Last Of The Primary Care Blockbusters? New Antithrombotics Line Up To Unseat Warfarin, Heparins, Plavix

Although the mainstays of antithrombotic therapy have remained the same for decades, a lengthy R&D assault by pharma - including some of the largest clinical trials ever conducted - has produced potential game-changers that have made it to FDA review for both major blood clot approaches: anticoagulation and platelet inhibition.

The holy grail of antithrombosis is an oral product with, at minimum, consistent dosing, no monitoring, and no food or drug interactions. The commercial rewards that would go to the developer of such a product have attracted a significant slice of big pharma as well as specialty firms, many looking for partnerships to advance their drugs through the tricky development area.

Treating thombosis is not an easy feat - therapies need to come within a specific window and block coagulation enough to prevent clots, but not so much that they create bleeds. That makes drug development very difficult. Further complicating the field is the legacy left by recent drugs that have failed to gain approval, but left behind safety concerns - such as AstraZeneca's Exanta , which added liver toxicity to the regulatory hurdles.

As a result, new molecular entities are stacked up in late-stage trials - and every player is desperately perched to refine clinical programs and fine-tune trial design and product formulations as news is released about category leaders like the pending oral antiplatelet prasugrel (Lilly/Daiichi Sankyo's Effient ) or oral anticoagulant rivaroxaban (Bayer/Johnson & Johnson's Xarelto ).

Effient and Xarelto are both slated for action next spring. The user fee goal for the rivaroxaban NDA, which covers prevention of deep vein thrombosis and pulmonary embolism in patients undergoing orthopedic surgery (the traditional proving ground for anticoagulants), falls on May 29, 2009.

Prasugrel's extended Sept. 26 user fee date came and went without FDA action - and no action is likely before March 2009 due to new plans for an advisory committee. The NDA seeks approval for acute coronary syndrome patients who are managed with percutaneous coronary intervention, including stents.

Newer Drugs, Greater Specificity

One of the benefits the new antithrombotics have to offer over the older, still reliable drugs is specificity. The targeted approaches of Effient and especially Xarelto - inhibition of specific platelet receptors and specific coagulation factors, respectively - represent a break with earlier antithrombotics, which, as products not far removed from their original biological models, have broader activity.

Heparin, for instance, inhibits both Factor IIa (thrombin) and Factor Xa, while new drugs like Xarelto target just Factor Xa, or, are direct thrombin inhibitors like Boehringer Ingelheim's dabigatran.

The Phase III thrombosis pipeline is dominated by platelet aggregation inhibitors and inhibitors of either Factor Xa or thrombin (see ¹ pie chart). Some earlier-stage anticoagulants target other coagulation factors, like Factor IX/IXa and Factor VIIa, Elsevier's drug development database Inteleos shows.

New Drugs Should Also Mean Greater Profit

If all goes according to plan, work on oral Factor Xa inhibitors, direct thrombin inhibitors, and novel platelet inhibitors could produce that near-dinosaur of contemporary drug development: a primary care blockbuster.

The massive clinical programs required to support broadly used drugs in front-line medical practice have been falling out of favor at big pharma. Most recently, Pfizer announced it was pulling out of traditional big pharma primary care strongholds like cardiovascular disease in favor of specialty areas like oncology.

But despite its move out of cardiovascular R&D, Pfizer is keeping a presence in anticoagulation; the company has partnered with Bristol-Myers Squibb on Bristol's Phase III Factor Xa inhibitor apixaban and has its own oral Factor Xa inhibitor in Phase II.

The blockbuster potential of an oral anticoagulant with clean dosing and few interactions explains the persistent interest by industry, especially as research continues to suggest that not only do a sizable proportion of patients fail to receive the accepted duration of anticoagulant treatment, but that even longer periods of anticoagulant therapy may be beneficial to patients at risk of thrombosis.

The federal government is contributing to raising the profile of DVT/PE and its effective prevention - which could mean a larger market for these drugs. Acting U.S. Surgeon General Steven Galson issued a "call to action" on Sept. 15. Although progress has been made in how to prevent, diagnose and treat DVT/PE, "it is also clear that we are not applying that knowledge on a systematic basis," he stated. "We must disseminate information more widely about the availability of effective interventions to prevent DVT/PE" in addition to investing in basic and translational research, he said.

There are many different settings for use of anticoagulant drugs, and an expanding universe of potential patients. That's something that the sponsors behind the new wave of antithrombotics are actively pursuing with broad clinical trial programs.

Whereas prevention of venous thromboembolism in patients who have undergone orthopedic surgery is commonly considered the initial indication for new anticoagulants, the typical program for the current crop of new agents also targets VTE treatment and long-term secondary prevention, VTE prevention in medically ill patients, prevention of stroke in atrial fibrillation patients, and secondary prevention of thromboembolic events in acute coronary syndrome.

The trials required to support such indications are mammoth. There are few surrogate markers in anticoagulation: all trials are outcome trials. The trials already ongoing for the cadre of drugs in late-stage development alone cover the enrollment of hundreds of thousands of patients.

Xarelto is a prime example of how large the development program for an antithrombotic must be. RECORD, Bayer and Johnson & Johnson's pivotal trial program, is "the largest ever conducted in the prevention of VTE in patients undergoing knee or hip replacement surgery." The application for DVT/PE prevention in orthopedic surgery was based on four trials comparing rivaroxaban to Sanofi-Aventis' injectable low molecular weight heparin Lovenox (enoxaparin) in over 12,500 patients (² Pharmaceutical Approvals Monthly August 2008, In Brief).

Bayer and J&J have bigger plans for the once-daily oral Factor Xa inhibitor, which J&J's Ortho-McNeil division will market if approved. The rivaroxaban trial program - which exemplifies the new antithrombotic development strategy of numerous indications - is enrolling over 45,500 patients.

The companies have also taken to heart the lesson about liver toxicity learned from AstraZeneca's Exanta (ximelagatran) experience; the first oral direct thrombin inhibitor was found "not approvable" due to liver toxicity. Bayer and J&J have spoken widely of the safety data from Xarelto trials, spreading word that the RECORD trial program showed good hepatic safety.

Some Caution Is Due

The payoff could be correspondingly large. But the corks remain in the champagne bottles: balancing the need for anticoagulation and the risk of bleeding is tricky business.

Early stumbles are to be expected in the development of new drug classes, but the failure of Exanta after major investment cast something of a pall on novel anticoagulants, especially when one of the next drugs in line, Bristol-Myers Squibb/Pfizer's apixaban, stumbled in late-stage studies. Not many companies have the scale to withstand the failure of a project of such scale.

And it is important to remember that despite their notorious difficulties in dosing, warfarin and heparin have withstood all challenges to their centrality in anticoagulation for half a century. Unfractionated heparin (derived from pig stomach mucosa) has been in use since the 1930s. It has been refined - low molecular weight heparins like enoxaparin and dalteparin were introduced in the 1980s, followed by the more selective fondaparinux - but not replaced. Warfarin (derived from rat poison) has been the only oral anticoagulant available for 50 years.

On the antiplatelet side of the thrombosis equation, one of modern medicine's oldest drugs, willow bark-derived aspirin, maintains a key role despite the availability of "super-aspirin" Plavix , one of the world's top-selling drugs. Thienopyridines like Plavix have shown modest efficacy and are often combined with aspirin in dual therapy regimens.

Lilly's prasugrel, another thienopyridine, hopes to challenge that perception of modest efficacy.

Of Platelets, Prasugrel - And Plavix

One player dominates the antiplatelet category - Bristol/Sanofi-Aventis' Plavix(clopidogrel) - although many companies are eager to unseat the mainstay of treatment, hopefully before Plavix loses exclusivity in 2011 and competitors have to contend with a cheaper generic alternative.

Chief among the companies lined up to take on Plavix is Lilly and partner Daiichi, with prasugrel. Approval of prasugrel in time to establish the new drug before generic clopidogrel floods the market is among Lilly's highest priorities.

But getting approval of prasugrel is proving not to be as easy as Lilly/Daiichi had hoped. Despite getting a priority review designation, usually a good indication of the chances for a first-cycle approval, FDA first extended the user fee date by three months and then missed that Sept. 26 deadline. The agency is understood now to be putting together an advisory committee review of prasugrel, potentially in February, which would push FDA action to March at the earliest (³ (Also see "Prasugrel Delay Could Extend Well Into 2009; FDA Eyes February Cmte. Review" - Pink Sheet, 20 Oct, 2008.), p. 3).

Lilly's position is that the prasugrel NDA is a "very large and complex submission, and it should not be surprising that delays occur."

Prasugrel's application is affected by the classic quandary of antithrombotics: too little activity and patients develop clots, too much activity and they develop bleeds. In the pivotal TRITON-TIMI 38 trial in ACS, prasugrel patients had significantly fewer ischemic events than clopidogrel patients, but with an increase in major bleeds. But the safety concerns are not limited to the bleeding issue - another concern appears to center on findings of more cancers in the prasugrel than the clopidogrel arm of the 13,000-patient TRITON trial.

Among those intently watching the prasugrel review are, no doubt, AstraZeneca and The Medicines Company. Both companies have Phase III candidates (oral AZD6140 and I.V. cangrelor, respectively) that target the same point in the platelet aggregation process: the ADP receptor P2Y12 receptor on the platelet cell membrane. The first I.V.-to-oral P2Y12 antagonist, Portola's PRT-060128, is in Phase II.

Still, the spector of generic Plavix looms large, as it will pose a serious challenge to sales of any future antiplatelet agents. Perhaps a desire to look beyond Plavix' ADP P2Y12 receptor target is contributing to the proliferation of new targets in early-stage levels of the antiplatelet pipeline (see ⁴ The Many Targets of New Platelet Inhibitors ).

Not surprisingly, smaller companies dominate the younger ranks of antiplatelet agents. New mechanisms being tested, according to an analysis of Elsevier's drug development database Inteleos, include phosphodiesterase and thromboxane A2 synthetase inhibition (Indigo's parogrelil, in Phase III for a modest indication of intermittent claudication), prostaglandin E2 receptor E3 antagonism (from the financially troubled deCODE, which seeks to outlicense its Phase II candidate), and targeting the serotonin 5-HT2a receptor on platelets (Arena's inverse agonist APD-791).

AstraZeneca Chooses Higher Degree Of Difficulty

AstraZeneca is highlighting its P2Y12 antagonist AZD6140 as an advance over both prasugrel and clopidogrel because it is the first reversible antiplatelet agent in the class. The company is following an arguably risky strategy to demonstrate its superiority to clopidogrel: one very large Phase III trial, the PLATO study.

PLATO has enrolled 18,000 patients with both non-ST and ST-elevation ACS, randomized to AZD6140 or clopidogrel. The trial is event-driven, with a primary endpoint of relative risk reduction for composite of vascular death, nonfatal MI and nonfatal stroke. Results are expected in late spring 2009.

AstraZeneca is also taking on some risk with its successor to Exanta, the once-daily oral direct thrombin inhibitor AZD0837. The firm has prioritized an AF indication instead of the established pathway of testing new anticoagulants in orthopedic surgery patients first. Indeed, Exanta's lead indication was VTE prevention in orthopedic surgery patients.

Phase III recruitment for AZD0837 is expected to begin this year (⁵ (Also see "Learning From Exanta: AstraZeneca Ready For Phase III With ‘0837" - Pink Sheet, 4 Aug, 2008.), p. 14).

AZD0837 could be a latecomer to the oral anticoagulant scene, but AstraZeneca maintains that it has used the Exanta experience to shape '0837 development; for instance, developing an extended-release formulation with less peak-trough variability after examining Exanta's immediate-release data.

Direct Thrombin Inhibitors Look to AF Patients

AstraZeneca is not alone in the oral DTI field in choosing an initial indication other than VTE prevention in orthopedic surgery. Boehringer Ingelheim is also targeting AF patients with its initial trials of dabigatran, the most advanced oral DTI (see ⁶ Direct Thrombin Inhibitors In Development ).

Boehringer Ingelheim completed enrollment of more than 18,000 patients in Phase III trials of dabigatran etexilate in January for stroke prevention in atrial fibrillation patients. The full dabigatran global clinical program, RE-VOLUTION, includes over 38,000 patients.

Results from the RE-LY trial, which the company calls the largest stroke prevention in atrial fibrillation trial conducted to date, are expected in 2009, as are treatment of acute VTE results. Other studies are looking at secondary prevention of VTE and prevention of cardiac events in ACS.

Dabigatran's U.S. prospects are brightened by the U.K.'s National Institute for Health and Clinical Excellence's Sept. 24 announcement that it recommended the new drug, approved in Europe as Pradaxa for primary prevention of VTE in orthopedic surgery patients, citing the potential for reduced administration costs and improved treatment adherence due to Pradaxa's once-daily oral dosing and lack of need for monitoring.

Trials of anticoagulants in Europe and the U.S. do not always cross-apply, because the background anticoagulation regimens in standard use differ across the Atlantic.

Parenteral DTIs Struggle To Make Impact

FDA has approved non-oral direct thrombin inhibitors before - The Medicines Company's Angiomax , GlaxoSmithKline's argatroban, and Bayer's Refludan - but sales have been limited, and parenteral formulations have limited the scope of use, leaving plenty of room for the oral products in development.

TMC has run into turbulence in trying to extend labeling for Angiomax. FDA issued a "not approvable" letter in May for a new dosing regimen for treatment of ACS initiated in the emergency room, based on the 13,800 patient ACUITY trial. TMC noted that FDA's decision "involved the appropriate use and interpretation of non-inferiority trials" in its most recent quarterly SEC filing. "We disagree," TMC stated.

Late-Stage Factor Xa Inhibitors Number Eight

Currently, at least eight Factor Xa inhibitor anticoagulants suitable for chronic therapy are in Phase II or later clinical trials, according to Elsevier's Inteleos drug development database (see ⁷ Factor Xa inhibitors In Development ).

Some, like Sanofi-Aventis' Phase III weekly subcutaneous injectable idrabiotaparinux, build on the parenteral indirect Factor Xa inhibitors on the market, such as GSK's Arixtra (fondaparinux).

Most of the work, however, is going into development of an oral, direct Factor Xa inhibitor. Behind the two in Phase III or beyond (Bayer/J&J's rivaroxaban and Bristol/Pfizer's apixaban) are at least five oral agents in Phase II U.S. trials, including three from Japanese firms (Daiichi Sankyo, Takeda and Astellas), one from big pharma (Pfizer's PD-348,292) and one from the anti-thrombotic specialty firm Portola (betrixaban).

Portola describes Factor Xa as "the preferred target for anticoagulant drug development because it occurs prior to the explosive step in thrombin generation." Also, the firm says, "since FXa is present in much smaller concentrations than thrombin it is relatively easier to effectively inhibit."

Making Adjustments

Sanofi-Aventis worked on modifying its Factor Xa inhibitor idraparinux, originally a joint project with Organon, to improve its dosing profile. Biotinylated idraparinux, or idrabiotaparinux, is a long-acting neutralizable Factor Xa inhibitor administered weekly by subcutaneous injection.

The company conducted a bioequipotency study (EQUINOX) to show pharmacodynamic similarity between the two versions and demonstrate a comparable safety and efficacy profile to idraparinux in the VAN GOGH VTE treatment trial.

Sanofi is enrolling patients into two large-scale Phase III trials of idrabiotaparinux: CASSIOPEA, a pulmonary embolism trial, and BOREALIS-AF, for prevention of stroke and systemic embolism in AF patients. Sanofi predicts filing for approval based on BOREALIS-AF in 2011. The firm has described CASSIOPEA as "a difficult study to be performed."

Sanofi-Aventis is also enrolling seven Phase III trials for AVE5026. The product is an ultra-low molecular weight heparin, and a potential successor to the company's low molecular weight heparin Lovenox.

Apixaban Surprises By Stumbling In Studies

Bristol and Pfizer have hit both safety and efficacy setbacks for their Factor Xa agent apixaban. The firms are retooling their plans after stumbles in the ADVANCE-1 and APPRAISE trials. The planned second-half 2009 apixaban NDA filing, for venous thromboembolism prevention, will be delayed.

ADVANCE-1 results released Aug. 27 surprised observers with apixaban's failure to demonstrate non-inferiority to Sanofi-Aventis' Lovenox (enoxaparin). The Phase II APPRAISE secondary prevention trial in heart attack patients, presented the following week to the European Society of Cardiology, identified a dose-dependent increase in bleeding events with apixaban, leading to restriction of dosing in future ACS trials to the two lower dose ranges of apixaban.

The firm has been sure to point out that apixaban's liver safety profile is clean.

Full ADVANCE-1 trial results can be expected to be a big draw at the American Society of Hematology meeting in December. The study is nonetheless only one of four VTE studies in the pivotal program.

Bristol Senior VP of Global Development in Medical Affairs Brian Daniels commented on a Sept. 3 conference call to discuss the ESC results that while the VTE program has the greatest number of studies in the apixaban program, "it has the smallest market potential for us. … It's a relatively niche indication, particularly orthopedic [VTE] prevention."

Bristol considers ACS the more exciting market for apixaban. Apixaban Development Lead Jack Lawrence told the call that the ACS population studied in APPRAISE represented a significant new market opportunity for anticoagulants. ACS patients, "despite contemporary evidence-based care that includes aggressive revascularization and potent antiplatelet therapy, often including dual antiplatelet regimens," still have undesirably high rates of recurrent ischemic events, he said.

ACS: The Next Frontier For Oral Anticoagulants?

"This new mechanism, which is looking at coagulation factor and inhibiting coagulation as a way in which to manage patients with ACS, is very different than the traditional antiplatelet therapy approaches that have been used for long-term treatment of patients who have had coronary events," Daniels said.

Small studies with warfarin and Exanta showed oral anticoagulation to be superior to aspirin following ACS, Lawrence observed. However, warfarin is "very rarely used" in ACS despite carrying an indication for it.

"To date, no placebo-controlled trial of an oral anticoagulate has been performed in patients with ACS who are taking dual antiplatelet therapy," Lawrence said. "Considering that that is the gold standard, we felt it important to get experience in that population."

"We see potential value in targeting two mechanisms of clotting, not just the platelet mechanism, but also the coagulation cascade," Lawrence said.

"Our [apixaban] program is 20,000-plus patients" with atrial fibrillation, Daniels noted. "There's going to be a lot of information about a variety of different subtypes."

"We opted not to perform a Phase II study in atrial fibrillation because the efficacy and bleeding rates expected are so low that we didn't think that that would be a very informative experience unless it was a quite large experience," Lawrence said.

Bristol expected to announce Phase II results in ACS at the AHA annual meeting this fall.

Schering-Plough's TRA Aims At New Target

The thrombin receptor antagonists offer the prospect of a new antithombotic class. The PAR-1 receptor targeted by the TRAs is the primary thrombin receptor on platelets. Compared to anti-platelet agents targeting the ADP receptor on platelets, like clopidogrel and prasugrel, thrombin receptor (PAR-1) antagonists are expected to show no variability.

Schering-Plough aims to submit the first agent in the new TRA class; its oral candidate, SCH-530348, is in Phase III. SCH-530348 is the subject of two large Phase III trials: TRACER, a 10,000-patient trial in non-STEMI ACS, and TRA2P TIMI-50, a secondary prevention trial with a one-year minimum follow-up.

Another TRA agent, Eisai's E-5555, is in Phase II.

Staying Alive

Two Phase III anti-clotting agents could represent the triumph of hope over experience - or repeat past failures. VDDI is keeping the oral antiplatelet agent xemilofiban, a Gp IIb/IIIa antagonist, alive with a restructured dosing schedule and narrower patient selection after original sponsors Searle and Pharmacia withdrew an NDA in 1999. VDDI sees a more limited indication in prevention of thrombotic complications following PTCA, with a short treatment period instead of the six-month duration tested originally.

Earlier this year, Lundbeck licensed PAION's desmoteplase, a biologic plasminogen activator thrombolytic engineered from vampire bat saliva, after Forest terminated its license based on failure to meet primary endpoints in a Phase III acute ischemic stroke treatment study. Lundbeck plans to initiate a new Phase III with an adjusted design in late 2008.

Licensing is a vital activity in such a difficult and expensive development area, and there is no shortage of potential deals in the field.

Available To Good Pharma Home

ARYx is looking to exploit warfarin's effective anticoagulation by improving the warfarin molecule. The company's oral warfarin analog ATI-5923 is in Phase III; ARYx is hoping to find a partner for the drug.

Other antithrombotics being publicly shopped to potential licensors include deCODE's Phase II anti-platelet agent DG-041, Myriad's Phase I oral direct thrombin inhibitor MPC-0920, and Vernalis' modified human plasminogen V-10153, a Phase II candidate that is activated by thrombin, according to the Inteleos database.

Bring On The Stents

One of the biggest (and most debated) developments in cardiology devices, drug-eluting stents, are also changing the landscape for antiplatelet drugs - and possibly changing the way major, class-based safety questions are addressed.

FDA, along with the four major drug-eluting stent manufacturers and four antiplatelet drug firms, is months away from launching an unprecedented $100 million, 20,000-patient trial to determine the optimal duration of dual antiplatelet therapy with drug-eluting stents. The drug firms participating are Plavix co-marketers Bristol and Sanofi-Aventis, as well as prasugrel sponsors Lilly and Daiichi Sankyo.

The design for the proposed randomized trial was presented at the Transcatheter Cardiovascular Therapeutics symposium in Washington, D.C., Oct. 15. The double-blind, placebo-controlled trial will compare a 12-month versus a 30-month duration of dual antiplatelet therapy (aspirin plus a thienopyridine) for drug-eluting and bare-metal stents. The 30-month endpoint will allow investigators to detect very late safety signals.

Professional guidelines recommend one month of dual antiplatelet therapy for bare-metal stent patients and 12 months for DES recipients, to prevent blood clots from forming in the stent. But many physicians are continuing therapy indefinitely in DES patient out of safety concerns, primarily the late-occurring stent thrombosis that has depressed the DES market and sparked controversy.

Perils Of Success?

The challenge for the new wave of antithrombotic drugs is not limited to the large, long studies needed for development, or the harsh examination of regulatory review - once past those, they also must carve out a place in the market.

Warfarin especially, but also heparins and aspirin, still work and are widely popular in spite of their various difficulties. And because patent protection is long gone, these older drugs have a significant cost advantage over novel agents.

The commercial scale of the antithrombotic market means that insurers have a significant stake in optimizing (and expanding) the use of older, cheaper and still effective drugs.

Further complicating the picture are the developments in pharmacogenetic testing that have made warfarin easier and safer to use. Since one of the major market opportunities was having a safer alternative to warfarin, the ability to make warfarin itself safer could mean that there is less of an opening for the next wave of anticoagulants than the drug makers had thought when they started all the R&D.

If their utilization improves, the new pharmacogenetic tests could close some of the window for new drugs by ameliorating warfarin's notoriously difficult dose targeting. Medco in particular has been advocating use, and reimbursement, of the warfarin test (see sidebar, ⁸ Medco Promoting Genomic Testing To Aid Warfarin Dosing ).

But the important role of insurers in the anticoagulant space isn't only limited to their vested interest in managing utilization of the products - they also have accumulated a vast amount of claims data that can be mined for insight that can in turn feed back into drug development.

For example, a recent retrospective analysis of data from United Healthcare's coverage of 116,969 patients with a diagnosis of AF or atrial flutter lead Alexander Walker (Harvard) and Dimitri Bennett (GlaxoSmithKline) to conclude that warfarin's indication for AF has not changed primary care practice - potentially an opening for new agents. The analysis, published in the October 2008 issue of HeartRhythm, found that only 45 percent of the population was prescribed warfarin, and only 52 percent had insurance claims for an anticoagulant or antiplatelet agent.

Aetna's mining of its claims data to identify risky prescription patterns recently produced a warning on use of proton pump inhibitors with the platelet inhibitor clopidogrel based on analysis of adverse events in its database. PPIs are often used with clopidogrel to temper gastric side effects - indeed, one company, Cogentus, is in Phase III with a PPI/clopidogrel combination known as CGT-2168. (Special web feature: ⁹ Chart of all novel antithrombotics in development, from Elsevier's Inteleos drug development database.)

- Bridget Silverman ([email protected])