Virus World

Although testing for CMV during pregnancy isn’t routine and there isn’t universal screening for infants, there are steps pregnant people can take to protect themselves and their newborns.

Takeda has scored the first-ever FDA approval of a treatment for refractory cytomegalovirus (CMV) infections in organ transplant patients, which can lead to an increased risk of complications and even death. Livtencity (maribavir) has been cleared for use in transplant patients aged 12 or over with CMV infections that do not respond to first-line treatment with current antiviral drugs for CMV, such as ganciclovir, valganciclovir, foscarnet and cidofovir. The FDA followed its advisory committee’s advice and backed Livtencity for use regardless of whether patients are infected with CMV strains that have resistance mutations, as checking for these could delay treatment. Maribavir works by blocking the activity of a CMV enzyme called pUL97 that is essential for replication of the virus, and also avoids some of the serious haematological side effects that are associated with the older antivirals. It was one of the drugs acquired by Takeda when it merged with Shire in 2019. The approval marks the culmination of a lengthy development for a drug that failed a phase 3 trial more than a decade ago for CMV prevention in hematopoietic stem cell transplant (HSCT) recipients.

Originally developed by GlaxoSmithKline, it was licensed to ViroPharma, which was subsequently bought put by Shire. The approval is based on the phase 3 SOLSTICE trial. which showed Livtencity was superior to conventional antiviral therapies in refractory CMV. More than 55% of transplant recipients with refractory infections achieved confirmed viral clearance with Takeda’s drug, compared to around 24% of those on the older drugs. CMV is one of the most common and serious post-transplant infections with an estimated incidence rate of between 16% and 56% in solid organ transplants, and 30% to 70% in HSCT procedures. Livtencity is one of Takeda’s ‘Wave1’ of new therapies that the company said a couple of years ago could collectively add more than $10 billion in aggregate peak sales, and the drugmaker has previously predicted sales revenues from the drug could top $700 million a year at peak. There’s no word yet on pricing, but Takeda said it would launch the drug “in the coming days.”

Takeda’s cytomegalovirus (CMV) drug, maribavir, beat Roche’s Valcyte at clearing the virus from patients’ blood in a phase 2 study. The study compared the drugs in patients with CMV infection after receiving an organ transplant or a stem cell transplant. 

Patients who have undergone a transplant are among the most vulnerable to CMV infection because they must take immunosuppressive drugs to ward off organ rejection. CMV doesn’t usually cause symptoms in healthy people, but once someone is infected, the virus stays in their body in a dormant state. However, it can “wake up” in people with weakened immune systems, like transplant patients. 

The phase 2, open-label study tested three doses of maribavir in 159 adults, comparing it to Valcyte (valganciclovir). After three weeks of treatment, 62% of patients taking maribavir had no signs of CMV in their blood plasma, compared to 56% of those on Valcyte. After six weeks, 79% of maribavir patients had cleared the virus, compared to 67% of Valcyte patients. The findings appear in the New England Journal of Medicine.  “The Phase 2 study showed that maribavir has demonstrated antiviral activity as a potential treatment of CMV infection and demonstrated a reduction of actively multiplying CMV in the blood, following hematopoietic cell transplant or solid organ transplant,” Takeda said in a statement. 

Takeda is already enrolling two phase 3 studies for maribavir. One will test the drug in stem cell transplant patients with their first CMV infection and the other will test it in patients who have received a stem cell or solid organ transplant and have a resistant or refractory CMBV infection. The second study will pit maribavir against treatments chosen by the study investigators, including Valcyte and a trio of antivirals that were approved in the 1980s and 1990s.  

Maribavir’s safety profile may pose a challenge—67% of patients taking maribavir had a treatment-related side effect, compared to 22% of those on Valcyte. Serious side effects, such as acute graft-versus-host disease, diarrhea and renal failure, affected 10% of maribavir patients versus 2% of Valcyte patients. But the lack of treatments for patients with stubborn CMV infections may outweigh these issues. Maribavir has orphan drug status in the U.S. and EU. “There is a significant unmet need for additional treatment for post-transplant patients with CMV infection especially those with a CMV infection that is resistant to currently available antiviral therapies,” said principal investigator Johan Maertens, M.D., Ph.D. of Universitaire Ziekenhuizen Leuven in Leuven, in a statement. “These results are encouraging and warrant further investigation of maribavir as a potentially effective and tolerated treatment for CMV in transplant patients.”  Maribavir, also called TAK-620, has had a checkered past. ViroPharma abandoned a phase 3 CMV trial in 2009 after the drug failed to beat placebo in reducing the rate of CMV in patients who had undergone a bone marrow transplant. Maribavir, along with the hereditary angioedema drug Cinryze in ended up at Shire through its $4.2 billion ViroPharma buyout in 2013, and eventually landed at Takeda following its $62 billion megamerger with Shire.

Study published on Sept. 19, 2019 in New England Journal of Medicine:

https://doi.org/10.1056/NEJMoa1714656

Aging, or senescent cells, which stop dividing but don’t die, can accumulate in the body over the years and fuel chronic inflammation that contributes to conditions such as cancer and degenerative disorders. In mice, eliminating senescent cells from aging tissues can restore tissue balance and lead to an increased healthy lifespan. Now a team led by investigators at Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB), has found that the immune response to a virus that is ubiquitously present in human tissues can detect and eliminate senescent cells in the skin. For the study, which is published in Cell, the scientists analyzed young and old human skin samples to learn more about the clearance of senescent cells in human tissue. The researchers found more senescent cells in the old skin compared with young skin samples. However, in the samples from old individuals, the number of senescent cells did not increase as individuals got progressively older, suggesting that some type of mechanism kicks in to keep them in check. Experiments suggested that once a person becomes elderly, certain immune cells called killer CD4+ T cells are responsible for keeping senescent cells from increasing. Indeed, higher numbers of killer CD4+ T cells in tissue samples were associated with reduced numbers of senescent cells in old skin. When they assessed how killer CD4+ T cells keep senescent cells in check, the researchers found that aging skin cells express a protein, or antigen, produced by human cytomegalovirus, a pervasive herpesvirus that establishes lifelong latent infection in most humans without any symptoms. By expressing this protein, senescent cells become targets for attack by killer CD4+ T cells.

“Our study has revealed that immune responses to human cytomegalovirus contribute to maintaining the balance of aging organs,” says senior author Shawn Demehri, MD, PhD, director of the High Risk Skin Cancer Clinic at MGH and an associate professor of Dermatology at Harvard Medical School. “Most of us are infected with human cytomegalovirus, and our immune system has evolved to eliminate cells, including senescent cells, that upregulate the expression of cytomegalovirus antigens.” These findings, which highlight a beneficial function of viruses living in our body, could have a variety of clinical applications. “Our research enables a new therapeutic approach to eliminate aging cells by boosting the anti-viral immune response,” says Demehri. “We are interested in utilizing the immune response to cytomegalovirus as a therapy to eliminate senescent cells in diseases like cancer, fibrosis and degenerative diseases.” Demehri notes that the work may also lead to advances in cosmetic dermatology, for example in the development of new treatments to make skin look younger.

Co-authors include Tatsuya Hasegawa, Tomonori Oka, Heehwa G. Son, Valeria S. Oliver-García, Marjan Azin, Thomas M. Eisenhaure, David J. Lieb, and Nir Hacohen. This study was supported by the Burroughs Wellcome Fund and Shiseido Co. Ltd.

Study Published in Cell (March 30, 2023):

https://doi.org/10.1016/j.cell.2023.02.033

Tailored T-cells specially designed to combat a half dozen viruses are safe and may be effective in preventing and treating multiple viral infections, according to research led by Children's National Hospital faculty. 

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children's National and the study's senior author, presented the teams' findings Nov. 8, 2019, during a second-annual symposium jointly held by Children's National and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Children's National and NIAID formed a research partnership in 2017 to develop and conduct collaborative clinical research studies focused on young children with allergic, immunologic, infectious and inflammatory diseases. Each year, they co-host a symposium to exchange their latest research findings. According to the NIH, more than 200 forms of primary immune deficiency diseases impact about 500,000 people in the U.S. These rare, genetic diseases so impair the person's immune system that they experience repeated and sometimes rare infections that can be life threatening. After a hematopoietic stem cell transplantation, brand new stem cells can rebuild the person's missing or impaired immune system. However, during the window in which the immune system rebuilds, patients can be vulnerable to a host of viral infections.

Because viral infections can be controlled by T-cells, the body's infection-fighting white blood cells, the Children's National first-in-humans Phase 1 dose escalation trial aimed to determine the safety of T-cells with antiviral activity against a half dozen opportunistic viruses: adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human Herpesvirus 6 and human parainfluenza-3 (HPIV3). Eight patients received the hexa-valent, virus-specific T-cells after their stem cell transplants:

• Three patients were treated for active CMV, and the T-cells resolved their viremia.
• Two patients treated for active BK virus had complete symptom resolution, while one had hemorrhagic cystitis resolved but had fluctuating viral loads in their blood and urine.
• Of two patients treated prophylactically, one developed EBV viremia that was treated with rituximab.

Two additional patients received the T-cell treatments under expanded access for emergency treatment, one for disseminated adenoviremia and the other for HPIV3 pneumonia. While these critically ill patients had partial clinical improvement, they were being treated with steroids which may have dampened their antiviral responses. 

"These preliminary results show that hexaviral-specific, virus-specific T-cells are safe and may be effective in preventing and treating multiple viral infections. Of note, enzyme-linked immune absorbent spot assays showed evidence of antiviral T-cell activity by three months post infusion in three of four patients who could be evaluated and expansion was detectable in two patients." Michael Keller, M.D., pediatric immunologist at Children's National and the lead study author.