Brincidofovir fails Phase III CMV trial. Did physicians mistake diarrhea for GVHD?

Chimerix announced on December 28th, 2015 that the Phase III trial of brincidofovir failed to meet its primary endpoint of suppressing CMV infection through week 24 after hematopoietic cell transplant (HCT). Although the drug showed impressive suppression of CMV infections during the 14 week trial, infections soared during the 10-week observation period that followed. CMV infections and graft vs. host disease (GVHD) were significantly higher in the treatment arm compared to the placebo arm six months post transplant. Deaths were also higher in patients taking the drug, although those results were not statistically significant.

Did confusion between diarrhea and GVHD cause unnecessary steroid administration?

Although a full analysis of the data won’t be available until February, Chimerix executives did propose a theory on why the drug failed. At an investor conference in January, CEO Dr. Michelle Berry suggested that when patients developed brincidofovir-related diarrhea (a known side effect) some physicians may have incorrectly diagnosed the patient with GVHD and administered corticosteroids. “In many cases physicians went on to second and third line immunosuppressants in the belief that they were chasing a worsening situation with GVHD,” noted Berry. Immunosuppressant use is  associated with increased viral infection and mortality.

The company plans to search for other explanations such as timing on the start of medication, and other infections such as HHV-6. The only difference in protocol from the successful Phase II trial is that in Phase III, the drug was started immediately after the transplant. In Phase II, the drug was started after engraftment (usually weeks after transplant). They will also look hard at various subsets such as the T- cell depleted patients (who don’t typically get GVHD). These patients did not have a rebound increase in CMV once they were off the antiviral.

Does early antiviral treatment impair CMV specific immune response, and create a rebound effect?

An unanswered question is whether starting the trial immediately instead of waiting until engraftment (10-30 days after the transplant) had an adverse impact on the development of CMV specific immune response. An older trial done at the University of Washington suggested that bone marrow transplant patients who received ganciclovir might have a higher incidence of late CMV disease because the treated group was slower to develop CMV specific CD8 cytotoxic lymphocytes. The investigators also found more severe GVHD in those treated with ganciclovir compared to the placebo (Li 1994). Developing a CMV specific immune response may be beneficial to certain patients. Newer studies have found that patients with CMV infections may develop mature NK cells at a faster rate, and have a beneficial  profile. For example, recent studies have found that CMV infections in certain categories of HCT patients (those with the strongest immunosuppression) have a lower rate of cancer relapse (Manjappa 2014).

Would a longer antiviral treatment period make sense?

In a study at Duke, extended treatment of valganciclovir treatment for 12 months did produce a positive result in a prophylaxis trial in lung transplant patients; 32% who took the drug for three months developed CMV compared to only 4% in the long term treatment group (Palmer 2010). At 3.9 years after transplant the group with extended treatment had a significantly lower rate of CMV disease (12%) compared to controls (55%).

Will brincidofovir get FDA approval?

Comments made at an investor conference suggest that Chimerix feels confident that brincidofovir will eventually be approved for other indications such as preemptive treatment for CMV and adenovirus. They explained  that although the company halted the CMV prevention trials in kidney transplant patients temporarily, solid organ transplant patients don’t typically develop GVHD, so they may have a more successful ouctome than what was found with the HCT patients.  Chimerix is also developing develop an IV form of the drug, which would eliminate any risk of diarrhea. Human trials will begin this year. Since Chimerix has patent exclusivity on brincidofovir until 2034, the company is confident that they will eventually find a successful formula for FDA approval.

Other drugs in development for CMV and HHV-6.

Foscarnet is currently being tested as prophylaxis for HHV-6 encephalitis in Japan, where HHV-6 is more likely to reactivate after transplantation. Foscarnet has better in vitro efficacy against HHV-6 than ganciclovir, and can pass the blood brain barrier very well.

Letermovir was successful in phase 2 trials against CMV in HCT patients, with dosing starting after engraftment. However, it is not effective against HHV-6, which has the highest rate of reactivation after HCT.

Also, Microbiotix is currently conducting a Phase I trial for MBX-100, a potent DNA polymerase inhibitor that shows efficacy against all herpesviruses.

Chimerix stock dropped 80% from an average of $35 per share to  $7 share after the announcement.

Brincidofovir is one of the most potent agents against CMV, HHV-6 in vitro.  A chart provided by Chimerix is shown below.

For more information, see the Chimerix press release.

Source: Chimerix