The European Commission has granted Orphan Drug Designation to loncastuximab tesirine (Zynlonta®; ADC Therapeutics); previously known as ADCT-402, a CD19-targeted ADC, for the treatment of diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma (NHL) in the United States and worldwide, accounting for about 22% of newly diagnosed cases of B-cell NHL in the United States. More than 18,000 people are diagnosed with DLBCL each year.

DLBCL is an aggressive, fast-growing, form of NHL that affects B-lymphocytes. And while the disease can occur in childhood, the occurrence of DLBCL generally increases with age, and most patients are over the age of 60 at the time of their diagnosis.

One of the features of the disease is that it can develop in the lymph nodes or in areas outside the lymph nodes known as “extranodal sites,” including the gastrointestinal tract, testes, thyroid, skin, breast, bone, brain, or essentially any organ of the body. DLBCL may be localized or generalized. Despite being an aggressive lymphoma, DLBCL is, in most cases, it is considered a potentially curable disease.

Orphan Drug Designation
“This Orphan Drug Designation recognizes the significant unmet need in patients with diffuse large B-cell lymphoma in the European Union (EU),” explained Joseph Camardo, MD, Senior Vice President and Chief Medical Officer of ADC Therapeutics.

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“We are committed to providing global access to loncastuximab tesirine for as many patients as may benefit. This designation is an important step in our collaboration with EMA for our marketing authorization in the EU,” Camardo added.

Orphan Drug Designation in the EU is granted by the European Commission based on a positive opinion issued by the EMA Committee for Orphan Medicinal Products (COMP). It is intended to encourage the development of drugs that may provide significant benefits to patients suffering from rare, life-threatening diseases. If approved for marketing, this designation will provide ten years of marketing exclusivity and also provide special incentives for sponsors, including eligibility for protocol assistance and possible exemptions or reductions in certain regulatory fees.

Mechanism of Action
Loncastuximab tesirine is a CD19-directed antibody and alkylating agent conjugate which consists of a humanized IgG1 kappa monoclonal antibody conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxic alkylating agent, through a protease-cleavable valine-alanine linker. SG3199 attached to the linker is designated as SG3249, also known as tesirine.

The drug has an approximate molecular weight of 151 kDa. An average of 2.3 molecules of SG3249 are attached to each antibody molecule. Loncastuximab tesirine is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis.

Once bound to a CD19-expressing cell, the drug is internalized by the cell, where enzymes release a pyrrolobenzodiazepine (PBD) payload.

The PBD-payload is designed to bind irreversibly to DNA minor groove with little distortion, remaining less visible to DNA repair mechanisms. It creates highly potent interstrand cross-links that block DNA strand separation, thus disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell cycle arrest and tumor cell death.

CD19 is a clinically validated target for the treatment of B-cell malignancies.

Regulatory approval
The U.S. Food and Drug Administration (FDA) has approved loncastuximab tesirine for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), DLBCL arising from low-grade lymphoma and also high-grade B-cell lymphoma. This indication is approved by the FDA under accelerated approval based on the overall response rate and continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA approval was based on data from LOTIS-2, a large (n=145) Phase 2 multinational, single-arm clinical trial of loncastuximab tesirine for the treatment of adult patients with r/r DLBCL following two or more prior lines of systemic therapy. The trial included a broad spectrum of heavily pre-treated patients (median three prior lines of therapy) with very difficult to treat disease, including patients with high-grade B-cell lymphoma. The trial enrolled patients who did not respond to first-line therapy, patients refractory to all prior lines of therapy, patients with double/triple hit genetics, and patients who had stem cell transplants and CAR-T therapy prior to their treatment with loncastuximab tesirine.

Results from the trial demonstrated an overall response rate (ORR) of 48.3% (70/145 patients), which included a complete response (CR) rate of 24.1% (35/145 patients) and a partial response (PR) rate of 24.1% (35/145 patients). Patients had a median time to response of 1.3 months.

At the most recent data cut-off for patients enrolled in the trial, the median duration of response (mDoR) was 13.4 months. In a pooled safety population the most common adverse reactions (≥20%) were thrombocytopenia, gamma-glutamyltransferase increased, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain. In LOTIS-2, the most common (≥10%) grade ≥3 treatment-emergent adverse events were neutropenia (26.2%), thrombocytopenia (17.9%), gamma-glutamyltransferase increased (17.2%) and anemia (10.3%).

Loncastuximab tesirine is being evaluated in combination for earlier lines of therapy and as a monotherapy in other B-cell malignancies.

Clinical trials
Loncastuximab Tesirine and Venetoclax for Relapsed/ Refractory Non-Hodgkin Lymphoma – NCT05053659
Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS-2) – 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
Loncastuximab Tesirine in Combination With Rituximab in Patients With Relapsed or Refractory Follicular Lymphoma – NCT04998669
Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine Versus Idelalisib in Participants With Relapsed or Refractory Follicular Lymphoma (LOTIS 6) – NCT04699461
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL) – NCT02669017
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute Lymphoblastic Leukemia (B-ALL) – NCT02669264
Study to Evaluate Loncastuximab Tesirine With Rituximab Versus Immunochemotherapy in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS 5) – NCT04384484
A Study to Evaluate the Safety and Anti-cancer Activity of Loncastuximab Tesirine in Combination With Other Anti-cancer Agents in Participants With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (LOTIS 7) – NCT04970901
A Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Antitumor Activity of Loncastuximab Tesirine in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Participants With Previously Untreated Diffuse Large B-cell Lymphoma (LOTIS-8) (LOTIS-8) – NCT04974996
Loncastixumab Tesirine (ADCT-402) Expanded Access Program (EAP) for Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma – NCT04705454

Highlights of Prescribing Information
Loncastuximab tesirine (Zynlonta®; ADC Therapeutics) [Prescribing Information]

Coding and Billing Guide (USA)
Coding information [Guide USA]

Reference
[1] Hamadani M, Radford J, Carlo-Stella C, Caimi PF, Reid E, O’Connor OA, Feingold JM, Ardeshna KM, Townsend W, Solh M, Heffner LT, Ungar D, Wang L, Boni J, Havenith K, Qin Y, Kahl BS. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021 May 13;137(19):2634-2645. doi: 10.1182/blood.2020007512. PMID: 33211842; PMCID: PMC8138546.
[2] Jain N, Stock W, Zeidan A, Atallah E, McCloskey J, Heffner L, Tomlinson B, Bhatnagar B, Feingold J, Ungar D, Chao G, Zhang X, Qin Y, Havenith K, Kantarjian H, Wieduwilt MJ. Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia. Blood Adv. 2020 Feb 11;4(3):449-457. doi: 10.1182/bloodadvances.2019000767. PMID: 32012214; PMCID: PMC7013258.
[3] Kahl BS, Hamadani M, Radford J, Carlo-Stella C, Caimi P, Reid E, Feingold JM, Ardeshna KM, Solh M, Heffner LT, Ungar D, He S, Boni J, Havenith K, O’Connor OA. A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. Clin Cancer Res. 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. Epub 2019 Nov 4. PMID: 31685491.
[4] Lee A. Loncastuximab Tesirine: First Approval. Drugs. 2021 Jul;81(10):1229-1233. doi: 10.1007/s40265-021-01550-w. PMID: 34143407.

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