Status: currently approved in U.S., withdrawn from U.S. marketing; awaiting FDA reevaluation

Organizations involved:

Palatin Technologies, Inc. – Manuf.; R&D; Tech.

Avantor™ Performance Materials – World mark..

Wistar Institute – Tech.

Ben Venue Laboratories – Manuf. other

Boehringer Ingelheim Pharma KG.– Parent

Cross ref: See the entry for Granulocyte Mab–Tc99m radioconj. (LeukoScan), which is used for the same indications:, radiodiagnosis of appendicitis. See also the entry for Monoclonal Antibodies (#300).

Description: [Kit for the Preparation of Technetium (99m Tc) fanolesomab] or NeutroSpec (formerly LeuTech) is a kit containing lyophilized (freeze-dried) fanolesomab, a murine IgM monoclonal antibody from culture of a murine hybridoma cell line with specificity for CD15 antigen on human granulocyte/neutrophil (particularly polymorphonuclear leukocyte) cell membranes, which is chemically conjugated to Technetium 99mTc radioisotope (using Technetium Tc 99m sodium pertechnetate), providing the radiodiagnostic imaging agent Technetium (99m Tc) fanolesomab. The IgM monoclonal antibody (fanolesomab; RB5) has a molecular weight of ~670 kDa, and consists of mouse monoclonal RB5 mu-chain, anti-human CD15, disulfide with mouse monoclonal RB5 light chain, pentamer.

Kits contain a single-use vial of fanolesomab as a sterile, non-pyrogenic, lyophilized mixture of 0.25 mg fanolesomab; 12.5 mg maltose monohydrate; 0.522 mg sodium potassium tartrate tetrahydrate, USP; 0.221 mg succinic acid; 54 µg stannous tartrate (minimum stannous 7 µg; maximum total stannous and stannic tin 24 µg); 28 mcg glycine, USP; and 9.3 µg disodium edetate dihydrate, USP; with no preservatives and no U.S. standard of potency. When sterile, pyrogen-free sodium pertechnetate Tc 99m Injection, USP in isotonic saline (no preservatives) is added to the single use fanolesomab vial, the Tc 99m complex of fanolesomab is formed with a pH of ~6.2.

Nomenclature: CD15 Mab–Tc 99m radioconj.[BIO]; technetium (99mTc) fanolesomab [FDA; INN; USAN]; Kit for the Preparation of Technetium (99m Tc) fano-lesomab [FDA on labeling]; Technecium labeled TC99M anti-CD15 antibody injection [FDA in reg. doc.]; immunoglobulin M, anti-(human CD15 (antigen)) (mouse monoclonal RB5mu-chain), disulfide with mouse monoclonal RB5 light chain, pentamer, technetium-99mTc salt [CAS]; immunoglobulin M, anti-(human CD15 antigen) (mouse monoclonal RB5µ-chain), disulfide with mouse monoclonal RB5 light chain, pentamer, [99m Tc]-techne-tium salt [CAS]; 225239-31-6 [CAS RN]; CD15 monoclonal antibody–Technetium TC99M radioimmune conjugate [SY]; RB5 IgM [SY]

Biological.: The CD15 antibody portion of NeutroSpec binds with high affinity and specificity to white blood cells, particularly polymorphonuclear leukocytes (PMN cells). Fanolesomab is directed against the carbohydrate moiety 3-fucosyl-N-acetyllactosamine that defines the cluster of differentiation 15 (CD15) antigen. The CD15 antigen is expressed on the surface of polymorphonuclear neutrophils (PMNs), eosinophils and monocytes. As a result of the in vivo systemic administration of NeutroSpec, Technetium (99m Tc) fanolesomab accumulates at the infection site, e.g., an infected appendix (appendicitis), allowing infections to be easily and rapidly imaged and detected with a Gamma camera.

Kits contain a 3 mL single-use vial of fanolesomab and a 2 mL single-use ampule of Cenolate (Ascorbic Acid, USP), which also contains sodium hydrosulfite (a sulfite that may cause allergic reactions, including anaphylaxis, in some patients). Fanolesomab is stored at 2-8˚C (refrigerated), and has dating period of 24 months from the date of manufacture, which is defines as the date of fmal sterile filtration of the formulated drug product. The dating period for the drug substance is 36 months when stored at -60˚C or below. The dating period for the intermediate drug product is 18 months when stored at -60˚C or below. The expiration date for the kit containing Fanolesomab and CenolateTM is the shortest expiration date of either component.

LeuTech preparation (radiolabeling of the antibody) by a on onsite or regional nuclear pharmacy involves the addition of Technetium Tc 99m sodium pertechnetate solution to an aseptic vial containing lyophilized monoclonal antibody. These are gently mixed and incubated for approximately 30 minutes. Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours, emitting gamma rays with a mean energy of 140.5 Kev.

Companies.: Palatin Technologies, Inc. concluded an agreement for development and marketing of NeutroSpec with Mallinckrodt Inc. in Aug. 1999. Mallinckrodt received an exclusive worldwide license (excluding Europe), and paid a licensing fee of $500,000 and $13 million for Palatin stock. Development expenses prior to FDA approval are equally shared. Palatin manufacture NeutroSpec and receives a transfer price on each product unit and a royalty on net sales. In July 2005, Pallatin’s licensing of NeutroSpect to Mallinckrodt was extended to include Europe, providing Mallinckrodt with worldwide rights.

In Oct. 2000, Tyco Healthcare, a subsidiary of Tyco International, Inc., acquired Mallinckrodt. In May 2002, Palatin and Tyco/Mallinckrodt modified their agreement, with Tyco/Mallinckrodt providing additional funds, receiving more Palatin stock, and paying Palatin a $10 million upon FDA approval and attainment of certain sales after launch. All development expenses were equally shared.

Mallinckrodt is now Avantor™ Performance Materials

Palatin, CBER/FDA est. no. 1588, manufactures LeuTech and receives a transfer price per unit and royalties on net sales fromTyco/Mallinckrodt . Finishing (filling, labeling, packaging) is performed by Ben Venue Laboratories, a subsidiary of Boehringer Ingelheim Pharma KG. The Mallinckrodt nationwide nuclear pharmacy network and the Cardinal Health Nuclear Pharmacy Services network prepare and distribute NeutroSpec in the U.S.

FDA class: Biologic BLA

Approvals: Date = 20040706; BLA, original approval

Indications: [full text of the "Indications and USAGE section of product insert/labeling, 4/2005]

NeutroSpec [Technetium (99m Tc) fanolesomab] is indicated for scintigraphic imaging of patients with equivocal signs and symptoms of appendicitis who are five years of age or older.

Status: Palatin filed a BLA in Nov. 1999. It was accepted in early Feb. 2000. In July 2000, the FDA Medical Imaging Drugs Advisory Committee (MIDAC) unanimously voted that NeutroSpec is safe and effective for the diagnosis of appendicitis and that it has clinical utility. However, in Sept. 2000 Palatin received a ‘complete review’ letter from the FDA that requested further manufacturing and process validation data prior to approval. No further data were requested on the safety and clinical efficacy. A BLA amendment was filed in late 2002.

NeutroSpec was approved on July, 6, 2004, and was exempt from CBER, FDA, lot release requirements. NeutroSpec was launched on Aug. 19, 2004.

No European Union application has been filed.

On Dec. 1, 2005, the FDA issued a warning letter requesting the market withdrawal of NeutroSpec and issued a public health advisory urging healthcare providers to discontinue its use. A number of cases had been reported in which NeutroSpec caused allergic type reactions that occurred within minutes following its administration. FDA stated, “These reactions lead to the deaths of two patients, and to cardiopulmonary failure, central nervous system reactions, and infusion reactions in other patients.” The FDA informed Palatin and Mallinckrodt that it had reconsidered the risk/benefit assessment of NeutroSpec and decided it should not be administered to patients until a further understanding and review of the relationship between NeutroSpec and reported serious adverse events is complete. Faced with this, Palatin and Tyco Healthcare Mallinckrodt decided to voluntarily suspend the sales, marketing and distribution of NeutroSpec and recall all existing customer inventories of this product. On Dec. 19, 2005, FDA issued a “Public Health Advisory” pending further review of reported deaths and serious and life-threatening adverse events associated with use of the product, and Palatin suspended sales, marketing. and distribution of Neutrospec. FDA urged health care providers to discontinue use of existing stocks and to contact Palatin Technologies regarding their return.

FDA planned to hold an advisory panel meeting in 2006 to discuss the use of NeutroSpec with additional safeguards, evidence needed to continue use of the product for equivocal appendicitis, and plans for other indications:, e.g., osteomyelitis. However, this meeting has yet to be held, and FDA has not yet taken action on NeutroSpec.

Tech. transfer: Murine monoclonal antibody with specificity for CD15 was licensed from the Wistar Institute.

Trials: The BLA was based on three years of clinical studies. A 10-site Phase II trial in 203 patients aged 5-86 years showed that NeutroSpec detected appendicitis in 91% of positive patients, and correctly predicted the absence of appendicitis in 96% of negative patients (i.e., surgeons could confidently discharge patients with a negative scan rather than admit them into the hospital for observation and additional tests), with no adverse effects. NeutroSpec allowed radiologists to quickly obtain accurate diagnostic images. The probability of correctly diag-nosing appendicitis was 6-13 times greater with the addition of NeutroSpec to the diagnostic process. NeutroSpec improved the quality and cost-effectiveness of patient care by helping avoid unnecessary surgery and hospital admissions for observations.

Disease: About 700,000 persons in the U.S. annually visit emergency departments and physicians with symptoms of appendicitis. More than 350,000 patients present with equivocal appendicitis, i.e., a specific diagnosis is uncertain and further testing is needed. In this situation, it is not always clear if the patient has appendicitis or another medical problem; nor is it clear where infection is located. If a diagnosis of appendicitis is missed, there can be significant medical consequences such as appendix perforation and peritonitis. More than 250,000 are diagnosed with the infection, acute appendicitis. Approximately 320,000 appendectomies are performed annually, of which about 250,000 may be considered equivocal. Of the performed surgeries, a normal appendix is found in about 20% of procedures, and perforated appendices are found in ~25%. it is currently considered acceptable to have a 10-20% negative laparotomy rate in which a normal appendix is removed.” Other non-invasive tests to diagnose appendicitis, i.e., spiral CT with contrast, are not available everywhere and can be difficult to perform and interpret.

Medical: For radiodiagnosis of appendicitis in adults, the recommended dose for imaging is 75-125 µg of fanolesomab labeled with 10-20 millicuries of sodium pertechnetate Tc 99m administered as a single intravenous dose of technetium Tc 99m fanolesomab. For the diagnosis of appendicitis in pediatric patients 5 years or older, a single intravenous dose of technetium Tc 99m fanolesomab 0.21 millicuries/kg (maximum of 20 mCi) is recommended. After intravenous injection, diagnostic imaging can be obtained within one hour with conventional planar gamma camera techniques. The liver has the highest radioactivity uptake and retention of the injected dose (50%), followed by the kidney, spleen and red marrow. Technetium Tc 99m fanolesomab has an initial half-life of 0.3 hours and a second phase half-life of ~8 hours

A positive NeutroSpec image specifically indicates that a patient has an active infection of the appendix. This is in contrast to computed tomography (CT) scan, which provides an anatomical image, and the physician must then determine if a change in an anatomical structure is due to infection or something else. With NeutroSpec, accurate diagnosis can be made in a matter of 90 minutes.

Market Since it was launched in Sept. 2004, Tyco Healthcare Mallinckrodt’s NeutroSpec sales through Sept. 30, 2005 (2 months before its withdrawal), totaled $9.8 million, of which Palatin received royalty payments of $2.5 million and product transfer sales of $2.5 million .

The 2005 Average Wholesale Price (AWP) is $1260.00/vial, with a Direct Cost (Manufacturer’s discounted price) of $1.050.00.

NeutroSpec is presumed to be more cost--effective than conventional computed tomography scans using oral and intravenous contrast media. NeutroSpec may cost about one-half the current cost for appendicitis diagnosis.

R&D: NeutroSpec may also be useful for diagnosis of ischaemic bowel, post-surgical infection, nosocomial and other infections. Palatin has been testing NeutroSpec in Phase II studies for detection of other infections including osteomyelitis (deep within bone), pulmonary infection, fever of unknown origin, inflammatory bowel disease, and post-surgical infection.