multiple malignancies. As a result, CD19 can be considered as a poor prognostic factor in human lymphomas, a validating CD19 as a target for the treatment of B-cell leukemia and lymphoma. [2]

The BLA submission is based on data from LOTIS 2, the pivotal Phase II multi-center, open-label, single-arm clinical trial evaluating the efficacy and safety of Lonca in patients with relapsed or refractory DLBCL following two or more lines of prior therapy.

In June 2020, ADC Therapeutics presented maturing data from LOTIS 2 at the virtual 25th Congress of the European Hematology Association (EHA). As of the April 6th cutoff date, loncastuximab tesirine demonstrated an overall response (ORR) rate of 48.3% (70/145 patients) and a complete response rate of 24.1% (35/145 patients).

The tolerability profile was manageable with the most common grade ≥3 treatment-emergent adverse events in ≥10% of patients being: neutropenia (25.5%) with a low incidence of febrile neutropenia (3.4%), thrombocytopenia (17.9%), GGT increase (16.6%), and anemia (10.3%).

Data from subgroup analyses of LOTIS 2 will be presented in a poster (abstract #1183) at the upcoming 62nd American Society for Hematology (ASH) Annual Meeting on Saturday, December 5, 2020.

In the poster presentation, the authors confirm that loncastuximab tesirine had substantial single-agent antitumor activity in patients who had failed established therapies, including analysis of response in high-risk, relapsed, or refractory DLBCL subgroups.

The authors also show that no new safety concerns were identified and no increase in toxicity was observed for patients aged 65 years of age and older. The study results show encouraging and durable responses in high-risk patient groups, including double- or triple-hit, transformed, or refractory DLBCL.  This was especially notable in patients who had progressed after prior CAR T-cell therapy. Finally, investigator-reported overall response rate (ORR) indicates that many patients also respond to CAR T-cell therapy given after loncastuximab tesirine.

Investigational program
Loncastuximab tesirine, ADC Therapeutics’ lead product candidate, has been evaluated in a 145-patient pivotal Phase II clinical trial for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) that showed a 48.3% overall response rate (ORR), which exceeded the target primary endpoint.

Loncastuximab tesirineis is also being evaluated in LOTIS 3, a Phase I/II clinical trial in combination with ibrutinib in patients with relapsed or refractory DLBCL or mantle cell lymphoma, and LOTIS 5, a Phase III confirmatory clinical trial in combination with rituximab in patients with relapsed or refractory DLBCL.

Clinical trials
Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma – NCT03589469
Safety and Antitumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma – NCT03685344
Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma – NCT03684694
Study to Evaluate Loncastuximab Tesirine With Rituximab Versus Immunochemotherapy in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS 5) – NCT04384484
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute Lymphoblastic Leukemia (B-ALL) – NCT02669264
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL) – NCT02669017

Highlights of prescribing information
Ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech) [Prescribing Information]
Rituximab (Rituxan®; Genentech/Biogen) [Prescribing Information]

[1] Hartley JA. Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy. Expert Opin Biol Ther. 2020 Jun 16:1-13. doi: 10.1080/14712598.2020.1776255. Epub ahead of print. PMID: 32543981.
[2] Comprehensive Medicinal Chemistry III (3rd Edition) Editors in Chief: Samuel Chackalamannil David Rotella Simon Ward / ISBN: 9780128032008 (eBook ISBN: 9780128032015); Elsevier. Published Date: 15th June 2017

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