Xemilofiban

Xemilofiban 

Repositioning Repurposing an Oral GPIIb/IIIa Inhibitor. Although coronary intervention has advanced considerably over the past 20 years, there remains a significant unmet medical need for safer, more potent anti-platelet therapy, lasting 24-72 hours after discharge from hospital, where there appears to be ‘low hanging fruit’ of medical benefit that parenteral therapies have not yet harvested. Given the pharmacoeconomic pressures for early discharge, an oral GP IIb/IIIa inhibitor offers the potential to capture this medical benefit, at a reasonable cost competitive with i.v. therapy inside the hospital. Current standards of practice, dictated by safety concerns with the drug eluting stents (DES), translates to a 50% utilization of bare metal stents (BMS) to avoid the continuous hazard of subacute stent thrombosis seen with DES stents. However, in the acute phase, This shift in practice, however, does not account for the risk of early stent thrombosis (within the first week) seen with both types of stents, and hence the need to identify additional potent anti-platelet inhibitors such as xemilofiban that could be used for 2-7 days post PCI on top of conventional regimens. On the safety side of the equation, we propose in our quick, relatively inexpensive Phase II program to confirm this hypothesis. We expect that acute dosing of oral xemilofiban will have a safety profile similar to the acute dosing of i.v. GP IIb/IIIa inhibitors, particularly when concomitant antithrombin therapy is administered at optimal doses demonstrated in recent clinical trials. Published data suggests that continuing a high level of platelet inhibition for several days yields incremental medical benefits, with bleeding risks well within the risk profiles of other oral outpatient therapies.

Xemilofiban

SC-54684A (MW 394.858) is a chiral compound chemically known as Ethyl 3S-[[4-[[4- (aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate, monohydrochloride. It is the orally available ethyl ester pro-drug of SC-54701A (MW 366.804), a mimetic of the RGD-containing peptide sequence that is recognized by platelet glycoprotein IIb/IIIa receptors, blocks the binding of fibrinogen to these receptors, and prevents platelet aggregation. SC-54684A was used for oral administration, while SC-54701A was used in most of the in vitro studies and for most intravenous administrations. SC-54684A and SC-54701A are monohydrochloride salts. When present in matrices such as plasma, SC-54684A and SC-54701A are referred to as the corresponding free bases (SC-54684 and SC-54701). All doses and plasma concentrations are expressed as free bases, unless otherwise stated.

Question 1:

''The studies of all the 3 oral GP IIb/IIIa agents have not shown a reduction in ischemic events, but trends towards increased mortality were observed. A meta analysis of oral GP IIb/IIIa inhibitors shows a 33% increase in mortality with long-term follow up.''

Answer 1 :

L. Kristin Newby et al. indeed conducted a meta-analysis as outline below. The duration of treatment in all of these studies far exceeds the intended treatment of xemilofiban as proposed by VDDI. Oral glycoprotein IIb/IIIa receptor antagonists have undergone phase 3 evaluation in three indications: percutaneous coronary intervention (EXCITE), management of acute coronary syndrome (OPUS, SYMPHONY, 2nd SYMPHONY), and secondary prevention in coronary artery disease ((BRAVO). Of these trials, OPUS and BRAVO were terminated early by their respective Data and Safety Monitoring Committees.

Mortality. Although overall mortality was low, it was higher in glycoprotein IIb/IIIa inhibitor–treated patients than in controls. In OPUS, mortality in the 50/30 regimen arm (orbofiban 50 mg twice daily for 30 days, followed by 30 mg twice daily) was significantly higher and led to early study termination (13). Excess mortality in EXCITE and SYMPHONY was not statistically significant. Mortality in 2nd SYMPHONY was increased non-significantly with low-dose sibrafiban plus aspirin, but was significantly higher for those who received high-dose sibrafiban (2.4% vs. 1.3% for aspirin, P=0.008).

The reason for the excess mortality is unknown, but presumably relates to paradoxical activation of platelets via occupancy of the glycoprotein IIb/IIIa receptor when incomplete blockade is present (see response to question 3 below). Long-term maintenance dosing regimens of the oral glycoprotein IIb/IIIa antagonists were selected to achieve approximately 50% inhibition of platelet aggregation, primarily to minimize the risk of excessive bleeding. This focus on outpatient safety may have thus inadvertently caused excess mortality by prolonged exposure to levels of drugs that activated, rather than suppressed, platelet function.

Thus xemilofiban was the only product studied specifically in the PCI indication and the only product that remains of all the oral GP IIb/IIIa programs because the FDA did not find sufficient evidence to halt development due to excess mortality.

Question 2:

''Bleeding rates were increased in all the active treatment groups. In EXCITE study of Xemilofiban, the bleeding occurred throughout the whole period instead of in the acute period after PCI and a dose related response on bleeding is also noted.'' Answer 2:

The bleeding event rate in EXCITE was driven primarily by the duration of therapy, rather than the dosing arm. The therapeutic dose required for 80% platelet inhibition is a separate measurement from clinical bleeding events. Although the two may be intuitively related, the correlation between platelet inhibition and bleeding is imprecise.2  In addition, the EXCITE trial was conducted nearly 10 years ago, an era during which much higher doses of heparin were being used than is current practice. In fact, heparin dosing has been reduced to 25% of the dosing regimens from the EXCITE era, and bleeding rates have dropped accordingly.

The risk of bleeding with xemilofiban is similar to the bleeding risk of commercially available glycoprotein IIb/IIIa inhibitors in clinical practice.3 A retrospective analysis of PCI patients in the SCAI registry revealed an unadjusted odds ratio of 1.87 (95% CI; 1.35, 2.59) for bleeding in patients who had received glycoprotein IIb/IIIa inhibitors compared to those who had not. In settings where the overall exposure to glycoprotein IIb/IIIa inhibitors was much shorter than in EXCITE, the odds ratio for bleeding at 30 days (xemi vs placebo) was 1.74 (95% CI; 1.55, 1.96) for the low dose xemilofiban group and 2.62 (95% CI; 2.32, 2.94) for the high dose xemilofiban group.

In EXCITE, the incidence of thrombocytopenia was low and similar among treatment arms during the study period (Table T25). Although some of this thrombocytopenia may stem from glycoprotein IIb/IIIa blockade, there is an underlying risk of thrombocytopenia attributable to heparin. Thus, thrombocytopenia does not substantially contribute to the bleeding risk from xemilofiban.

As noted above, clinical practice has evolved substantially since EXCITE that has reduced the degree of heparin anticoagulation to the point where bleeding rates are comparable regardless of the administration of glycoprotein IIb/IIIa inhibitor therarpy. A series of observations and reports regarding the relationship of heparin anticoagulation to PCI outcomes spanning two decades illustrates a clear inverse relationship between the degree of heparin anticoagulation and both bleeding and outcomes.20-25 As expected, higher doses of heparin anticoagulation lead to increased bleeding  rates. Paradoxically, efficacy decreases as the degree of heparin anticoagulation increases. An (adverse) synergistic relationship also exists whereby increasing doses of heparin anticoagulation in the presence of GP IIb/IIIa antagonists further enhance rates of bleeding. The key to managing bleeding with concomitant GP IIb/IIIa blockade is to minimize the degree of anticoagulation from adjunctive heparin or other anti-thrombin therapies. The anticoagulant dose should be just sufficient to control the coagulation cascade, rather than to abolish coagulation. This principle is reflected in the history of heparin anticoagulation over the past two decades (Appendix II). The xemilofiban program affords the opportunity to build on prior studies to better define the ideal anti-thrombin dosing regimen that maximizes safety (minimizing bleeding and /or thrombocytopenia) when used in conjunction with GP IIb/IIIa inhibition. Such a definition would be very influential in the practice of medicine in this area and a driver for market share.

Question 3:

Some papers have discussed the reasons of the discrepancy on clinical benefits between oral and iv.: suboptimal dosage due to the individual variability, lack of sustained platelet inhibition, prothrombotic effects and possible toxic mechanism.

Answer 3: A critical issue with the use of the fibans, either oral or intravenous, is the extent, duration and timing of platelet inhibition. According to the AU-Assessing Ultegra (GOLD) study at the time of PCI, greater than 80% inhibition is required for maximum efficacy.13 Failure to achieve these high levels of inhibition is associated with lack of protection from acute events, mainly periprocedural MI. In fact, it is likely that the level of platelet inhibition, rather than pharmacological differences between Integrilin®, ReoPro® or Aggrastat®, is the major factor in the observed differences in efficacy between the agents at the time of PCI. This was clearly seen in TARGET (do Tirofiban And ReoPro Give similar Efficacy Trial?), in which abciximab was superior to tirofiban in the prevention of early ischemic events after coronary stenting. 24 Recent data suggest that the tirofiban dose used in this trial fails to achieve 80% platelet inhibition in the early stages of the infusion.25-26 Similar conclusions can be drawn from the GOLD study, which related the degree of inhibition after an abciximab bolus and 12-hour infusion to ischemic outcome in patients undergoing PCI. Platelet inhibition below 95% at 10 minutes, 80% at 1 hour, or 70% at 8 hours was associated with a marked increase in major adverse cardiac event (MACE) rates; as many as 1 in 4 patients sustained a major adverse cardiac event with the lowest levels of inhibition.13 It is not only the loss of platelet inhibition but also prolonged exposure to low, subthreshold levels of platelet inhibition, as occurred in GUSTO IV and with long-term oral therapy, that has the potential to lead to a paradoxical increase in major adverse cardiac events (MACE). Moderate levels of platelet inhibition not only lack efficacy but, when prolonged, are associated with a paradoxical increase in ischemic events due to the unmasking of antagonist-induced prothrombic and proinflammatory effects.27

Question 4:

''Difficulty in identifying the optimal dosage among individuals: The starting point is 20mg tid in EXCITE study+30mg loading dosage. The investigators of the EXCITE study comment that the lack of long-term efficacy is unlikely to be due to a insufficient dose of Xemilofiban because the blood levels were sufficiently high.''

Answer 4:

The primary goal of the VDDI Phase II, ascending dose-ranging study is to explore the pharmacodynamic effects of xemilofiban in the patient population of interest over a range of doses. As noted in the response to question 3, the goal of treatment is to achieve maximal platelet inhibition. The stoichiometry of the 2 small molecule intravenous glycoprotein IIb/IIIa antagonists (Integrilin and Aggrastat) exceed 100 molecules of drug to every native glycoprotein IIb/IIIa integrin, demonstrating that over-saturation of the receptor is actually the nominal target. The doses selected for study in the subsequent phase III trial will thus be based on the (much smaller) phase II pharmacodynamic studies, minimizing the total number of patients exposed to higher dosing strategies.

The additional dose levels to be studied in phase II will result in exposure to the drug that is within the range determined to be safe in previous Phase I and II studies. In single dose trials conducted by Searle and Pharmacia, up to 50 mg has been administered to healthy volunteers. Based on earlier trials in healthy volunteers, a 30 mg dose provides a minimum of 60% inhibition over 6 hours. In multiple dose trials, up to 30 mg TID has been administered. Phase I and II data reveal that maximum levels of platelet inhibition are noted between two and four hours post-dose and are sustained for up to six hours after dosing. Dose Selection In previous Phase I studies, the maximum tolerated single dose of xemilofiban HCl was 35 mg and 30 mg TID on a multiple dose level. In one pilot Phase II studies, a loading dose of 35 mg was utilized before PTCA procedures followed by maintenance dose levels of 25 mg or 20 mg TID for up to one month of therapy. Serious bleeding events occurred in 3 of 35 randomized patients in the two pilot Phase II studies. These events developed during the first 12 hours after initiation and completion of revascularization procedures. In one case, bleeding occurred in the context of emergency coronary artery bypass surgery. The other case involved hematemesis in a patient who had been on a heparin infusion for 10 days prior to entering the study. In both cases, prolonged bleeding events developed in the presence of sustained levels of near complete inhibition of platelet aggregation. The last case involved the presence of a femoral hematoma that was thought to be probably related to heparin. Proposed Phase II study

A loading dose of 30 mg has been chosen as the starting loading dose and will be increased to 40 mg and 50 mg in this study if safety and dynamic studies warrants. The maintenance regimen selected is 20 mg xemilofiban TID for the first cohorts. If appropriate, a QID regimen will be utilized based on data cited above which indicates activity for 6 hours post-dose. The 20 mg QID maintenance dose provides a total daily exposure which is slightly less than the 30 mg TID dose, the dose felt to be upper dose level in earlier development studies. Confidence needs to be restored in xemilofiban by a demonstration of the pharmacokinetic/pharmacodynamic relationship in a peri-procedural setting. Once the dose is clearly delineated based on concentrations achieved in the target population and resultant platelet inhibition, then an additional larger study would be required to provide sufficient data for regulatory submission. Variables effecting bioavailability and platelet inhibition with xemilofiban include drug interactions, obesity, fatty meals and poor compliance. All of these issues will and can be address by a significant portion of the dosing will be done under direct supervision in a hospital setting. Below are company sponsored studies conducted in the course of complying with the requirements for an NDA.

Previous Phase II studies INTEGRATED CLINICAL AND STATISTICAL REPORT FOR SAFETY OF SC-54684A (XEMILOFIBAN HYDROCHLORIDE) ADMINISTRATION TO PATIENTS PRIOR TO CORONARY ANGIOPLASTY OR STENT PLACEMENT: OPEN-LABEL TRIAL Protocol Number: NG7-96-02-057

•	Xemilofiban hydrochloride maintenance doses of 10 and 20 mg TID were safe and well tolerated when administered for up to 30 days following a pre-procedural (30 - 90 minutes) 20 mg dose of xemilofiban hydrochloride administered in patients who underwent PTCR; •	Xemilofiban hydrochloride 10 and 20 mg TID administered for up to 30 days resulted in attainment of platelet inhibition of aggregation levels (ADP) within the 50 - 80% target range desired for efficacy. •	 By two hours after administration of the pre-procedural 20 mg dose of xemilofiban hydrochloride, patients had mean platelet aggregation responses corresponding to greater than 50% inhibition of ADP-induced platelet aggregation. At the time of peak activity (five hours after dosing), aggregation levels corresponded to approximately 80% inhibition of platelet aggregation.

IV vs Oral dosing REVISED INTEGRATED CLINICAL AND STATISTICAL REPORT FOR AN OPEN-LABEL, RANDOMIZED, CROSSOVER STUDY TO COMPARE THE PHARMACOKINETICS OF ORAL AND INTRAVENOUS XEMILOFIBAN HCL IN HEALTHY ADULT SUBJECTS Protocol Number: NG7-95-02-046

•	Plasma concentration-time curves for SC-54701 were similar following IV and oral dosing. Mean Cmax values were 45.36 ng/mL (18.325) and 59.66 ng/mL (17.700) for oral and IV doses, respectively. AUC0-lqc was smaller after oral dosing compared to IV dosing, with mean values of 290.24 ng-hr/mL (104.275) and 344.46 ng-hr/mL (114.559), respectively. •	Not all drug was converted to SC-54701 after IV dosing. Based on AUC0-lqc, the absolute bioavailability of a single 25 mg oral dose of xemilofiban HCl relative to a single 4.8 mg IV infusion is approximately 14%, with a 95% confidence interval of (12%, 17%). Based on AUC0-_, the absolute bioavailability of a single 25 mg oral dose of xemilofiban HCl relative to a single 4.8 mg IV infusion is approximately 15%, with a 95% confidence interval of (12%, 18%).

•	The pharmacodynamic results suggest that the extent of inhibition of platelet aggregation followed the plasma concentration of SC-54701. Complete (approximately 100%) inhibition was achieved after both oral and IV dosing.

•	Single oral doses of 25 mg xemilofiban HCl capsules and single IV doses of 4.8 mg infused over three hours were shown to be safe and well-tolerated by healthy subjects in this study.

Implications: a 2-6 Mg loading dose of xemilofiban intravenously in our clinical studies will be used.

Obese Subjects

REVISED INTEGRATED CLINICAL AND STATISTICAL REPORT FOR COMPARISON OF THE PHARMACOKINETIC PROFILE OF XEMILOFIBAN HCL IN OBESE SUBJECTS AND IN NORMAL WEIGHT SUBJECTS Protocol Number: NG7-95-02-044

The pharmacokinetic and pharmacodynamic profiles of a 15 mg dose of xemilofiban were different in obese compared to normal weight subjects. Obese subjects exhibited a slower rate of absorption, however, extent of SC-54701 absorption (Cmax and AUC) was not significantly different from normal weight subjects after single-dose and multiple-dose (twice daily) administration. Associated with this finding, there was a lesser pharmacodynamic response (reduced degree of inhibition of platelet aggregation activity) in obese subjects.

Interpretation: Obese subject will need larger doses.

Elderly vs. Young

INTEGRATED CLINICAL AND STATISTICAL REPORT FOR COMPARISON OF THE PHARMACOKINETIC PROFILE OF XEMILOFIBAN HCL IN ELDERLY SUBJECTS AND IN YOUNG SUBJECTS Protocol Number: NG7-95-02-011

•	The pharmacokinetic profiles of single and multiple doses of xemilofiban HCl 15 mg and 20 mg were similar between elderly and young subjects for Cmax, Tmax, and XU parameters. Mean Tmax was between 2.2 and 3.1 hours for both groups. However, compared to the young, elderly subjects had at least 40% higher mean AUC values over all measured time intervals, and a lower Cmax/AUC0-lqc. •	After multiple doses of 15 mg or 20 mg xemilofiban there were no statistically significant differences between the elderly and young groups in the dose-adjusted mean values of AUC0-12, Cmax, XU0-12, and XU0-24. •	Maximal inhibition of aggregation to ADP and collagen exceeded 90% for both age groups with repeated dosing. Following single and multiple doses of 15 mg xemilofiban HCl there were no significant differences in ADP or collagen-induced platelet aggregation between the elderly and young. For the 20 mg dose, elderly subjects demonstrated significantly greater predose aggregation to ADP and collagen during the repeat dose phase of the study, consistent with the somewhat higher plasma concentrations of SC-54701 seen with 20 mg dosing in the elderly. •	Although there were numerous adverse events in both dose groups, all but two (vomiting and syncope) were mild in severity. There were no deaths, serious or severe adverse events. No clinically significant changes in clinical laboratory parameters or physical examination were noted in either the young or elderly. •	For both dose levels, the incidence of bleeding events was greater in the elderly than in the young. However, all bleeding events were considered by the investigator to be mild in severity.

Interpretation: elderly have higher blood levels largely related to age reduced renal function; dose adjustments downward will need to be made for elderly poor renal function patients Drug Interactions

REVISED INTEGRATED CLINICAL AND STATISTICAL REPORT FOR BIOAVAILABILITY OF XEMILOFIBAN HCL IN PRESENCE OF PROPANTHELINE BR- AND METOCLOPRAMIDE HCL IN HEALTHY ADULT SUBJECTS Protocol Number: NG7-95-02-034

The results of the study showed that Pro-Banthine® (propantheline Br-), but not Reglan® (metoclopramide HCl), administration increased the bioavailability of SC-54701 and the pharmacodynamic effects of a single 25 mg oral dose of xemilofiban HCl, administered to fasting healthy adult male volunteers, compared to administration of xemilofiban HCl alone. All three treatment regimens greatly inhibited platelet aggregation, and the results were similar for both ADP- and collagen-induced platelet aggregation. Inhibition of platelet aggregation was directly related to SC-54701 plasma concentrations and Cmax and Tmax. The results of the study also indicated that xemilofiban HCl administered fasting in a single oral 25 mg dose to fasted subjects, alone or one hour following Reglan or Pro- Banthine, was safe and well-tolerated by healthy adult male volunteers. Adverse events were mild to moderate in intensity, and none were serious. No bleeding events were noted.

Implications: if you have an ulcer avoid use of antiplatelet drugs. If taking one then elective dosing should exclude propantheline before a PCI procedure

REVISED INTEGRATED CLINICAL AND STATISTICAL REPORT FOR ASPIRIN INTERACTION - A LOW DOSE EVALUATION OF XEMILOFIBAN HCL Protocol Number: NG7-95-02-045

•	The inhibition of platelet aggregation with ADP after co-administration of xemilofiban HCl and aspirin was statistically significantly increased at 12 hours after both initial (p<0.001) and continued dosing (p=0.043) and at 24 hours after continued dosing (p<0.001). •	2. The inhibition of platelet aggregation with collagen after co-administration of xemilofiban HCl and aspirin was statistically significantly (p<0.001 for all) increased at all time points, beginning at 2 hours postdose, both after initial and continued dosing. •	3. Mean bleeding time at 4 hours postdose after the initial dose and after continued dosing was twice as long after co-administration of xemilofiban HCl with aspirin than with xemilofiban alone, and approximately the sum of bleeding times with xemilofiban HCl alone and aspirin alone. •	4. The number of subjects who met the endpoint criteria for clinically significant bleeding increases was statistically significantly larger (p-values ranged from 0.002 to 0.016) after continued co-administration of xemilofiban HCl and aspirin when compared to single or continued dosing of either xemilofiban HCl alone or aspirin alone. •	5. Administration of 10 mg xemilofiban HCl BID for 4.5 days alone and for 4.5 days co-administered with aspirin over a 21-day period was well tolerated. Three subjects were discontinued at the request of the sponsor because of prolonged bleeding times. The incidence of adverse events was similar in all three treatment groups, and there were no bleeding events. Xemilofiban HCl 10 mg BID alone or in combination with once-daily 162 mg aspirin was shown to be safe when administered to healthy subjects.

Implications: ASA and xemilofiban will increase bleeding episodes.  Antacids and cimetidine

REVISED INTEGRATED CLINICAL AND STATISTICAL REPORT FOR COMPARATIVE BIOAVAILABILITY OF XEMILOFIBAN HCL ADMINISTERED FASTING, WITH ANTACID, AND WITH AN H2-ANTAGONIST IN HEALTHY ADULT SUBJECTS, IND #46,247 Protocol Number: NG7-95-02-029 

The results of this study indicated that concomitant administration of antacid (Mylanta_) or H2-antagonist (cimetidine) changed the pharmacokinetic parameters, the bioavailability of SC-54701, and pharmacodynamic effects of a single 25 mg oral dose of xemilofiban HCL, administered to fasted subjects, compared to administration of xemilofiban HCl alone. All three treatment regimens greatly inhibited platelet aggregation, and the results were similar for both ADP- and collagen-induced platelet aggregation. The results of this study also indicated that xemilofiban HCl was safe and well-tolerated in normal healthy male volunteer subjects, in a single oral 25 mg dose administered fasting, alone and with concomitant Mylanta_ or cimetidine. Adverse events were mild to moderate in severity; none were serious, none resulted in the subject_s withdrawal from the study, and only one may have been related to study drug. None of the abnormal clinical laboratory results or vital signs and none of the changes from pretreatment to post-treatment were considered clinically significant.

Concomitant administration of Mylanta_ significantly reduced the average extent and rate of xemilofiban HCl absorption and the average cumulative SC-54701 urinary excretion compared to xemilofiban HCl alone. Rate of absorption was equivalent between xemilofiban HCl + Mylanta_ and xemilofiban alone. Concomitant administration of Mylanta_ decreased the mean maximum inhibition of both ADP- and collagen-induced platelet aggregation, which was reached two hours earlier, compared to xemilofiban alone. Concomitant administration of the H2-antagonist, cimetidine, significantly lengthened the time to attainment of maximum plasma SC-54701 concentration (Tmax) and slowed the rate of absorption (Cmax/AUC(0-lqc)). Bioequivalence (AUC(0-lqc)) was concluded between concomitant administration of the H2-antagonist, cimetidine, and xemilofiban HCl alone. The 90% confidence intervals (Schuirmann's test) demonstrated equivalence for cumulative urinary excretion (XU(0-48)).

Concomitant administration of cimetidine delayed the mean maximum inhibition of platelet aggregation, which was reached two hours later compared to xemilofiban HCl alone, but the magnitude of inhibition was similar for xemilofiban HCl alone and with cimetidine.

Implications: Avoid combined use of cimetidine, Mylanta and xemilofiban.

Question 5:

''How to manage the individual variance: according to PK/PD data of Xemilofiban, there is a large variance among individual patients which causes different inhibition levels. This will also affect the study result.''

Answer 5:

Inter-individual variability is expected, and is to be addressed in several ways. The phase II study will enroll a sufficient number of patients to determine optimal dosing based on targets identified from the experience with the parenteral GP IIb/IIIa antagonists. Specifically, the goal for inhibition of platelet aggregation is to achieve >80% inhibition in 100% of patients and >90% inhibition in 90% of patients throughout the period of treatment. This is expected to require higher doses and / or more frequent dosing than was used in the maintenance phase of EXCITE. Specifically, dosing will need to be discovered that achieves a ratio of >100 active molecules to every GP IIb/IIIa integrin. Once these levels are attained, inter-individual variability will be minimized.

Xemilofiban is also affected significantly by absorption parameters. Compliance, food effects and drug interactions can markedly increase both individual and inter-individual response to the drug. Individualized dosing regimens (e.g., adjusted by weight or renal function) can be explored to minimize variance in platelet inhibition and results. Proper trail design will address variance and outcome variables.

Question 6:

Benefit-risk ratio in combination therapy with other agents: aspirin, heparin, clopidogrel have been used routinely after PCI. In phase III trial, Xemilofiban needs to be used together with these drugs. which will lead to an increase of adverse event, esp. bleeding and also uncertainty on showing clinical benefits.

 Answer 6:

The evaluation of xemilofiban is to occur in the context of standard clinical practice, including aspirin, heparin, and clopidogrel as adjuncts to PCI. As complete vessel and platelet passivation requires 2-5 days following the requisite barotrauma injury that occurs during PCI, this period of time has been recognized to be the period of greatest risk. Endothelialization of bare-metal stents also requires 7-10 days to complete. These observations are felt to account for the increased risk of early stent thrombosis observed within the first week following stent implantation. Therefore, the greatest opportunity for benefit will also be seen in the immediate post-procedure time frame and serves as the rationale for evaluating a short-term treatment strategy (as opposed to long-term prevention embraced by the previous failed trials of the oral glycoprotein IIb/III antagonists).

There is an interaction between platelet GP IIb/IIIa inhibition and (increasing doses) of heparin anticoagulation. As described in the response to question 2, the key to reducing bleeding thus appears to be minimizing the degree of anticoagulation. The protocol will stipulate that heparin (or other anti-thrombin anticoagulants) is to be terminated at the completion of the procedure and specify that anticoagulants (such as further heparin infusion or warfarin) are specifically prohibited while the patient is receiving the study drug. As described in the response to question 3, the key to improving outcomes is to maximize antiplatelet effects. Thus both aspirin and clopidogrel (inhibitors of platelet activation) will be used in conjunction with xemilofiban (an inhibitor of platelet aggregation) to maximize efficacy.

Question 7: Short or long treatment period: In Xemilofiban's EXCITE study, it shows clinical significant difference at 48hr.(which is aligned with iv, all approved for short-term usage), but not at 14 days.

Answer 7:

There was a relative loss of efficacy between 48h and 14d in EXCITE. While the reasons have not been elucidated, it is believed that this may be attributable to the incomplete inhibition of platelet aggregation achieved with the xemilofiban dosing strategy used during the 48h-14d time frame, a period of time of high risk for vascular thrombosis.

The duration of therapy proposed for the xemilofiban development program is 5-7 days, coinciding with the period of time required for both vessel passivation and for stent endothelialization. As noted in the response to Question 6, this is the period of greatest risk following stent implantation and therefore will provide the greatest opportunity to demonstrate benefit. The intent is to completely suppress platelet aggregation for the entire duration of study drug treatment, and then to terminate treatment, rather than to enter into a maintenance phase.

Bonus Questions and Observations

1.	What was the % of platelet inhibition and bleeding times for ReoPro and Aggrastat at their therapeutic doses in the first 24-72 hours and over the first week in this (PCI) indication? The pharmacodynamics of abciximab, tirofiban, and eptifibatide have been studied extensively. Kereiakes5 reported the first randomized comparison of platelet pharmacodynamics between these three agents using light transmission aggregometry (LTA) and rapid platelet function assays (RPFA), in which a reduced intensity of platelet inhibition by LTA was observed for tirofiban compared with either eptifibatide or abciximab. Simon et al.6 compared platelet function by LTA and two bedside function assays in 36 PCI patients assigned to one of the three parenteral GP IIb/IIIa receptor antagonists. This study used single-bolus dosing for eptifibatide and RESTORE dosing for tirofiban, doses which achieved less platelet inhibition than abciximab. Batchelor et al.7 randomized 70 patients undergoing PCI to abciximab, eptifibatide, or tirofiban at doses used in EPISTENT, PURSUIT, RESTORE, and PRISM-PLUS.6-11 At 15 minutes, the proportion of patients with > 80% platelet inhibition was lower for RESTORE-dose tirofiban compared to either abciximab or eptifibatide. At 12 hours, however, abciximab had significantly fewer patients with < 80% platelet inhibition compared to the small molecule agents.

Clinical endpoints were evaluated in the placebo-controlled CAPTURE (abciximab), PURSUIT (eptifibatide) and PRISM-PLUS (tirofiban) trials. In CAPTURE, patients had scheduled PCI 18-24 hours after randomization, with study drug infusion continued until 1 hour after the PCI. In PURSUIT, patients received study drug for 72 hours after randomization, and for an additional 24 hours after PCI, which was performed at the discretion of the treating physician. In PRISM PLUS, study drug was administered for 48-96 hours after randomization, with planned coronary angiography at 48-96 hours after randomization. PCI was at the discretion of the treating physician, and prompted an additional 12-24 hours of study drug therapy. No randomized controlled trial of parenteral GP IIb/IIIa inhibitors for PCI has evaluated long-term therapy beyond these time points.

2.	''Several authors authors mentioned that IIb/IIIa inhibitors may have a relatively narrow therapeutic window. Is this true for Xemilofiban? How does this comment relate to the need for achieving 80+% inhibition of platelets (in 90% of the patients?) with a very low oral bioavailability? It seems that to achieve this level of platelet inhibition across the dose interval, it may be necessary to achieve blood levels in excess of those required to achieve 100% inhibition for part of the dose interval. If this is true, what will the bleeding profile be? Is there a way to predict this?''

Prospective evaluations of the relationship of the degree of inhibition of platelet aggregation with efficacy have not been formally conducted. However, all available data suggests that efficacy is proportional to the degree of inhibition of platelet aggregation. Ex vivo dosing studies have correlated the concentration of GP IIb/IIIa inhibition directly with the extent of “de-thrombosis” (disaggregation of fresh thrombus).12 In the ESPRIT study13 (eptifibatide versus placebo in stent PCI), the dosing regimen of eptifibatide was nearly 4 times higher in concentration than the regimen used in the IMPACT II trial14 (eptifibatide versus placebo in balloon PCI). Relative to IMPACT II, the eptifibatide regimen in ESPRIT resulted in a near-doubling of the benefit (in terms of relative risk reduction) with treatment. In the GOLD registry, efficacy again was found to be directly correlated with the degree of inhibition of platelet aggregation around the time of PCI as determined by the Accumetrics Ultegra point of care assay – the greater the degree of inhibition, particularly 4-8 hours following PCI, the greater the efficacy.15 The failure of tirofiban to achieve non-inferiority relative to abciximab in the TARGET trial of PCI similarly has been ascribed to less than maximal inhibition of platelet aggregation with tirofiban.16

Thus with regard to the GP IIb/IIIa antagonists, there is the sense that the therapeutic window has a “floor” (somewhere >80% inhibition of platelet aggregation) but is without a “ceiling” – i.e., no upper bound where increasing inhibition fails to augment efficacy. While the precise PK/PD dosing relationship of GP IIb/IIIa inhibitors and clinical outcomes has not been, and as a practical matter is unlikely to further be investigated in large scale clinical trials, the consensus is that the target for GP IIb/IIIa inhibition (including both parenteral preparations and oral xemilofiban) is to achieve the highest possible levels of inhibition of platelet aggregation, up to and including 100% inhibition, in the peri-PCI period. Oral bioavailability is thus relevant insofar as oral xemilofiban can achieve platelet inhibition in excess of the 80% range. The phase II study design thus targets the identification of a suitable dosing regimen defined by the considerations described above (Appendix I).

''3.	What would be an acceptable safety profile for an efficacious dose with regard to bleeding for a patient on oral drug at home? If there is a greater tendency to bleed on the drug, will there be a hesitation to release patients from the hospital?''

When the treatment is short-term, 100% inhibition of platelet aggregation does not appear to be associated with an unacceptable risk of bleeding. While administration of platelet GP IIb/IIIa antagonists is associated with an increased overall risk of bleeding, the bleeding is generally classified as minor and is counterbalanced by the disastrous consequences of thrombosis. Even with all of the advances in stent PCI technologies, recent reports (including abstract publications at the 2005 American College of Cardiology meetings) continue to report a 0.5% - 1.0% risk of stent thrombosis in the immediate peri-PCI period and post-PCI period.17 Furthermore, the risk of bleeding appears to not be determined primarily by the degree of inhibition of platelet aggregation; instead, bleeding risk increases with increasing degrees of concomitant anticoagulation therapy and technical factors related to vascular access. For example major bleeding (per the TIMI scale) in the EPIC Trial of PCI (conducted in the early 1990’s) was observed in over 15% of patients; in the subsequent EPISTENT Trial of PCI, using the same TIMI bleeding scale, major bleeding was observed in only 1.5% of patients.18;19 There were 3 major differences that accounted for the 10-fold reduction in major bleeding: markedly reduced heparin dosing, the use of smaller vascular access sheaths (predominantly 8Fr in EPIC versus 6Fr in EPISTENT), and earlier sheath removal (within 3-4 hr following PCI in EPISTENT as opposed to the next day in EPIC). Finally, the net risk of bleeding over the couple days post-PCI is expected to be well below the accepted risks of bleeding associated with long-term therapies including warfarin (Coumadin®), aspirin, and clopidogrel.

References

1.	Newby, KL, Califf, RM, White, HD, Harrington, RA, Van de Werf, F, Granger, CB,, Simes, JR, Hasselblad, V, Armstrong, PW. The Failure of Orally Administered Glycoprotein IIb/IIIa Inhibitors to Prevent Recurrent Cardiac Events. Am J Med. 2002;112:647–658. 2.	O'Neill WW, Serruys P, Knudtson M et al. Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization. EXCITE Trial Investigators. Evaluation of Oral Xemilofiban in Controlling Thrombotic Events. New England Journal of Medicine. 2000;342:1316-1324. 3.	Kleiman NS. Pharmacokinetics and pharmacodynamics of glycoprotein IIb-IIIa inhibitors. [Review] [67 refs]. American Heart Journal. 1999;138:263-275. 2.	Horwitz PA, Berlin JA, Sauer WH et al. Bleeding risk of platelet glycoprotein IIb/IIIa receptor antagonists in broad-based practice (results from the Society for Cardiac Angiography and Interventions Registry). American Journal of Cardiology. 2003;91:803-806. 3.	Kereiakes DJ, Broderick TM, Roth EM et al. Time course, magnitude, and consistency of platelet inhibition by abciximab, tirofiban, or eptifibatide in patients with unstable angina pectoris undergoing percutaneous coronary intervention. American Journal of Cardiology. 1999;84:391-395. 4.	Simon DI, Liu CB, Ganz P et al. A comparative study of light transmission aggregometry and automated bedside platelet function assays in patients undergoing percutaneous coronary intervention and receiving abciximab, eptifibatide, or tirofiban. . Catheterization & Cardiovascular Interventions. 2001;52:425-432. 5.	Batchelor WB, Tolleson TR, Huang Y et al. Randomized COMparison of platelet inhibition with abciximab, tiRofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes: the COMPARE trial. Comparison Of Measurements of Platelet aggregation with Aggrastat, Reopro, and Eptifibatide. Circulation. 2002;106:1470-1476. 6.	Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. The EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet. 1998;352:87-92. 7.	Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. New England Journal of Medicine. 1998;339:436-443. 8.	The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis. Circulation. 1997;96:1445-1453. 9.	Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS). New England Journal of Medicine. 1998;338:1488-1497. 10.	Moser M, Bertram U, Peter K et al. Abciximab, eptifibatide, and tirofiban exhibit dose-dependent potencies to dissolve platelet aggregates. Journal of Cardiovascular Pharmacology. 2003;41:586-592. 11.	ESPRIT I, Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. [erratum appears in Lancet 2001 Apr 28;357(9265):1370]. Lancet. 2000;356:2037-2044. 12.	Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II. . Lancet. 1997;349:1422-1428. 13.	Steinhubl SR, Talley JD, Braden GA et al. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study. . Circulation. 2001;103:2572-2578. 14.	Simon DI, Liu CB, Ganz P et al. A comparative study of light transmission aggregometry and automated bedside platelet function assays in patients undergoing percutaneous coronary intervention and receiving abciximab, eptifibatide, or tirofiban. . Catheterization & Cardiovascular Interventions. 2001;52:425-432. 15.	Stone GW, Ellis SG, Cannon L. Outcomes of the polymer-based, paclitaxel-eluting Taxus stent in complex lesions: principal clinical and angiographic results from the Taxus-V pivotal randomized trial. Late-breaking trial presented at the American College of Cardiology Scientific Session 2005.March 6-9, 2005.Orlando. 2005. 16.	Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. . New England Journal of Medicine. 1994;330:956-961. 17.	Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. The EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. . Lancet. 1998;352:87-92. 18.	Harrington, R. A., Marchant, K., Kleiman, N. S., Leimberger J.D., Tcheng, J. E., Sigmon, K. N., Smith, D. D., Kitt, M., Topol, E. J., and Califf, R. M. Bleeding associated with use of a platelet glycoprotein IIb/IIIa inhibitor during routine coronary angioplasty: Is too much heparin the culprit? Journal of the American College of Cardiology. 1994;22. 19.	Narins CR, Hillegass WB, Jr., Nelson CL et al. Relation between activated clotting time during angioplasty and abrupt closure. Circulation. 1996;93:667-671. 20.	Tcheng JE. Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: bleeding, reversal, thrombocytopenia, and retreatment. [Review] [22 refs]. American Heart Journal. 2000;139:S38-S45. 21.	Ashby DT, Dangas G, Aymong EA et al. Relation between the degree of procedural anticoagulation and complications after coronary stent implantation. American Journal of Cardiology. 2003;92:319-322. 22.	Tolleson TR, O'Shea JC, Bittl JA et al. Relationship between heparin anticoagulation and clinical outcomes in coronary stent intervention: observations from the ESPRIT trial. Journal of the American College of Cardiology. 2003;41:386-393. 23.	Kong DF, Califf RM. Post-procedure heparin: boon or burden? American Heart Journal. 1998;136:183-185. 24.	Topol EJ, Moliterno DJ, Herrmann HC, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med. 2001;344:1888–1894. 25.	Kabbani SS, Aggarwai A, Terrien EF, et al. Suboptimal early inhibition of platelets by treatment with tirofiban and implications for coronary interventions. Am J Cardiol. 2002;89:647–650. 26.	Lakkis N, Lakiss N, Bobek J, and Farmer J. Platelet Inhibition With Tirofiban Early During Percutaneous Coronary Intervention: Dosing Revisited Cathet Cardiovasc Intervent 2002;56:474–477.] 27.	The GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet. 2001;357:1905–14.]