Status: withdrawn from the market

Organizations involved:

NeoRx Corp. – R&D; Tech.; USA mark.

Boehringer Ingelheim Pharma KG – Manuf.; Intl. mark.

DuPont Pharmaceuticals – USA mark.

Syncor International, Inc. – Manuf. other

Dr. Karl Thomae GmbH – Former

Invitron Inc. – Former

Cross ref: See Monoclonal Antibodies (entry #300).

Description: Verluma is a kit for the preparation of Technetium Tc 99m nofetumomab merpentan, a metal radioisotope-labeled murine hybridoma cell cultured monoclonal antibody Fab fragment with specificity for CD20 antigen administered intravenously for radiodiagnostic imaging of tumors, particularly small cell lung cancer (SCLC) metastases. Technetium Tc 99m nofetumomab merpentan is formed by chemical conjugation of the nofetumomab (NR-LU-10) monoclonal antibody Fab fragment with a complexed radioisotope, Technetium Tc 99m-phenthioate ligand (sodium pertechnetate Tc 99m), resulting in the nofetumomab monoclonal antibody Fab fragment linked covalently to the Technetium-99 radionuclide ligand complex. The active targeting monoclonal antibody fragment component, nofetumomab (NR-LU-10), is an enzymatically-derived Fab fragment of a murine (mouse) IgG2b monoclonal antibody produced by in vitro murine hybridoma culture with specificity for an approximately 40 kDa glycoprotein (CD20) antigen expressed on the surface of tumor cells, particularly carcinomas, and some normal tissues.

The Fab monoclonal antibody fragment component of Tc 99m nofetumomab merpentan causes it to concentrate selectively in target antigen-expressing tissues (e.g., small cell lung cancer tumors), and the radioactive decay of the Technetium radioisotope component and resulting gamma radiation emission allows tumor detection and radiodiagnostic imaging of concentrations of tumor cells expressing CD20, particularly small cell lung cancer (SCLC). The distribution of potential small cell lung cancer metastatic sites, in decreasing order of prevalence, for radiodiagnostic imaging is lung, mediastinal lymph nodes, supraclavicular lymph nodes, pleura, liver, brain, bone, and bone marrow.

The nofetumomab Fab fragment is prepared from purified NR-LU-10 monoclonal antibody (prepared by conventional hybridoma serum-free cell culture) by enzymatic digestion with papain, and purified by chromatographic separations including viral inactivation and removal procedures. Nofetumomab retains the binding specificity of the NR-LU-10 monoclonal antibody. The radioimmune conjugate, Technetium-99m nofetumomab merpentan, is prepared in local nuclear pharmacies by chemical conjugation (chelation) of the nofetumomab Fab fragment to the radionuclide technetium-99, by combining nofetumomab and other non-radioactive kit components with sodium pertechnetate Technetium Tc 99m (radioactive Tc 99m radioisotope bound to the pertechnetate chelator-linker group). Technetium-99m (Tc 99m) radioisotope is conjugated to the NR-LU-10 monoclonal antibody Fab fragment using ligand technology developed by NeoRx Corp. (see the Tech. transfer section), The sodium pertechnetate Tc 99m is usually generated only as needed by the nuclear pharmacy preparing the product. Technetium Tc99m decays by isomeric transition, giving off gamma radiation, with a physical half-life of 6.02 hours.

The final product contains 5-10 mg of Technetium Tc 99m Nofetumomab Merpentan radiolabeled with 555-1110 mBq (15 to 30 mCi) of Technetium Tc 99m radioisotope diluted with 0.9% Sodium Chloride Injection, in a final volume of 15 to 20 mL, with pH of 7.25 +/- 0.75. The radiochemical purity is determined using a thin layer chromatography (TLC) assay prior to use and must be ≥ 85%. The final compounded product should be administered to the patient within six hours of preparation (during which radiation emission decreases by about 1/2). Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours, emitting gamma radiation with a mean energy of 140.5 Kev. The specific gamma ray constant for Technetium Tc 99m is 5.4 microcoulombs/kg-MB1-hr (0.78 R/mCi-hr) at 1 cm.

Each Verluma kit contains the following non-radioactive components: a) Nofetumomab – NR-LU-10 Fab fragment in Phosphate Buffered Saline, 10 mg in 1 mL; b) Phenthioate Ligand – pertechnetate or 2,3,5,6-tetrafluorophenyl-4,5-bis-S-(1-ethoxyehtyl)-thoaceto-amido-pentoate), 0.28 mg (freeze-dried); c) Anion Exchange Column, 5 ml with 0.2 µm Sterile Filter; and d) other components – isopropyl alcohol (99%, 1.5 ml); Glacial Acetic Acid and 0.2 N Hydrochloric Acid 1:7 (vol/vol), 0.16 ml; Stannous (tin) Gluconate Complex containing Sodium Gluconate (45 mg) and Stannous Chloride, Dihydrate (0.79 mg, lyophilized); 1 M Sodium Bicarbonate Buffer (pH 10, 1 ml); and an Elution Vial (10 mL). All components are sterile, pyrogen-free, and contain no preser-vatives. The dating period of nofetumomab is two years from date of manufacture, defined as the date of final sterile filtration of the formulated bulk.

The isopropyl alcohol kit component is used to dissolve the freeze-dried phenthioate ligand which is involved in two different reactions: a) complexation (chelation ) of the Technetium Tc 99m metal with phenthioate; and b) conjugation of the resulting radioactive complex to nofetumomab via the phenthioate group. The stannous gluconate complex performs two functions – stannous ions reduce the oxidation state of Technetium Tc 99m; and the gluconate acts as an intermediate transfer agent to stabilize the reduced Technetium Tc 99m for chelation to the phenthioate ligand. Sodium bicarbonate buffer is used to adjust the Technetium Tc 99m-phenthioate ligand (pertechnetate; active ester) reaction mixture to pH 10. This basic pH deprotonates the epsilon amino groups of the available lysine residues on the nofetumomab Fab. These neutral amino groups react with the active ester to form a covalent amide bond, resulting in the formation of the monoclonal antibody Fab fragment-pertechnetate complex (nofetumomab merpen-tan), later reacted with Technetium Tc 99m to form to radioimaging product, Tc 99m nofetumomab merpen-tan. The anion exchange chromatography column with sterile filter is used to filter and retain non-protein bound radioactive species, and acts to neutralize the pH. Purified Technetium Tc 99m nofetumomab merpen-tan ready for intravenous administration is eluted from the column. [Detailed instructions for preparation of Verluma are provided in the product label/insert].

Nomenclature: NR-LU-10 Mab Fab radioconj. [BIO]; Verluma [TR for kit]; nofetumomab [FDA for monoclonal antibody fragment]; Kit for the preparation of Technetium Tc 99m Nofetumomab Merpentan [FDA]; Technetium Tc 99m nofetumomab merpentan [FDA for final radioimmune conjugate]; immunoglobulin G2b, anti-(human tumor) Fab fragment (mouse monoclonal NR-LU-10 gamma2b-chain), disulfide with mouse monoclonal NR-LU-10 kappa chain, oxo(N,N’-(1-(3-oxopropyl)-1,2-ethan-diyl)bis(2-mercaptoacetamido))(4-N,N’,S,S’)technetate(1-), 99mTc conjugate [CAS for radio-immune conjugate]; nofetumomab merpentan [SYfor Fab fragment–linker group]; NR-LU-10–99mTc [SY or radioimmune conjugate]; CD20 monoclonal antibody Fab fragment–Tc 99m [SY for radioimmune conjugate]

Note, “nofetumomab” is primarily used to refer to the NR-LU-10 Mab Fab fragment, although the term is sometimes used to also refer to the parent, NR-LU-10 monoclonal antibody. FDA refers to Verluma as “Nofetumomab and associated components for the preparation of Technetium Tc 99m Nofetumomab Mer-pentan” (the “kit”). “Verluma” is also commonly used to refer to the radioimmune conjugate produced by the kit.

Companies.: Verluma was developed and is marketed in the U.S. by NeoRx Corp. Nofetumomab and Verluma (kit) are manufactured by Boehringer Ingelheim Pharma KG (formerly Dr. Karl Thomae GmbH), CBER/FDA est. no. 1251. Boeh-ringer Ingelheim has worldwide manufacturing rights granted by NeoRx Corp. Dr. Karl Thomae GmbH, subsequently acquired by Boehringer Ingelheim, received the original FDA approval. The source NR-LU-10 monoclonal antibody was apparently originally manufactured by Invitron Inc. under contract to NeoRx.

Verluma is co-marketed in the U.S. by NeoRx and DuPont Pharmaceutical Co. Boehringer Ingelheim holds exclusive international (ex-U.S.) marketing rights. In the U.S., the Syncor chain of radiopharmaceutical pharmacies offers local preparation of Verluma for rapid delivery to hospitals.

FDA class: Biologic BLA

CBER class: Blood And Blood Derivatives

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 19960820; BLA ref. no 94-0305 and 94-0308; granted to Dr. Karl Thomae GmbH

Date = 19981013; licenses revoked and granted (reissued) to Boehringer Ingelheim Pharma KG, new owner

Indications: [full text from "INDICATIONS AND USAGE” section of recent product insert/labeling]:

Technetium Tc 99m Nofetumomab Merpentan is indicated for the detection of extensive stage disease in patients with biopsy-confirmed, previously untreated small cell lung cancer. Where Technetium Tc 99m Nofetumomab Merpentan is interpreted as limited stage disease (limited to one hemithorax, mediastinum, bilateral hilar lymph nodes, ipsilateral supreclavicular nodes), additional diagnostic tests should be performed to exclude extensive stage disease. Bone scan, CT examinations of the head, chest, abdomen, chest x-ray, and/or bone marrow aspirate/biopsy have been shown to demonstrate additional sites of involvement in some patients.

Technetium Tc 99m Nofetumomab Merpentan imaging is not indicated for differential diagnosis of suspected lung cancer or suspected metastases. Technetium Tc 99m Nofetumomab Merpentan is intended for single use prior to treatment: it is not intended for assessment of response or evaluation following chemotherapy radiotherapy (see Precautions).

Status: Verluma is no longer approved, manufactured or marketed.

The BLA was submitted on March 28, 1994 and approved on Aug. 20, 1996; review time= ~29.6 months (~ 2.5 years). Verluma was launched in the U.S. in Feb. 1997.

Nofetumomab and Verluma were exempt from FDA CBER/FDA lot release requirements.

Verluma did not receive European Union approval, with no application apparently ever filed.

Tech. transfer: Related U.S. patents include 4,897,255; 5,037,630; 5,120,526; 5,175,343; and 5,242,679. Due to the time Verluma spent in FDA regulatory review (under 35 USC §156), the expiration date of 4,897,255 was extended 1,298 days (3.56 years) to Aug. 20, 2010.

U.S. 5,242,679, “Metal radionuclide labeled proteins for diagnosis and therapy,” Fritzberg, et al., Sept. 7, 1993, assigned to NeoRx Corp. (and related patents, including 4,897,255; 5,037,630; 5,175,343 and 5,242,679) describes intermediates and methods for forming protein conjugated/chelated metal radionuclides. U.S. 5,120,526, “Method of producing metal radionuclide labeled proteins for diagnosis and therapy,” Fritzberg, et al., June 9, 1992, assigned to NeoRx Corp., describes chelated radionuclide protein conjugates, their use for diagnosis, and diagnostic kits for onsite preparation of the radioimmune conjugates.

Based on FDA’s determination that the regulatory review period for Veluma was 3,360 days (925 days during the testing phase and 2,435 days occurred during the approval phase), the U.S patent office extended the expiration date of 4,897,255 by 1,298 days.

Trials: The pivotal Phase III clinical trial was initiated in Aug. 1988 at 23 sites in the U.S. and one site in Denmark. In its clinical trials, Verluma predicted staging of SCLC in 82% (73/89) of patients. However, if the radiodiagnostic imaging indicated limited disease, it was less valuable as a diagnostic aid, and Ver-luma failed to image tumors in some body organs in approximately 23% of the patients. Thus, if imaging shows limited stage disease, additional diagnostic tests are generally performed to exclude extensive stage disease, e.g., bone scintigraphy; computed tomographic [CT] examinations of the head, chest, and abdomen; x-ray of the chest; and/or bone marrow aspirate/biopsy.

Medical: Verluma allows simplified imaging of metastases throughout the body in a single test for biopsy-confirmed, previously untreated small cell lung cancer (SCLC) patients. Most but not all tumors and not all patients with small cell lung cancer express the antigen targeted by NR-LU-10, so the product may not image all tumors in all patients.

Verluma is administered intravenously as a single dose of 5-10 mg nofetumomab merpentan labeled with 1,110 MBq (30 mCi) Technetium Tc 99m in 15-20 ml Sodium Chloride Injection. At least 555 MBq (15 mCi) of the final preparation (Tc 99m nofetumomab merpentan) should be administered to assure adequate images. The optimal time for imaging is 14-17 hours after injection of Tc 99m nofetumomab merpentan. Because of the potential for false negative readings, additional standard diagnostic tests, such as a bone or CT scan or a bone marrow biopsy, should be performed when limited disease is found.

As with any murine antibody, the nofetumomab Fab portion may induce human anti-mouse antibodies (HAMA), a form of rejection, in some patients.