The Josh Hardy story puts a human face on both the lifesaving potential of compassionate use programs and the wrenching decisions company executives must make about who receives access to compounds in clinical development.

The Hardy family's social media campaign to gain access to an experimental therapy has apparently saved the seven-year-old boy's life.

But along the way, television news programs depicted the situation as a simple case of corporate bad behavior that was corrected by the righteous attention of the media combined with the power of millions of people who became aware of Josh Hardy and joined the campaign to save him on Twitter.

If that were the whole story, there would be no need for new policies. But in fact, the situation was more complex.

Chimerix Inc. had been providing compassionate access to brincidofovir, an antiviral to prevent cytomegalovirus and other viral infections in stem cell transplant patients, prior to beginning pivotal trials. Following dramatic results for some patients, the demand for compassionate access to the compound far outstripped the company's ability to administer an access program.

With demand so large and too few human resources to address it, Chimerix felt it had no way to adjudicate the requests. The company also could not ethically divert all or most of its resources away from the formal development programs that are required to provide access to brincidofovir to thousands of future patients.

In this case, FDA and the company worked together quickly to craft a development program that could allow Josh Hardy and a finite number of other patients to participate in a new study, one which could lead to approval of the molecule in a second indication of adenovirus infection.

The story could just as easily have been about any of thousands of companies working on potentially lifesaving medicines. And Josh Hardy could easily have been any of thousands of patients dying from a disease with no treatment options and no possibility of enrolling in an existing trial.

The case has sparked conversations in Congress and at drug companies about creating policies that could change the way similar cases are resolved in the future (see Cover Story).

Ghost of access past

There was a period of time - before Chimerix began pivotal studies of brincidofovir (CMX001) - when the company had public funding and was able to grant compassionate access to the molecule to treat double-stranded DNA virus infections.

Brincidofovir is based on Vistide cidofovir, an IV drug marketed by Gilead Sciences Inc. to treat cytomegalovirus (CMV) retinitis in AIDS patients. Potentially fatal nephrotoxicity caused by Vistide has limited its use.

Chimerix created brincidofovir using a technology that makes it possible to create oral formulations of IV drugs with improved potency and reduced systemic exposure (see BioCentury, Feb. 24, 2003).

Chimerix started approving compassionate use applications in 2009, CEO Kenneth Moch told BioCentury. Using funding from HHS's Biomedical Advanced Research and Development Authority (BARDA), between 2011 and 2012 the company provided the compound to more than 200 patients under emergency INDs in the U.S. or equivalent regulations outside the U.S.

In February 2011, the Journal of Clinical Virology published a dramatic report on a 12-year-old severely immunocompromised pediatric stem cell transplant recipient who had developed an adenovirus infection - the same kind of infection Josh Hardy contracted.

Like Josh Hardy, the patient in the JCV paper was treated with Vistide, but it damaged her kidneys and had to be stopped.

The JCV paper reported that treatment with brincidofovir under an emergency IND resulted in "successful eradication" of the infection with no drug-related serious adverse events.

It concluded: "Our extremely high-risk patient exhibited complete response to treatment with CMX001."

In December 2012 - when the BARDA contract that had funded the access program had completed - Chimerix stopped accepting emergency IND applications for compassionate use in order to focus its resources on controlled trials that were designed to lead to FDA approval, Moch told BioCentury.

In 2012 and 2013, the company completed two Phase II trials. A trial to prevent CMV disease in patients receiving hematopoietic stem cell transplant met its primary endpoint.

Another study evaluating preemptive therapy for adenovirus infection in allogeneic hematopoietic stem cell transplant patients missed its primary endpoint but showed a lower rate of mortality.

The Chimerix timetable anticipates results in 2015 from the Phase III SUPPRESS trial to prevent CMV infection in adults undergoing hematopoietic stem cell transplantation. If successful, the trial could support accelerated approval of brincidofovir.

No good options

According to Moch, if brincidofovir had been made available outside of SUPPRESS, his 54-person company would have been swamped by demands for the compound.

The company received and denied "hundreds" of requests in 2012 and 2013, including many for children, Moch said, and there would have been more requests if the medical community had not known compassionate access was no longer available.

"Most of the physicians with whom we have close contact and are working on the SUPPRESS trial know this drug is not available on a compassionate use basis, so they tend not to request it for their patients," he said.

"Should we allow one patient to receive the drug for whatever reason, particularly based on demands from social media, there would be tremendous demand from other patients and doctors," Moch said. "How would we say no to any other patient with any other DNA virus, not only adenovirus?"

Chimerix believed it was making the ethical choice.

"We held firm to the ethical standard that, were the drug to be made available, it had to be on an equitable basis, and we couldn't do anything to slow down approval that will help the hundreds or thousands of Joshes," Moch said.

"Not only could we not ethically say no to other requests coming at us, which would swamp our resources, but it would divert our capabilities from ongoing clinical trials, which would slow our ability to get our drug approved. Patients who get sick a couple of years from now would be disadvantaged. Who are we to make this decision?" he said.

Moch stressed that constraints on providing compassionate access to brincidofovir were not caused by limited drug supply, and the cost of the drug was not the limiting factor. The limitations were the time, personnel and expertise required to process applications to FDA, and especially the time and resources required to monitor adverse events.

Social media

Josh Hardy is typical of the patients who had sought compassionate access to brincidofovir.

He developed a life-threatening adenovirus infection following a bone marrow transplant. His physicians at St. Jude Children's Research Hospital had treated it with Vistide, but were forced to stop by severe nephrotoxicity.

As it had done hundreds of times before, Chimerix denied the family's request for brincidofovir.

What was different this time is that the Hardy family launched a social media campaign in a desperate effort to persuade the company to change its decision.

It started with a Facebook page that garnered 48 "likes" on the first day. Cancer patient advocates began spreading the word using a #savejosh Twitter hashtag, an online petition and calls to the news media.

On March 8, CNN began broadcasting reports about Josh Hardy, and Fox News picked up the story the next day.

Celebrities and athletes with millions of Twitter followers joined the campaign. Chimerix's email and telephones were flooded with angry demands to help Josh Hardy - including threats of violence to company management - and newspapers around the world ran stories. Over 200,000 people "liked" the Hardy's Facebook page.

On March 10, FDA contacted Moch to discuss options for getting brincidofovir to Josh Hardy.

The next day, Chimerix announced it had reached agreement with the agency for the "immediate initiation of a pilot trial of open-label brincidofovir for the treatment of adenovirus infections in immunocompromised patients."

In a statement, Chimerix said "Josh Hardy's story brought to public attention the often-devastating impact of adenovirus infection, and helped accelerate a discussion between the FDA and Chimerix regarding the need for additional clinical development to assess brincidofovir's potential in adenovirus infection."

The trial is capped at 20 patients.

The company said FDA also "committed to work expeditiously with Chimerix on the design of a pivotal Phase III study that would be a continuation of this pilot study."

The number of patients who will be enrolled in the Phase III trial has not been determined, according to Moch.

He told BioCentury that Chimerix "had been talking with FDA since last August on the best way to proceed on adenovirus."

Moch added that the path Chimerix forged with FDA "may or may not be generalizable to other drugs, but for brincidofovir it helped us progress towards regulatory approval."

A quick response

Brincidofovir started to help Josh Hardy very quickly. On March 19, his mother, Aimee Hardy, told BioCentury that following two doses given on March 12 and 15, his viral load had dropped from 250,000 copies of adenovirus per mL to 1,000 copies.

On March 25, she reported that it dropped to 100 copies and he had been transferred out of the ICU.

The creation of an open-label trial helped Josh Hardy and has given hope to the families of several other patients who have already enrolled in the trial.

And the Hardy family's success has inspired several other families and advocates to take their causes to social media.

Friends and relatives of Nathalie Traller, a 15-year-old with the rare cancer alveolar soft part sarcoma (ASPS), have created a Facebook page and posted videos online as part of an effort to persuade companies to provide compassionate access to investigational drugs targeting programmed cell death 1 (PD-1).

She is ineligible for all of the current trials of PD-1 inhibitors because the studies exclude patients who are under 18 years old.


Chimerix Inc. (NASDAQ:CMRX), Durham, N.C.

Gilead Sciences Inc. (NASDAQ:GILD), Foster City, Calif.

St. Jude Children's Research Hospital, Memphis, Tenn.

U.S. Department of Health & Human Services, Washington, D.C.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.