BETA
This is a BETA experience. You may opt-out by clicking here

More From Forbes

Edit Story

The Rationale For Clinical Trials Of Brincidofovir (BCV) In West African Ebola Patients

This article is more than 9 years old.

On Tuesday, Dr. Craig Spencer, 33, was released from Bellevue Hospital in Manhattan and declared free of the Ebola virus infection that the physician contracted while treating disease victims in the West African country of Guinea. Spencer spent five weeks there volunteering with the worldwide medical aid agency, Médecins Sans Frontières (MSF). 

During his self-monitoring period after returning from Guinea, Dr. Spencer developed a fever and was diagnosed with Ebola virus disease on October 23.

His socializing the night before spiking a fever triggered a pre-election flurry of political machinations on mandatory quarantine requirements that flew in the face of all public health best practices for infection control. In the final analysis, not a single other New Yorker contracted Ebola – neither subway rider, bowler, or direct caregiver at Bellevue.

Related - NYC Doctor Craig Spencer Followed Proper Protocol After Returning From Ebola-Stricken West Africa

Spencer's 20-day treatment and recovery was due in large part to his infection being caught early when he had minimal viral burden. His treatment was longer than the 13 days required for Dallas nurses, Nina Pham and Amber Vinson, both of whom are in their twenties.

But last week, the Columbia University expert in international emergency medicine was feeling so much better that he was able to play his banjo and ride an exercise bike in his treatment isolation room at the hospital.

Experimental treatments

In addition to supportive care, Dr. Spencer received a blood transfusion from Ebola survivor, Nancy Writebol, and the antiviral drug, brincidofovir (BCV).

We've written previously of our surprise that this drug has been used in Ebola patients – Thomas Eric Duncan in Dallas and Dr. Rick Sacra at the University of Nebraska – because it has been developed as a broad-spectrum agent against viruses with a DNA genome. The reproduction of an RNA genome like that of Ebola virus requires a different class of enzymes.

In fact, AP quoted noted Ebola scientist Thomas Geisbert, PhD, as saying that no one in the field even had this drug on their radar. Geisbert has been involved in the development of both Ebola vaccines and RNA interference therapeutic from Canada's Tekmira Pharmaceuticals called TKM-Ebola.

Brincidofovir has been under development by North Carolina-based Chimerix, Inc., initially as a biodefense agent against the virus that causes smallpox. But the drug has progressed to Phase III trials in the treatment of both adenovirus and cytomegalovirus (CMV) infections. But why Ebola?

We reported over a month ago that BCV emerged from a CDC laboratory screen against a cell culture model of human Ebola infection. While the company did not respond to our interview requests, they have posted a short distillation of the Ebola data on the investor relations section of their website.

These data are buried in an October 11 presentation by Roy F. Chemaly, MD, MPH, of the MD Anderson Cancer Center at the Infectious Disease Society of America annual meeting in Philadelphia. Dr. Chemaly reported the Chimerix BCV data generated by the Virus Special Pathogens Unit of the CDC demonstrating that BCV inhibits infection of cells by the 1976 Mayinga strain of Ebola.

A CDC team led by Jonathan S. Towner published a June 2014 paper in the journal Antiviral Research on a testing method for Ebola drugs that can be done in less-stringent biosafety level-2 facilities whose results could then be confirmed with live virus in a biosafety level-4 facility.

Using this method, BCV was shown to be a relatively potent inhibitor of Ebola virus replication relative to normal cells. Drug potency is expressed by a term called the half-maximal inhibitory concentration – meaning the drug concentration required to inhibit 50% of maximum viral infection. More simply, it's called the EC50 value.

According to the Chemaly presentation, the EC50 of BCV against Ebola virus in culture is 524 nanomolar after a two-hour incubation and 21 nanomolar after a two-day incubation.

How does that compare with BCV's activity against other viruses where it shows clinical activity?

BCV's EC50 ranges from 0.4 to 20 nanomolar for viruses like CMV, is 20 nanomolar against adenovirus (AdV-B7), and 100 nanomolar against variola, and 800 nanomolar against vaccinia pox viruses.

So BCV's action against Ebola virus in is the general ballpark of its effectiveness against all of these DNA viruses.

Perhaps more importantly, BCV kills the virus 54 to 2351 times better than it does uninfected cells. This antiviral selectivity is absolutely essential in determining how useful a drug might be (i.e., a potent antiviral is of no use if it kills uninfected cells at similar concentrations to which it kills virus).

Depends on the specific polymerase enzyme, says BCV discoverer

But why?

To answer this question, we went directly to the source. Karl Hostetler, MD, was a University of California at San Diego professor when his chemist, Jim Beadle, first synthesized BCV and other related compounds that built upon the approved antiviral, cidofovir (sold as Vistide by Gilead).

BCV gets into cells and stays there better than cidofovir. But more importantly, it does not cause the kidney toxicity that often limits the use of cidofovir, especially in critically ill patients. Dr. Hostetler originally helped Chimerix get its start in testing the drug for human infections by CMV, adenovirus, and pox viruses.

Hostetler is no longer associated with Chimerix but now heads his own antiviral drug development company, Hera Therapeutics in Seattle. But, in an email exchange, he shared his thoughts and experience in why BCV might work against an RNA virus like Ebola while being developed for DNA viral infections:

"We published a paper several years ago showing that ODE-(S)-HPMPA (an adenine analog of brincidofovir) had antiviral activity against an RNA virus (hepatitis C).  The activity was not very great (1-2 micromolar EC50 [equal to 1,000-2,000 nanomolar]), but shows the principle.  It probably just depends on the specific polymerase as to whether it is incorporated into viral DNA where it can cause blockage of DNA or RNA elongation by slowing chain elongation or by template strand inhibition which we described for DNA viruses and HIV several years ago.  Our collaborators Magee and Evans then published a review of the mechanisms by which cidofovir inhibit viral DNA/RNA synthesis."

So, it seems that the activity of an antiviral like BCV depends upon its affinity for the combination of viral and human enzymes required for replication of that particular virus. Of course, we still have yet to see what BCV does in non-human primate models of Ebola infection, the gold standard against which antibody drugs, RNA interference therapeutics, and vaccines are tested before going into humans.

But the advantage of BCV in Ebola seems to be that it has already been tested in clinical trials with over 1,000 critically-ill patients with other viral infections, thereby giving a much greater assurance of its safety in Ebola patients.

BCV is also a small molecule that 1) can be given orally and 2) possesses much greater stability than biologic agents that require refrigeration or freezing. With the West Africa outbreak of Ebola continuing, just passing 5,000 deaths this week, BCV may end up being one player in ending that epidemic.

As a result, FDA has granted an emergency IND to Chimerix to use BCV in Ebola patients at the request of the patient's physician. The company is currently negotiating with the FDA for a proper Phase II trial of BCV in Ebola-infected individuals.

Investors seem to support the overall plans to develop BCV for all of its indications: last week, the company raised $121.7 million in a new public stock offering.

Also on Forbes:

Follow me on Twitter or LinkedIn