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ViroPharma’s Phase III drug Camvia (maribavir) for the prevention of cytomegalovirus (CMV) disease may change the current treatment paradigm in the stem cell transplant market from preemptive therapy to prophylaxis, physicians told Pharmawire.

CMV is a significant cause of morbidity and mortality in transplantation patients. Both prophylaxis and preemptive therapy are used to prevent the development of CMV infection after transplantation.

Controversy exists over which method, prophylactic or preemptive therapy, is the optimal strategy to adopt for the prevention of CMV disease. With the prophylaxis approach, antivirals are administered to all patients for a period of usually three months after transplantation. The preemptive approach exposes the least number of patients to the toxic effects of antiviral agents, which is also costly, but requires more frequent patient monitoring.

Although current literature suggests the prophylactic method is more advantageous, many physicians have been hesitant to adopt this therapy due to the toxicity profile of currently approved drugs.

As Viropharma’s Camvia shows no myelosuppression and less toxicity compared with current ganciclovir-based treatments, it may effectively increase the current market size for CMV drugs since more patients can receive preventative, or prophylactic treatment due to the better risk-benefit ratio.

Dr Stephen Berger, Director of Geographic Medicine and of Clinical Microbiology at Tel Aviv Medical Center, said the current standard of care, oral ganciclovir is quite toxic, and has 41 toxicities and 14 drug to drug interactions. In addition to myelosuppression, other side-effects include hair-loss and anemia.

The therapeutic effectiveness of current drugs on the market such as Roche’s Valcyte (an oral version of ganciclovir) and ganciclovir itself are also compromised by the emergence of drug-resistance. Camvia is also effective against ganciclovir-resistant strains of CMV.

Dr Drew Winston, an investigator at UCLA Medical Center, said Camvia can reduce the incidence of CMV infection and, unlike the current drug ganciclovir, it does not cause myelosuppression. ”The reason why ganciclovir in prophylaxis hasn’t been used in stem cell treatment is because of the drug’s effect on myelosuppression. However, preemptive therapy with ganciclovir was effective.

”Camvia will represent major advancement to preventing CMV in stem cell transplant patients, if Phase III trials confirm efficacy,” said Winston.

Dr Colin Broom, Vice President and Chief Scientific Officer at Viropharma, said with the current market size it is estimated to be USD 500m-600m, but under the current treatment paradigm - only patients who are at very high risk for CMV receive prophylactic treatment, due to the toxicity profile of currently marketed drugs.

”Hopefully, the current treatment paradigm will change from one where you use as little treatment as possible, to one where you will prophylax all patients,” said Broom. Out of the 100,000 annual transplants, less than 20% of the current patient population gets prophylaxis treatment, he estimated. Every patient could potentially receive Camvia for three months in terms of preventative treatment. Viropharma is looking to change the treatment paradigm, to get physicians to use Camvia in first-line prophylaxis therapy. Although Valcyte is a good drug, there are always worries about toxicities, Broom added.

Dr Don Diamond, director of the Laboratory of Vaccine Research at City of Hope National Medical Center in California, said Camvia might have some positive effect, but the problem is you have an immature immune response in transplant patients.

Although oral ganciclovir is not as effective as the IV form, it does not make sense to replicate the problems with IV administration due to the central venous catheter. ”As an oral drug, you can also give it in the outpatient setting,” said Diamond.

However, Diamond believed that Camvia has the same problems as ganciclovir, as it also involves a chemotherapy approach at disabling the virus replication via immune response suppression. ”You have to stop giving these drugs because otherwise people get resistance. But once you stop, the CMV becomes active again,” said Diamond. Patients may face the problem of late CMV infection after discontinuing prophylaxis treatment.

Another criticism of Viropharma’s trial is there is no data comparing Camvia against the current standard of care, which is Roche’s Valcyte (valganciclovir).

ViroPharma also chose to compare Camvia against oral ganciclovir - not the more effective IV ganciclovir formulation. When asked whether oral drugs show less efficacy than IV formulations, Winston countered that the bio-availability of oral Camvia is much better than oral ganciclovir. Camvia may also be available in IV form in the future, he added.

The Phase III stem-cell transplant trial has recruited over 300 patients. A total of over 600 patients are needed for the stem-cell transplant study, said Winston. Enrollment for this trial is expected to be completed by mid-year.

”All the patients in this study have to be followed for 6 months, so final data will be available sometime in early 2009,” said Winston. The liver transplant study is enrolling at a slower rate, since enrollment started later.

In the liver transplant study, about 100 out of 300 patients have been enrolled. This study compares Camvia with oral ganciclovir, and when asked why Viropharma did not choose to test Camvia with Valcyte, Winston said at that time, Valcyte was not approved for use in liver transplant patients. ”To satisfy FDA requirements, we had to compare Camvia to an approved drug,” he said.

The preliminary results clearly show that Camvia can be safe and effective for preventing CMV infection in stem cell transplant patients. ”There has not been significant improvement in the ability to prevent CMV infection in stem cell transplants in the last 10 years,” said Winston.

Without any type of prophylaxis, more than 50% of stem cell transplant patients are infected with CMV.

The drug inhibits viral encapsulation and prevents the virus from exiting the nucleus, which is a novel mechanism of action compared with currently approved drugs, which include Roche’s ganciclovir and Valcyte.

Viropharma has a current market cap of USD 632m.

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