Cytomegalovirus (CMV) is one of the most common viruses in the world. It's ubiquitous in all populations, and it's a herpesvirus, meaning it causes a lifelong, persistent infection in its host. In healthy individuals, it's generally asymptomatic. It goes unnoticed in the vast majority of these cases and causes no real issues.
In a certain category of the infected, however, it's a different story. If patients are infected with CMV during or after stem cell transplants, or solid organ transplants, which is very common in both instances, it can be a cause of substantial morbidity and death among patients. If pre-natal infection occurs, babies are often born with deformities or mental disability. In immunosuppressed patients, infection can lead to retinitis, hepatitis, pneumonitis, gastroenteritis, or other end-organ diseases.
There's a large unmet need for a vaccination, yet to-date, none have made it past mid to late stage trials.
A number of companies are working to change this right now. Here are three of the most advanced, with a look at the assets under investigation and what to expect going forward from each.
The first company on the list is Merck & Co., Inc. (NYSE:MRK).
Merck's CMV asset is called letermovir and the company is currently investigating the drug as a potential treatment for the prevention of CMV infection in adult (18 years and older) CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT). This is a high-risk population, as outlined above, and this program represents the most advanced program in the space right now.
The drug, letermovir, is a once-daily antiviral medicine and it is part of a family of drugs called non-nucleoside CMV inhibitors. To simplify the mechanism of action (MOA), viruses rely on what's called the viral terminase complex to replicate and proliferate from cell to cell. Terminase packages DNA into viral heads, which then make their way into cells. Letermovir inhibits this process, and theoretically, inhibits the replication of the CMV.
The drug completed a phase III study in October last year, at which point Merck put out a small amount of data and said it would submit for a detailed presentation at a future event. This event turned out to be the February 2017 BMT Tandem Meetings, and the data turned out to be very strong. The trial met its primary endpoint of an improvement in clinically significant CMV infection through week 24 post-HSCT when compared to placebo. Further, the safety profile of the drug was relatively clean, inducing no real side effects outside of those expected for patients undergoing this procedure.
So what's next?
Merck has to put an application together for submission to the FDA. While we don’t have a specific timeframe slated for submission, the company has noted it expects to have the submissions ready before the end of 2017. With fast track designation in place, this means we could see a mid 2018 approval in the US.
Next up, Astellas Pharma Inc (OTC:ALPMY).
This Japanese biotech is developing a drug called ASP0113.
Whereas the Merck asset is attempting to inhibit the replication of the virus, this one is more of a traditional vaccine type – it attempts to harness the body's ability to recognize CMV associated antigens to spark an immune response to the virus if and when it presents itself post procedure.
The company pitched ASP0113 against placebo in a phase II study investigating the safety and efficacy of the asset in kidney transplant patients receiving an organ from a CMV-seropositive donor. It was a double blind trial and data hit press mid-September last year.
Unfortunately for Astellas and its shareholders, the trial didn’t turn out as hoped. The drug failed against its primary endpoint of patients having CMV viremia, defined as a plasma viral load of ≥ 1000 IU/mL through one year after first injection of study drug. It also missed on a couple of secondary endpoints, and while the safety profiles of the placebo and active arms were similar, the latter resulted in more injection site reactions.
That's not the end of the program, however. There are two phase III studies for this one – the above mentioned study in solid organ transplants (in this case, kidney transplants) and a second mirroring that of Merck, investigating the drug in an HSCT indication.
This second trial is set to wrap up during the fourth quarter of this year. While there's justification for pessimism ahead of the results, it's too early to write off the drug. If Astellas can prove efficacy in HSTC patients, there's plenty of room for revaluation as the company carries the drug into a pivotal study in the US.
Closing out the list, VBI Vaccines Inc (NASDAQ:VBIV).
This company just announced that an update for a phase I clinical study of its own CMV asset, a drug called VBI-1501A. VBI is investigating the vaccine as a potential candidate to prevent congenital CMV infection – the third of the three major risk groups outlined in the introduction to this piece. Pre-natal CMV infection affects more live births than Down Syndrome or Fetal Alcohol Syndrome and the direct economic cost of infection exceeds $2.0B annually. Many of the live births affected by the virus will develop serious issues, including blindness and deafness.
Similar in concept to Astellas asset, VBI-1501A incorporates the more traditional antigen-driven vaccine model in its construction. It differs from most approved (and in-development) vaccines, however, in that it's created using what's called the eVLP platform. The platform is proprietary to VBI and allows for the creation of vaccines that more closely mimic the structure of the virus against which they are trying to trigger an immune response.
Pre clinical models suggest that this vaccine can induce neutralization of CMV up to 32X greater than natural immunity and that it can induce potent neutralization in fibroblasts and epithelial cells, which are two cell types that are susceptible to CMV infection.
The ongoing phase I study is investigating the vaccine in an estimated 125 healthy patients, with safety and tolerability the primary endpoint. However, and of more interest to a biotechnology investor, the trial is set up to also potentially indicate clinical benefit through measuring levels of vaccine-induced CMV neutralizing antibodies.
All patients have now been fully dosed (with three doses of immunization) and the latest update announced the unanimous recommendation of a Data and Safety Monitoring Board (DSMB) for continuation. While this recommendation doesn’t offer any insight into clinical benefit, it's a good sign that the trial is working towards a primary endpoint hit, which in turn supports the potential advance of the asset into phase II development.
An interim safety report from the trial (which will also address immunogenicity) is set to hit press mid 2017, with the trial set to finish before the end of the year.