EP Vantage Interview - Regado seeking solution to clotting conundrum

Changes are certainly afoot in the anti-thrombotic landscape, what with the approaching loss of patent protection for Lovenox and Plavix, which generated combined sales of $14bn last year, and the rise of new oral agents like Effient and Pradaxa which, if they live up to their potential, could represent a big shift in the way patients are treated on a day-to-day basis.

Back in the pipeline another product is shaping up to make waves. Regado BioSciences believes it has found a way to overcome a major anti-thrombotic conundrum: how to prevent harmful clots developing whilst allowing healing clots to form. It has developed a mechanism to turn the clotting cascade on and off quickly and safely, and phase IIb results from a large 800-patient trial of its therapy, REG1, are due towards the end of the year. This has not escaped the notice of big pharma, and chief executive David Mazzo tells EP Vantagethat a couple of potential partners are already very interested in striking a partnering deal.

Two better than one

Regado’s expertise is in two-component drug systems: aptamers that are controlled by a specific oligonucleotide active control agent. Its lead programme, REG1, comprises a highly selective factor IXa inhibitor, RB006, and a control agent called RB007.

The presence of RB006 in the blood stream inhibits factor IXa, preventing clots from being formed. When RB007 is administered it binds to RB006, rendering it incapable of inhibiting factor IXa, allowing the clotting cascade to resume normally. Uniquely, RB007 can reverse the action of RB006 in minutes.

REG1 is being explored in percutaneous coronary intervention (PCI), or angioplasty, a procedure where patients have blocked arteries cleared or held open with stents. Because the introduction of foreign matter into the vascular system will naturally prompt the clotting cascade, prior to the operation patients will typically be given heparin, or another anti-coagulant, to thin the blood.

Based on the half-life of heparin, it is commonplace for physicians to wait four to six hours before removing the arterial sheath in a heparinized patient post-PCI, to reduce the probability of a bleeding event. If haemorrhage occurs in a patient anticoagulated with a currently available anticoagulant, nothing can be done to attenuate the affect of the drug. Similarly, as the effect of heparin recedes, the risk of an ischaemic event, or clotting, rises.

“At the moment, it is very hard to find the perfect balance between preventing bleeding and protecting against ischaemia,” Dr Mazzo says. “All our clinical and pre-clinical data indicates that when we choose the appropriate dose (for REG1) we should be in a position to be clearly much safer. There is a good probability we will be better than existing therapies at controlling bleeding and, perhaps, also ischaemic events.”

Better than heparin?

The large phase IIb trial underway will hopefully go some way to establish what benefit REG1 has over heparin.

Heparin is a very effective anti-coagulant but unfortunately safety and quality issues, such as high inter-patient variability and contamination scares, means it has several drawbacks. Regado believes the advantage of REG1 include a rapid onset of action and a long half life, but predictable and rapid reversibility, no immunogenicity, reduced bleeding rates and low patient variability, which means less monitoring is required.

Additionally, because the oligonucleotides are metabolised by nucleases in the blood with no active metabolites, the potential for side effects are limited and the ability to use the product in renally or hepatically impaired patients should be unrestricted..

Dose range

With the dosage of RB006 already understood, the primary endpoint of the trial, called Radar, has been designed to define the dose range of the reversal agent; four dosage groups are being tested. Around 600 of the patients will be exposed to REG1, with the remainder given heparin.

The trial began recruiting in September 2009 and the first safety review will take place after 100 patients are treated, which will probably happen this quarter. Reviews will also be conducted after 200 and 400 patients, at which point any RB007 arm with a bleeding rate in excess of heparin will be discontinued.

Specifically, the primary endpoint is the composite incidence of major and minor bleeding through day 30. Secondary endpoints will look at the proportion of subjects with a composite of ischaemic events or urgent target vessel revascularisation through day 30.

Big pharma ready

The trial is certainly a huge undertaking for a small, private company; Dr Mazzo estimates it will cost $15m to run. He says it was designed to ensure that REG1 was developed in a manner as thoroughly as would have been done by a big pharma company, ahead of any pivotal trials.

“We wanted to complete a programme that would give a partner a significant level of confidence that, had they had the programme in their own hands, they would have done it like this.”

Regado would prefer to have a partner take the product into phase III, and a $40m Series D financing round, completed in December and signaling significant investor confidence in the project, has brought flexibility. The group now has enough cash to finish the trial and operate through at least mid-2011, and is keeping one eye on the public markets, should that option become the most desirable.

Given the level of interest reported by Dr Mazzo, another private funding round should not be necessary. Whilst some are waiting to see the results, others are showing keener interest.

“A couple of companies are already actively conducting due diligence,” he says. “Our preference is for a global deal and most companies [we are talking to] are global companies, and big players in the cardiovascular space.”

Indeed, Dr Mazzo sees REG1 as complimentary to the new oral pills recently launched by many of those big players; they would be used in very different settings and a company could theoretically "own the patient from the operating room to the home". And in the pipeline Regado has other projects that could be used in broader anti-coagulant settings, such as REG2, which is a longer acting agent that could be useful in similar settings to Lovenox.

In the meantime, an instantly reversible, safer alternative to heparin has no doubt got many companies interested and the phase IIb data will make very interesting reading.