Individuals at risk for clotting issues—such as deep vein thrombosis or a pulmonary embolism—or those with cardiac disorders, will likely find themselves being prescribed an oral anticoagulant. For decades, warfarin has largely ruled the market, which, according to Global Industry Analysts Inc., is expected to reach $30 billion by 2020. Many companies are looking to grab a piece of the pie, among them Espero BioPharma, a Jacksonville, Fla.-based biopharmaceutical company. Espero is advancing tecarfarin, an oral anticoagulant, and recently reached Phase 3 development for the drug candidate. We spoke with Espero CEO Quang Pham to discuss current market options and why the company believes its drug candidate will be a disruptive addition.
DDNews: What are the most commonly used options for the oral anticoagulant market at present? Where is there room for improvement?
Quang Pham: Anticoagulants for chronic, oral indications can be divided into two groups: the vitamin K antagonists (VKAs) and the non-VKAs (NOACs). The only VKA in use in the U.S. is warfarin, the standard of care for over 60 years since its introduction in 1950 as a rodenticide. Warfarin acts by interrupting the production of a variety of coagulation factors within the coagulation cascade. The level of anticoagulation can and must be measured periodically with a simple and widely available blood test called the international normalized ratio (INR). Anticoagulation with warfarin is readily reversible with vitamin K supplementation or with fresh frozen plasma.
Four NOACs have been approved in the U.S. since 2010; all act by a direct inhibitory effect on either thrombin, or factor Xa. Pradaxa (dabigatran) is a direct thrombin inhibitor with a reversal agent, Praxbind. The factor Xa inhibitors Xarelto (rivaroxaban), Eliquis (apixaban) and Savaysa (edoxaban) were subsequently approved, but they don’t have reversal agents for bleeding control. Earlier this year, Portola Pharmaceuticals’ reversal agent for these three products was not approved by the FDA.
According to prescription data available through November 2017, warfarin still maintains a 51-percent TRx share against the newer four products. Warfarin is the only anticoagulant that can be used to prevent thromboembolic complications in a number of conditions including patients with mechanical prosthetic heart valves (in whom NOAC use is specifically contraindicated), recurrent deep vein thrombosis (DVT), and advanced valvular heart disease. All NOACs depend on some degree of renal clearance more than warfarin.
Warfarin is eliminated by the liver through CYP2C9 metabolism. As a result, anticoagulation with warfarin is prone to unpredictable instability due to genetic variation and drug interactions inherent in the CYP clearance system. The warfarin label warns of more than 100 potential drug interactions through this CYP clearance pathway, many of which are used commonly in anticoagulation patients. Warfarin accounts for the single highest number of drug-interaction-related hospitalizations, also known as adverse drug reactions, and has been dubbed as “The most dangerous drug in America.”
Tecarfarin is not metabolized via the CYP450 enzymes, thus eliminating the numerous potential drug-drug interactions.
DDNews: How do anticoagulants fit into Espero’s product portfolio?
Pham: Espero BioPharma is solely focused on developing and commercializing cardiovascular drugs, so anticoagulants are a perfect fit. Espero’s in-market products include Nitrolingual Pumspray and GoNitro (acute angina) and Durlaza (antiplatelet).
DDNews: Are there specific indications in which Espero hopes to position this new compound, beyond being an alternative to warfarin?
Pham: Yes. All of the NOACs were approved based on a comparative analysis with warfarin. The margin of benefit that tecarfarin provides over warfarin is likely to demonstrate equivalence or superiority of tecarfarin over the NOACs in the current indications for which NOACs are approved (non-valvular atrial fibrillation (AF), DVT, etc.). Thus, tecarfarin is likely to be a direct competitor to the NOACs. Assuming non-inferiority or superiority over the NOACs, tecarfarin can be monitored, is easily reversible, and is unaffected by chronic kidney disease (CKD). Thus, tecarfarin would be a legitimate competitor with the current NOAC market for patients who in the view of their physicians do better with monitoring. If closely monitored and well cared for, these patients can do better than on an unmonitored therapy.
As a VKA demonstrating superiority over warfarin, tecarfarin would not be an “alternative,” but a true “replacement” for warfarin. It is also possible the label for warfarin would be downgraded to recognize the advantage of tecarfarin not having any known drug interactions and its clearance being independent of genetics and renal function.
Patients with CKD, particularly end-stage renal disease (ESRD), and the elderly have high rates of thromboembolic disease, but also exhibit high rates of bleeding complications on anticoagulants. It is likely that tecarfarin could provide a treatment for patients who are currently not being treated.
DDNews: How has tecarfarin performed in preclinical studies in terms of safety and efficacy?
Pham: Tecarfarin has demonstrated sufficient safety in non-clinical studies to support an IND and allow for the performance of several clinical trials. Because tecarfarin metabolism occurs within the placental tissues, experimental evidence in animals suggest that it is likely to have reduced potential for teratogenicity compared to warfarin (a known teratogen). In-vitro studies showed that tecarfarin is as potent as warfarin against its target, VKORC1. Its metabolic half-life is only a few hours in human hepatocytes and its main metabolism is through human carboxylesterase type-2 (hCE2), to yield a metabolite that is essentially devoid of activity. Because of this type of metabolism, tecarfarin is not subject to the drug-drug interactions that are seen with warfarin. Tecarfarin has been studied in dogs up to nine months and in rats up to two years. Although the results of the two-year carcinogenicity study in rats have not been reported, there was no obvious incidence of carcinogenic potential compared to control. Section-3 reprotox remains to be performed.
DDNews: As noted above, oral anticoagulants are divided into VKAs and non-VKAs. What is the difference between these groups?
Pham: VKAs inhibit the production of factors II, VII, IX and proteins C and S within the coagulation cascade. Although it may take a few days to achieve adequate anticoagulation from the initiation of therapy, the level of anticoagulation achieved is consistent throughout the day, once a stable dose is demonstrated. Missing or delaying a dose is not likely to have a significant impact on the overall state of anticoagulation.
Anticoagulation with a VKA is mandatory when the risks of thromboembolism are greatest—i.e. after nechanical heart valve (MHV) implantation or recurrent DVT. This is likely because of the effects at multiple points along the coagulation cascade gives superior and reliable anticoagulation. It is also possible (and necessary) to monitor the level of anticoagulation produced by a VKA. VKAs are readily reversible with vitamin K supplementation or fresh frozen plasma infusion. VKAs are familiar to physicians, and the means of managing, monitoring and reversing them are understood throughout the global medical community.
NOACs act through the inhibition of a single factor within the coagulation system (either thrombin, or factor Xa). They produce an effect shortly after administration. The level of anticoagulation varies throughout the day, and missing a dose may increase this tendency, and hence some have to be given twice a day. The level of anticoagulation is not measurable, and compliance cannot be confirmed or denied through objective testing nor is it possible to meaningfully adjust the dose downward in patients with renal insufficiency.
NOACs have been tested in non-inferiority studies against warfarin in limited indications that represent about 40 percent of the people who need a chronic oral anticoagulant. When dabigatran was evaluated in MHV patients, an excess of catastrophic problems, including valve thrombosis—which is virtually unheard of in patients treated with warfarin—and death led to study termination, and a listing of all NOACs as contraindicated in MHV patients. Although dabigatran has a reversing agent, the others do not. The reversing agent for dabigatran is a monoclonal antibody (idarucizumab) ,costs about $3,500 wholesale, must be refrigerated and has a shelf-life of three years. Its introduction several years ago has not resulted in increased use of dabigatran, which will soon have a generic competitor by Mylan.
DDNews: Moving forward, what is the plan for the Phase 3 tecarfarin program, in terms of primary and secondary endpoints?
Pham: The primary efficacy endpoint is the percentage of time within the time in therapeutic range (TTR) for each treatment among the on-treatment or mITT subjects. TTR is a measure of stability of anti coagulation and an improved TTR means the patient is being more safely and effectively anticoagulated. The analysis of this endpoint will be performed once the last subject randomized has completed at least seven months of study treatment or discontinued prematurely.
The secondary endpoints are:
- Population of patients who are taking a CYP2C9-interacting medication and have a CYP2C9 genotype variant allele
- The percentage of time within the TTR for each treatment among patients who are taking a CYP2C9-interacting medication and have chronic kidney disease stage 3 or 4 (eGFR ≥ 15 to <60 mL/min/1.73 m2)
- Percentage of patients with INR above 4.0
- Percentage of patients with INR above 5.0
- Time to first thromboembolic event (positively adjudicated events by the CEC including stroke, pulmonary embolus, deep vein thrombosis, myocardial infarction, etc.).
DDNews: In addition to tecarfarin, your company is advancing budiodarone through the clinic as well, as an anti-arrhythmia agent. How is the clinical program progressing for this drug candidate?
Pham: We have had discussion with KOLs that strongly support the development of budiodarone, recognizing an unmet need for an effective anti-arrhythmic for various AF suppression and inhibition. They also support the development of an agent to support VT storm in the setting of a previously implanted ICD.
Quang Pham is a biopharmaceutical entrepreneur with over 20 years of experience in founding, financing and growing companies, having launched Lathian Systems—an innovative company that provided online data and marketing services to pharmaceutical and biotech companies—before founding Espero. He served as president and CEO of Monarch Staffing, a healthcare staffing company in California and vice president and general manager with QTC Management, the largest private provider of government-outsourced disability examinations.
