Summary Basis of Decision for Leukoscan ®

3.3.1 Pharmacodynamics

Three open-label, non-randomized, multi-centre studies related to PD/PK considerations were performed on a total of 53 patients. Data from the three trials were presented together. Study objectives were identified as evaluation in the areas of safety, PK and dosimetry, and dose ranging. Patients had a wide range of infections, proven by clinical signs and other diagnostic tests. Imaging was performed at 2, 6, and 24 hours following infusion. An additional study, cited as a Phase I trial, was also conducted to investigate the effect of the drug product on granulocyte function. A subgroup of 52 patients from the three main studies was studied for effects of dose on imaging efficacy. Based on diagnostic sensitivity and specificity, the investigation amounted to a dose ranging study. Patients entered into the studies were administered doses ranging from 0.1 to 1.0 mg LeukoScan, radiolabelled with 5-25 mCi Tc-99m. It was stated that there was no difference in the sensitivity or specificity over the range of doses, based on a per lesion analysis for the antibody.

In 5 patients with proven abscesses, granulocyte function was measured before and after LeukoScan administration. Chemiluminescence assays of peripheral granulocytes were performed at baseline, 1-4 hours, 24 hours, and 7-10 days post-injection. The percent receptor reserve response at 1-4 hours post-injection was slightly reduced for the LeukoScan patients, but was indistinguishable from normal values at 24 hours post-injection. Since the chemiluminescence assay is extremely sensitive, and the changes were mainly confined to one patient, this reduction may not be clinically significant. Patients administered ^99mTc-Sulesomab had responses typical of other patients with infections and could not be characterized as abnormal or uninhibited.

The 53 patients who were dosed with the product were also analyzed for safety. All patients tolerated the product without any adverse drug reactions (ADRs) and no changes of significance were said to be revealed which could not be explained by the patient's condition. In 18 patients in whom post-administration human anti-murine antibody (HAMA) assays were performed, no production of HAMA reactive with intact IgG was observed. Safety data in the 53 patients indicated that the product was safe at doses up to 1.0 mg Fab' fragment. This is four times higher than the protein dose used in the Phase III trials. Subdose analysis indicated no difference in sensitivity or specificity between patients administered 0.1, 0.3, or 1.0 mg of the protein. The only clinically significant pre- to post-injection change noted for the 53 patients who were administered the test article was a transient increase in neutrophils between the baseline (mean = 64.1%) and 24 hour (mean = 69.9%) time points. This value returned to normal at one week post injection. These findings represent small and transient laboratory deviations that do not appear to be clinically significant or interfere with the ability to indicate disease sites in imaging studies. There were no significant vital sign changes noted with respect to the pre- and post-infusion data compiled for the 53 patients.

No control population was used in these studies as all patients had presented with suspicion of acute or chronic infections of unknown origin or extent. Readers of scans were not aware of the dose administered nor the time of image acquisition.

In terms of concomitant medication, there were no observable drug interactions which were deemed to affect the safety or efficacy of the product, however no pre-clinical studies have been performed to specifically determine drug interactions with LeukoScan.

3.3.2 Pharmacokinetics

Eleven patients with suspected or established infection had PK investigative work-up. Protein doses ranged from 0.1-1.0 mg. Following infusion (approximately 20 minutes), samples were collected at 5 minutes, 30 minutes, 1, 3, 6, and 24 hours. Total urine was collected in fractions at 0-2, 2-12, and 12-24 hours. Eight patients also underwent dosimetry investigations. The average percent injected dose in the blood 5 minutes post-infusion was 66.3±22.1%, which dropped to 22.2±6.1% by 6 hours, and further to 9.6±3.8% by 24 hours post-infusion. The average biological half life (T½) of blood clearance was estimated to be 0.917 hours and 10.5 hours for the first elimination rate constant and second elimination rate constant, respectively. Total urine excretion over the 24 hour period was 25.2% of the injected dose. An estimate of fecal excretion was cited as 9.5%. The kidneys and red bone marrow had the greatest uptake of tracer accounting for 22.0% and 25.7% of the injected activity, respectively. No significant difference in disposition was observed between the patients receiving different protein doses of the radiolabelled antibody fragment.

3.3.3 Bioavailability

Pharmacokinetic properties were determined in 13 uninfected subjects receiving 26 injections in total. Each patient received one dose of investigational product and one dose of the commercial formulation.

The following results were observed: biological distribution half-life of 1.47±0.2 hours; biological elimination half-life of 25.1±11.7 hours; clearance of 0.46±0.14 mL/min; AUC of 593±205 %ID x time (hours); volume of the central compartment of 5.4±0.8 L; and volume of distribution at steady state of 14.6±4.1 L. The parameter cited as volume of distribution at steady-state is perhaps misstated however, since a single dose, cross-over approach would not be expected to yield steady state with a compound reported to exhibit a second elimination half-life of 10.5 hours.

Dosimetry was equivalent for the two products, with the kidney receiving the highest dose of 46±9 uGy/MBq and the heart wall receiving 12±2 uGy/MBq. Organs receiving 5-10 uGy/MBq included lungs, liver, bone, red marrow, thyroid, adrenals, pancreas, gallbladder wall, and uterus.

Although this was a cross-over study, hence two doses per subject were administered, this particular study was not specific to investigate the effects of repeated administration.

3.3.4 Clinical Efficacy

A total of three pivotal Phase III studies and six non-pivotal studies were conducted to examine the clinical safety and efficacy of LeukoScan. The total number of patients evaluable for efficacy in the three Phase III trials was 345. The combined results showed sensitivity 88%, specificity 73%, accuracy 79%, positive predictive value (PPV) 70% and negative predictive value (NPV) 90%. All these parameters except specificity are within the 80%±95% C.I. For specificity, the upper bound of the C.I. is just below the guidelines, at 79%.

The sponsor claims that since the mechanism of action for imaging is the recognition of an epitope expressed on activated leukocytes by a monoclonal antibody fragment, it was reasonable to combine imaging results across the different sites of infection studied in the clinical trials (infection in bones, infection in deep soft tissue, and infection in acute appendicitis) as proof of phenomenon. It should be noted however, that deep soft tissue was not one of the sites studied in any of the clinical trials. There was uptake in the soft tissue of patients with diabetic foot ulcers with suspected underlying osteomyelitis and this uptake in soft tissue was at times difficult to distinguish from infection in the underlying bone.

In the osteomyelitis studies the independent clinicians' ability to correctly identify the anatomical sites of infection/inflammation showed good agreement with the on-site assessment, however they had a lower ability to localize the infection in bone. Some of the factors attributed to this difference were: the capability of the on-site clinician to examine the patient (and position the limb or foot such that inflamed soft tissues do not overlay the suspected osseous bone) or to consult with the referring physician, in addition to the ability to access the results of the white blood cell (WBC) scans for some patients, as well as technical factors such as familiarity with one's own equipment. These options were not available to the independent clinicians. This explanation was not acceptable as it is the product which should give a correct diagnosis, not the equipment used or the extra information available. The independent assessment more accurately reflected the situation in which this drug will be used.

As in the osteomyelitis studies, the results of the independent informed assessment for atypical appendicitis showed deterioration in performance compared to the on-site evaluations. In total, 88 efficacy patients had overall imaging studies evaluated as readable by both readers during informed reading sessions. The sponsor stated that these readings may reflect the typical performance deterioration expected for any diagnostic agent when centralized readings are compared to site evaluations performed in a clinical setting.

Of the 232 patients who received WBC imaging as well as LeukoScan in the two osteomyelitis studies, LeukoScan was statistically significantly superior to WBC imaging with respect to sensitivity (87.3% vs. 73.6%), and equivalent in the other parameters assessed (specificity 67.2% vs. 68.0%, accuracy 76.7% vs. 70.7%, PPV 70.6% vs 67.5%, and NPV 85.4% vs. 74.1%).

Comparing the diagnostic utility parameters for the two studies, in patients who had both LeukoScan and WBC scanning, there was a higher sensitivity but lower specificity for the diabetic foot ulcer osteomyelitis study compared to the long bone osteomyelitis study. It should be noted that the areas of uptake on the scans were correct anatomically (i.e. there was local inflammation present), but incorrect in the assessment of bone involvement. The sponsor provided the following explanations for the difference: 1) a tendency for diagnosticians to apply more liberal interpretation criteria when reading scans for the clinical condition of osteomyelitis in the diabetic foot as compared to other forms of long bone osteomyelitis, and 2) a greater mass of infected soft tissue and cellulitis and the more anatomically and pathophysiologically complicated clinical setting of the diabetic foot, which makes the differentiation of infection/inflammation in bone from that in soft tissue more problematic than in long bone osteomyelitis. None of the patients in whom there was uncertainty before scanning were found likely to have osteomyelitis on the basis of false-positive scans. In all cases, putting the positive scan into the context of the full clinical picture allowed the managing physician to differentiate true-positive from false-positives. Another factor which appeared to influence the rate of false-positive readings was experience with the agent. In each trial, specificity was higher at clinical sites imaging 11 or more patients than at the centres imaging 10 or fewer patients.

Patients in these studies had imaging procedures performed at two time points: 1-2 hours following injection, and 5-8 hours after injection. Of the 257 evaluable patients who had readings at both time points, 244 of their readings were the same. The data indicate that there is little advantage of performing more than one scan anytime between 1-8 hours post-dosing. Of the 30 patients with overall positive imaging studies, 25 of these were by planar images. The sponsor claims that the majority of the positive images were acquired one hour after injection, however, according to the data only 52% were positive after one hour. Therefore, in the absence of positive uptake, an imaging study should not be classified as negative without obtaining images at later time points.

In the two osteomyelitis studies, there was an 88% reduction (218 to 26) in the number of patients requiring other diagnostic imaging procedures. As an additional consequence of the LeukoScan diagnostic results there was a 52% decrease in the number of patients requiring antibiotic treatment and a 51% reduction in those requiring close observation on clinical follow-up. There was however, a 32% increased need for surgery/or biopsy procedures noted.

LeukoScan and bone scan had a similar sensitivity but the apparent superiority for LeukoScan over bone scan in specificity and NPV was difficult to interpret because of small patient numbers. Therefore, the data is insufficient to support such a claim. Similarly, compared to a ^99mTc labelled bone scan, there were no substantial differences in any of the diagnostic utility parameters between LeukoScan and the bone scan for the 66 patients who underwent both procedures. LeukoScan showed potential that the diagnosis could have been made by LeukoScan alone, independent of other diagnostic data, in 70% of patients.

3.3.5 Clinical Safety

In total 600 patients were exposed to LeukoScan in clinical trials. Eleven clinical trials have been conducted to investigate the safety of LeukoScan. Two of the trials studied LeukoScan in a total of 26 healthy volunteers; five trials studied a total of 78 additional patients with a wide range of infections; two Phase III trials studied patients with suspected osteomyelitis and one Phase III trial studied 109 patients with suspected appendicitis. Adverse events were monitored for up to 30 days following injection of LeukoScan. As the trials in patients with general infections, suspected osteomyelitis, and suspected appendicitis included no control patients, the analysis of these trials relies on descriptions of the patients before and after LeukoScan administration, as well as knowledge of the expected clinical course in the type of patients studied. The primary parameters used to assess safety in these studies were death, clinical adverse events (AEs), laboratory tests results, vital signs, and Human Anti-Mouse Antibody (HAMA) determinations.

Twenty-one patients over four of the studies had a two-step shift in a laboratory chemistry value, however there was no suggestion that LeukoScan affects clinical chemistries or hematologic parameters to any substantive or clinically meaningful degree as these changes were consistent with the patient's underlying disease.

A total of 101 adverse events were reported in 61 patients (out of 600); only five of these were considered possibly related (none were considered probably or definitely related) to the study drug. There was one case of pruritic rash (non-serious), three cases of eosinophilia (two considered non-serious, one considered serious by the investigator while the sponsor considered it non-serious due to other complications in this patient), and one case of increased monocytes (non-serious).

Serum collections were made at baseline prior to injection of LeukoScan and approximately 4-6 weeks and three months after injection of LeukoScan. The overall analysis indicated that none of the 330 patients examined developed a positive or positive-boost HAMA response to the antibody fragment as measured with the Immu STRIP fragment assay. In the three pivotal studies, six patients developed a positive boost response to the intact IgG antibody. No increase of HAMA was observed after administration of LeukoScan in the one patient with pre-existent fragment-reactive HAMA.

Serum carcinoembryonic antigen (CEA) levels were also examined in 227 patients as it is known that LeukoScan is cross-reactive with serum CEA. Levels were obtained at baseline and archived in the event of an unexpected safety occurrence or other unusual finding potentially requiring explanation, however none occurred. Only four serum CEA levels were slightly elevated above the normal range for non-smokers or smokers. Based on this, cross-reactivity with serum CEA would not be expected to alter the biodistribution or pharmacokinetics of LeukoScan, nor interfere with the ability to target an infectious lesion.

The inclusion criteria in both pivotal trial protocols required an age of 21 years as a minimum accepted level therefore no claim for the use of LeukoScan in children with osteomyelitis may be approved.