Cardiovascular disease is in fact a geriatric disease as the average age of ACS patients has risen steadily to ~70 years. With the increasing number of DM and elderly patients, there will be a strong market (estimated in the hundreds of millions dollars or more, per annum) for our product. This is evident from the market values of existing P2Y12 antagonists (see Table 1). From 2001-2011, the annual sale of clopidogrel reached $6-9 billion, and the annual sales of prasugrel and ticagrelor also reached a few hundred millions from 2009 to 2013. The main competition with our product will come from generic clopidogrel, prasugrel and ticagrelor in treatment of ACS/PCI patients. With our product’s competitive advantages it will benefit a large group of patients including patients with diabetes and advanced age, and of Asian descent. These groups of patients represent the fastest growing market for our product.
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) plays a major role in management of coronary heart diseases. Approximately one million patients receive DAPT for acute coronary syndrome (ACS) in the United States every year. The 2014 ACC/AHA guidelines recommend DAPT for all ACS patients undergoing percutaneous coronary intervention (PCI), but give no preference for a particular P2Y12 inhibitor (1). Recent clinical trials have demonstrated the benefits of DAPT beyond one year (2). It is anticipated that long-term use of DAPT will likely increase.
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) plays a major role in management of coronary heart diseases. Approximately one million patients receive DAPT for acute coronary syndrome (ACS) in the United States every year. The 2014 ACC/AHA guidelines recommend DAPT for all ACS patients undergoing percutaneous coronary intervention (PCI), but give no preference for a particular P2Y12 inhibitor (1). Recent clinical trials have demonstrated the benefits of DAPT beyond one year (2). It is anticipated that long-term use of DAPT will likely increase.
Current DAPT will not meet the medical needs of a growing number of DM patients in clinical cardiology because of its clinical limitations and concerns with safety and side effects. Approximately ~30% ACS patients are diabetic, and this number is projected to increase significantly in the next decade due to the epidemic growth of obesity in the United States. In spite of the availability of newer P2Y12 inhibitors such as prasugrel and ticagrelor, clopidogrel is the most broadly used P2Y12 inhibitor to prevent arterial thrombosis. Although it is generally effective and well tolerated, clopidogrel has manifested clinical limitations of inter-individual variability, delayed onset of action, and drug-drug interactions (DDIs). Approximately ~30% of Caucasians and up to 60% of Asians lack adequate responses to clopidogrel. Genetic factors and diabetes are the two main contributors to this non-responsiveness.
Studies have shown that DM patients have higher platelet reactivity while on clopidogrel compared with non-DM patients. As a result they are at elevated risk of ischemic complications (3, 4). Angiolillo and colleagues have recently provided strong evidence that low levels of the active metabolite (AM) of clopidogrel in the DM patients is primarily responsible for the lack of response to clopidogrel (5). The possible causes for the poor pharmacokinetics (PK) of clopidogrel are attributed to metabolic disorders and poor gastrointestinal absorption associated with diabetes mellitus.
In light of the clinical limitations of clopidogrel, the FDA approved prasugrel and ticagrelor to treat ACS/PCI patients. Compared with clopidogrel, prasugrel and ticagrelor have a faster onset of action and more potent inhibition of platelet aggregation (IPA) (see Table 1), which translate to clinical outcomes of reduction in major adverse cardiovascular events. However, recent clinical studies comparing ticagrelor with prasugrel in STEMI patients undergoing PCI showed that both drugs exhibit initial delay in the onset of antiplatelet action (6, 7). At least four hours were required to achieve effective platelet inhibition in 50% of the patients (7). Furthermore, the benefits of prasugrel and ticagrelor are at the expense of increased risks of bleeding (8, 9) compared to clopidogrel. Due to delayed gastrointestinal bleeding, the FDA recommended only short-term use (< 30 days) of prasugrel after PCI (10). In addition, prasugrel is not recommended for elderly (>75 years) and under-weighted (< 60 kg) patients because of safety concerns with bleeding (8). The primary safety concern with ticagrelor is also bleeding as indicated in the PLATO trial supporting the approval of ticagrelor by the FDA (9). In addition, ticagrelor is not recommended for patients with hepatic and renal diseases. Nearly one-third of patients in the PLATO trial experienced dyspnea after taking ticagrelor. As a result patients on ticagrelor are nine times more likely to discontinue the use of drug than those on clopidogrel. Clopidogrel seems to represent the safest alternative for DAPT (11).
It is apparent that development of antiplatelet drug by targeting potency alone is not sufficient to maximize the benefit/risk ratios, which require delicate balance of hemostasis. Elimination of the clinical limitations of clopidogrel while retaining its antiplatelet “warhead” or the AM represents an alternative strategy to improve the benefit/risk ratios for antiplatelet therapy. The clinical limitations of clopidogrel stem from its metabolism. As shown in Scheme 1, clopidogrel is a prodrug requiring metabolic bioactivation by P450s to the AM for antiplatelet action. The overall yield of the AM is estimated to be only ~5% of ingested clopidogrel due to extensive metabolism of clopidogrel by competing metabolic pathways which generate almost 20 metabolites (12, 13). This low level of bioactivation is responsible for the delayed onset of action. The inter-individual variability of clopidogrel is closely associated with the genetic polymorphism of CYP2C19 (14-16) which is primarily responsible for bioactivating clopidogrel to the AM. Patients carrying CYP2C19 loss-of-function (LoF) genes are unable to produce the AM. Although the downstream effects of the multiple metabolites of clopidogrel are unknown, it is reasonable to assume that some of these metabolites have unwanted activity based on a number of studies on the metabolism of ticlopidine, the first generation of thienopyridinyl antiplatelet agent. Reactive metabolites of ticlopidine are associated with idiosyncratic toxicity of agranulocytosis and the side effects of neutropenia and bone marrow aplasia. The counterparts of these reactive metabolites are also produced in the metabolism of clopidogrel.
Studies have shown that DM patients have higher platelet reactivity while on clopidogrel compared with non-DM patients. As a result they are at elevated risk of ischemic complications (3, 4). Angiolillo and colleagues have recently provided strong evidence that low levels of the active metabolite (AM) of clopidogrel in the DM patients is primarily responsible for the lack of response to clopidogrel (5). The possible causes for the poor pharmacokinetics (PK) of clopidogrel are attributed to metabolic disorders and poor gastrointestinal absorption associated with diabetes mellitus.
In light of the clinical limitations of clopidogrel, the FDA approved prasugrel and ticagrelor to treat ACS/PCI patients. Compared with clopidogrel, prasugrel and ticagrelor have a faster onset of action and more potent inhibition of platelet aggregation (IPA) (see Table 1), which translate to clinical outcomes of reduction in major adverse cardiovascular events. However, recent clinical studies comparing ticagrelor with prasugrel in STEMI patients undergoing PCI showed that both drugs exhibit initial delay in the onset of antiplatelet action (6, 7). At least four hours were required to achieve effective platelet inhibition in 50% of the patients (7). Furthermore, the benefits of prasugrel and ticagrelor are at the expense of increased risks of bleeding (8, 9) compared to clopidogrel. Due to delayed gastrointestinal bleeding, the FDA recommended only short-term use (< 30 days) of prasugrel after PCI (10). In addition, prasugrel is not recommended for elderly (>75 years) and under-weighted (< 60 kg) patients because of safety concerns with bleeding (8). The primary safety concern with ticagrelor is also bleeding as indicated in the PLATO trial supporting the approval of ticagrelor by the FDA (9). In addition, ticagrelor is not recommended for patients with hepatic and renal diseases. Nearly one-third of patients in the PLATO trial experienced dyspnea after taking ticagrelor. As a result patients on ticagrelor are nine times more likely to discontinue the use of drug than those on clopidogrel. Clopidogrel seems to represent the safest alternative for DAPT (11).
It is apparent that development of antiplatelet drug by targeting potency alone is not sufficient to maximize the benefit/risk ratios, which require delicate balance of hemostasis. Elimination of the clinical limitations of clopidogrel while retaining its antiplatelet “warhead” or the AM represents an alternative strategy to improve the benefit/risk ratios for antiplatelet therapy. The clinical limitations of clopidogrel stem from its metabolism. As shown in Scheme 1, clopidogrel is a prodrug requiring metabolic bioactivation by P450s to the AM for antiplatelet action. The overall yield of the AM is estimated to be only ~5% of ingested clopidogrel due to extensive metabolism of clopidogrel by competing metabolic pathways which generate almost 20 metabolites (12, 13). This low level of bioactivation is responsible for the delayed onset of action. The inter-individual variability of clopidogrel is closely associated with the genetic polymorphism of CYP2C19 (14-16) which is primarily responsible for bioactivating clopidogrel to the AM. Patients carrying CYP2C19 loss-of-function (LoF) genes are unable to produce the AM. Although the downstream effects of the multiple metabolites of clopidogrel are unknown, it is reasonable to assume that some of these metabolites have unwanted activity based on a number of studies on the metabolism of ticlopidine, the first generation of thienopyridinyl antiplatelet agent. Reactive metabolites of ticlopidine are associated with idiosyncratic toxicity of agranulocytosis and the side effects of neutropenia and bone marrow aplasia. The counterparts of these reactive metabolites are also produced in the metabolism of clopidogrel.
We, in collaboration with scientists at the UM (17, 18), are developing novel conjugates of clopidogrel as antiplatelet agents. With this approach we can deliver the AM of clopidogrel without metabolic
bioactivation by P450s as shown in Scheme 2. Our approach elicits several advantages: 1). It eliminates the inter-individual variability due to the genetics of CYP2C19(7). It accelerates the onset of action because of the rapid release of the AM. 3). It is efficacious at lower doses (figure 1A). 4) It has less bleeding risk at the same dose (figure 1B). 5) It reduces P450-related drug-drug interactions and downstream effects of reactive metabolites (figure 2). 4). It retains the AM of clopidogrel as the antiplatelet “warhead” that has excellent safety record. Taken together, we expect that novel conjugates of clopidogrel should provide improved benefit/risk ratios for antiplatelet therapy, especially for DM and elderly patients who are prone to contraindications of DDIs and metabolic disorders.
bioactivation by P450s as shown in Scheme 2. Our approach elicits several advantages: 1). It eliminates the inter-individual variability due to the genetics of CYP2C19(7). It accelerates the onset of action because of the rapid release of the AM. 3). It is efficacious at lower doses (figure 1A). 4) It has less bleeding risk at the same dose (figure 1B). 5) It reduces P450-related drug-drug interactions and downstream effects of reactive metabolites (figure 2). 4). It retains the AM of clopidogrel as the antiplatelet “warhead” that has excellent safety record. Taken together, we expect that novel conjugates of clopidogrel should provide improved benefit/risk ratios for antiplatelet therapy, especially for DM and elderly patients who are prone to contraindications of DDIs and metabolic disorders.
Figure 1. Comparison of efficacy and bleeding time of ClopNPT with clopidogrel.(A) time to occlusion after IV dose of ClopNPT and clopidogrel. (B) Tongue bleeding timeafter IV dose of ClopNPT and clopidogrel. The two sets of data were obtained in the same animals after IV dosing. The data show that ClopNPT is effective to prevent thrombosis at 1 mg/ml with no significant increase in bleeding time. In comparison clopidogrel at 1 mg/ml is ineffective. At 5 mg/ml clopidogrel is effective but the bleeding time is dramatically increased compared with ClopNPT at the same dose. These data suggest that ClopNPT is more effective than clopidogrel with reduced risks of bleeding.
Figure 2. Comparison of the microsomal stability of ClopNPT with Clopidogrel. (A) Metabolism of ClopNPT and Clopidogrel in human liver microsomes (HLMs). ClopNPTor clopidogrel (5 M each) was incubated in HLMs in the presence of 1 mM NADPH for 1 h and the compounds remaining were plotted over time. (B) Metabolism of ClopNPT and clopidogrel by carboxylesterase (CES). ClopNPT or clopidogrel (5 M each) was incubated in cytosols of human liver tissues for 1 h and the compounds remaining were plotted over time.The results show that clopidogrel in either HLMs and cytosols are rapidly decreased todue to rapid metabolism by cytochromes P450 and CES respectively. In marked contrast ClopNPT is very stable, indicative of lack of metabolism.
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