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  • Regado Biosciences is currently involved in a Phase III clinical trial for Revolixys Kit, its system for precisely controlling blood clotting.
  • That clinical trial is currently on hold pending the results of an investigation of serious adverse effects involving allergic reactions.
  • Understanding more about allergic reactions to this treatment can help investors judge the risks going forward.

Three recent articles in Seeking Alpha have described the medical advantages of Revolixys, the uncertainty of the future for Revolixys due to a hold on the current Phase III clinical trial, and the opportunity that Regado Biosciences (NASDAQ:RGDO) presents as a long play at its currently depressed price. What is missing to make an informed investment decision on RGDO is a clear explanation of why allergic reactions may be a problem with Revolixys, an assessment of the risks that additional serious adverse events represent, and a prediction as to what the FDA might do under the most likely circumstances.

1. Introducing the Revolixys Kit

The Revolixys Kit is called a kit because it is a two-component system. The two components are administered separately to achieve precise control of the anticoagulation effect. We need to consider the molecular nature of these two components in order to understand the allergic side effect situation.

Pegnivacogin is a potent and selective anticoagulant that acts on a protein called factor IXa (pronounced "Nine A"). Factor IXa is an essential actor in the cascade of events that leads to formation of a blood clot. Individuals lacking factor IXa suffer from hemophilia, a deadly blood-clotting deficiency. The active portion of pegnivacogin is a ribonucleic acid (RNA) which binds to factor IXa and prevents it from acting to form a blood clot. In addition, attached to the RNA is a molecule of polyethylene glycol.

In controlling coagulation, clearly, a physician does not want blood clots in the wrong places to cause problems such as heart attack or stroke, nor does he want to give a patient the symptoms of hemophilia. Precise control of clotting is required to walk the line between those two extremes, and the Revolixys Kit provides that control. Here is how.

The second component of the kit, anivamersen, is another piece of RNA, and it is attracted to pegnivacogin very strongly and specifically. When the two RNA pieces are bound together, the pegnivacogin cannot interact with factor IXa. Being able to deactivate the pegnivacogin in that way allows a physician to dependably stop the effect of some or all of the pegnivacogin molecules and reduce the anticoagulation effect. The fact that the Revolixys Kit components are made from RNA could be relevant to the allergic reaction, as we shall see.

2. Previous known allergic reactions to Revolixys

During the Phase II RADAR trial of Revolixys, three patients out of 465 were observed to have allergic reactions somehow related to treatment. What we know about these reactions comes from the publication of the RADAR trial.

Three patients had allergic-like reactions shortly after pegnivacogin administration; two of these reactions were serious. The first patient had a history of allergic urticaria treated with corticosteroids and antihistamines 1 month prior to enrolment. She developed nausea, pruritus, and shortness of breath 5 min after pegnivacogin administration and was treated with corticosteroids, antihistamines, and short-term vasopressor support with resolution of all symptoms within 2 h of onset. The second patient had a history of allergy to radiographic contrast and multiple other allergies. She developed generalized urticaria without respiratory or haemodynamic changes, and was treated with steroids and antihistamines with resolution within 25 min. The third patient had listed allergies to beta-blockers and steroids. After receiving pegnivacogin, she developed dyspnoea and cutaneous tingling. She was treated with corticosteroids, antihistamines, and haemodynamic support after developing tachycardia prompting cardioversion.

This paragraph may seem rather turgid, but stripping away the medical jargon, the meaning becomes clear enough to the layman. Urticaria means the patient developed hives. Pruritis is itching. Dyspnoea is shortness of breath. Tachycardia is essentially a fast heart rate, a condition frequently mentioned in TV medical dramas. Clearly, the second patient had a minor reaction, and the other two patients were in some significant distress that, if left untreated, might result in death as one possible outcome. In the clinical trial setting and while under the care of an experienced physician, none of these three patients were in deadly peril.

3. The simplest explanation for the halt

The Phase III REGULATE-PCI trial that was recently interrupted for concerns over allergic reactions has enrolled 3234 patients. Although the allergic reactions may have occurred in the control arm of the study with the drug bivalrudin, allergic reactions such as hives are not an observed side effect of this drug, so the safer assumption is that Revolixys was involved here. Exclusion criteria for this trial would not have eliminated patients such as the three described above from the RADAR trial. One can project approximately 21 similar events would have been seen in this trial so far, considering the rate of observations from the RADAR trial.

If allergic reactions were more numerous than projected or incrementally more severe, that could account for the halt in the trial. These types of adverse events probably would not be serious enough to derail the REGULATE-PCI trial permanently. Such allergic reactions can occur with a number of commonly-prescribed pharmaceuticals, including many antibiotics. The plans for REGULATE-PCI give no indication that the FDA was particularly concerned about allergic reactions observed in RADAR. Thus, under this scenario, the FDA is likely to eventually allow the continuation of the trial after months of deliberation.

The problem with this explanation is that the company itself sounded an alert that the trial might be demonstrating a problem, instead of waiting for the Data Safety Monitoring Board to evaluate serious events during a planned review. Therefore, I am inclined to think that one or more incidents observed in REGULATE-PCI did not fit the pattern of the RADAR events. To fail to consider what other serious allergic reactions might have been observed would be unwise.

4. More severe allergic reactions

Many of the symptoms described from the RADAR trial are consistent with mild to moderate anaphylaxis. Anaphylaxis is usually associated with bee stings and food allergies, but medications can also be the cause. One or more severe anaphylactic reactions may have been observed in the large REGULATE-PCI trial. Such severe reactions can lead to shock and, without immediate medical attention, death may occur in as little as 15 minutes. Although death is extremely rare for those who receive timely treatment, such an event is likely to be emotionally traumatic for the patient and physicians, and receive some notoriety.

The chemical nature of the two components of the Revolixys Kit is potentially related to other new severe allergic reactions. Combination of the two RNA components leads to the production of a double-stranded ribonucleic acid (dsRNA), an entity not commonly found in the body. The immune system assumes that the presence of dsRNA is the result of infection by a pathogenic virus that has RNA as its genetic material. Rhinovirus, the cause of the common cold, is detected in this way, as are many other viral infections. The system for sensing and responding to the presence of dsRNA releases inflammatory cytokines, which are responsible for some of the symptoms of the common cold experienced while the body tries to control the infection. Asthma and COPD are exacerbated by the detection of dsRNA and the release of these cytokines. Thus, severe breathing difficulty could be an allergic side effect of Revolixys for a few patients with related pre-existing conditions.

These possible side effects could have been markedly more severe than any seen in the RADAR trial. The most likely consequence for REGULATE-PCI would be a modification of the trial protocol to exclude all patients with any previous severe allergic reactions or with lung disease. The allergic reactions described in this section are not likely to derail the clinical trial or threaten the continued development of Revolixys Kit. However, with increasing severity comes increasing risk that the FDA might act contrary to these expectations.

5. Scenarios with severe chronic consequences

One scenario leading to severe chronic consequences from dsRNA is supported by only somewhat weak evidence. A link has been established in mice between the allergic reaction to dsRNA and the autoimmune reactions that lead to type 1 diabetes. How significant that link might be in humans is unclear. The usual source of dsRNA exposure in humans would be viral, and the connection of type 1 diabetes to viral infections is murky. Nevertheless, the development of type 1 diabetes by even a single patient could put into jeopardy the entire Revolixys program at RGDO.

Other diseases with an autoimmune component have not been linked to dsRNA-related allergic reactions, but any one of the dozens of autoimmune-related diseases might be made worse by such allergic reactions. Note that this concern is extremely speculative, but is the type of unanticipated allergic reaction that might have been observed with very low frequency in the large sample from this clinical trial. If only a single event was observed, it might be judged as unrelated to the treatment, at least as a tentative conclusion. Continuation of the REGULATE-PCI trial would be consistent with good medical ethics, as long as precautions were instituted to watch for the occurrence of that event in other patients. However, if several such events were observed, the entire Revolixys program would be at risk.

6. Putting everything in perspective

Considering all of the information presented above, the REGULATE-PCI trial is not likely to be terminated by the allergic reactions now under investigation. Under the most probable scenarios, some additional patients will be excluded from the current clinical trial, and from future use of Revolixys should it be approved by the FDA. The involvement of Revolixys with type I diabetes or some totally unexpected severe chronic autoimmune disease has a very low probability of being observed, but not low enough to be completely discounted as an issue.

The Data Safety Monitoring Board report is expected by RGDO by the end of August. Announcement of the DSMB findings could serve as a binary point leading to either an additional price decrease or a partial rebound in the share price. The key to that binary point will be the number and seriousness of the adverse events. An investor might reasonably consider establishing a long position before the DSMB report is available, although not without some significant risk. Whether the anticipated rewards justify that risk is difficult to determine and is beyond the scope of this article.

Another binary point could occur when the decision by the FDA on a trial restart is announced, likely many months after completion of the DSMB report. The key to this anticipated second binary point will be the decision-making process within the FDA. The wise investor might wish to avoid exposure to that type of uncertainty in his investment decisions.

Editor's Note: This article covers one or more stocks trading at less than $1 per share and/or with less than a $100 million market cap. Please be aware of the risks associated with these stocks.

Source: Regado Biosciences' Revolixys Kit: Assessing The Risks Of Allergic Reactions