Highlights
Livtencity (maribavir) is a new drug indicated for the treatment of adults and pediatric patients (12 years of age and older and weighing at least 35 kg) with post-transplant cytomegalovirus infection/disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet.
Importantly, Livtencity can be prescribed without genotyping treatment resistance. The point is that even modern diagnostic tools give appropriate results in a few days, but treatment of cytomegalovirus infection does not tolerate any delay. In other words, such tests are untenable in clinical practice.
Livtencity, proposed by Japan’s Takeda Pharmaceutical, is approved by the U.S. Food and Drug Administration (FDA) in November 2021.
Takeda estimates that Livtencity’s peak sales have the potential to reach $700–800 million a year. According to industry projections, demand for maribavir will cross the $355 million mark by 2026.
What Is Cytomegalovirus
Cytomegalovirus (CMV) is a widespread betaherpesvirus: serologic evidence of previous CMV infection is found in 40–100% of adults. Typically, cytomegalovirus persists in the body asymptomatically, but can reactivate during periods of immunosuppression.
Cytomegalovirus infection is a common complication of hematopoietic stem cell transplantation procedures (among 30–70%) and solid organs (16–56%), dramatically increasing morbidity and mortality. [1] [2] [3]
Available drugs are effective, but characterized by a fair amount of toxicity. Thus, ganciclovir and valganciclovir used off-label exhibit myelosuppressive effects [4] [5], foscarnet and cidofovir are nephrotoxic, and the latter also causes electrolyte imbalance. [6] In addition, 5-14% of transplant recipients develop a CMV infection that is resistant to treatment. [7] [8] [9] Prevymis (letermovir), a viral DNA terminase complex inhibitor produced by Merck & Co. is only suitable for the prevention of cytomegalovirus infection, not its treatment.
This is why there is a need for new anti-CMV drugs that are effective, safer and work differently from existing medications.
Livtencity: Maribavir’s Mechanism of Action
Oral maribavir (TAK-620) is a strong selective small-molecule benzimidazole riboside that has a mechanism of action that differs from all other anti-CMV drugs that are involved in inhibiting viral DNA polymerase, which is reflected in inhibiting DNA replication.
The antiviral activity of maribavir is due to the ATP-competitive inhibition of the protein kinase activity of the viral enzyme pUL97, which is responsible for phosphotransferase activity. The latter is critical for several important processes of the cytomegalovirus life cycle, such as viral DNA replication, viral gene expression, encapsulation and exit of mature capsids from the nucleus of the infected cell. [1] [2] [3]
The unique and multimodal mechanism of action of maribavir not only endows it with activity against CMV strains resistant to existing antiviral drugs, but also reduces susceptibility to cross-resistance.
Maribavir was finalized by Takeda, which got it after the takeover of Shire, which acquired it through the purchase of ViroPharma, which licensed it from the originator, GlaxoSmithKline.
Livtencity: Efficacy and Safety of Maribavir
The SOLSTICE (NCT02931539) phase 3 (randomized, open-label, active-controlled, multicenter, international) clinical trial enrolled patients (n=352) who underwent hematopoietic stem cell or solid organ transplantation and experienced reactivation of cytomegalovirus infection.
Participants’ CMV infection should be refractory to therapy with standard antiviral drugs: ganciclovir, valganciclovir, cidofovir, or foscarnet.
Patients whose CMV disease involved the central nervous system, including the retina, were excluded from the study.
Subjects were given maribavir 400 mg twice daily or standard antivirals (mono-administration or combination) for up to 8 weeks. A 12-week follow-up was then performed.
The primary endpoint was the proportion of patients whose viral load was undetectable at the end of week 8: plasma levels of cytomegalovirus DNA fell below the lower limit of quantification (less than 137 IU/mL).
This was achieved by 55.7% of patients in the maribavir group — versus 23.9% in the control group: a statistically significant difference of 32.8% (95% CI: 22.8–42.7; p<0.001). We are talking about the whole population of subjects: with refractory cytomegalovirus infection (or disease), resistant or not.
Among patients with initially resistant CMV infection, as confirmed by genotypic testing, viral clearance was successful in 62.8% — vs. 20.3%: a difference of 44.1%(95% CI: 31.3–56.9).
In terms of patient subgroups, among those who underwent hematopoietic stem cell transplantation, successful viral clearance was fair for 55.9% of patients — vs. 20.8%; among those who underwent solid organ transplantation, 55.6% — vs. 26.1%.
According to the criterion of which solid organ was transplanted, among lung recipients, viral clearance was confirmed in 47.5% — vs. 13.6%, kidney in 59.5% — vs. 34.4%, and heart in 42.9% — vs. 11.1%.
A greater proportion of patients in the maribavir group than in the control group demonstrated viral clearance regardless of baseline viral load: 61.1% and 43.9% of subjects in the low viral load (less than 9100 IU/mL) and medium-high (greater than 9100 IU/mL) subgroups — vs. 24.7% and 21.9%.
Several reasons for treatment failure were registered. Thus, 34% and 36% of subjects in the maribavir and control groups experienced either a detectable viral load (20% and 30%) or a breakthrough CMV infection (14% and 6%), where the viral load was initially undetectable and then returned. Other reasons for treatment discontinuation included: adverse side effects (3% and 22%), deaths (4% and 3%), unwillingness to follow protocol (1% and 8%), and others (1% and 5%).
The secondary endpoint, stated absence of viral load and controlled disease symptoms (resolution or improvement of tissue-invasive disease or CMV syndrome in initially symptomatic patients or absence of new symptoms in initially asymptomatic patients) at week 8 with the maintenance of this status up to week 16, was evidenced for 18.7% and 10.3% of patients (p=0.013).
Among those who responded to treatment, 50% experienced a virologic relapse in the maribavir group — vs. 39% in the standard anti-CMV therapy group. Most relapses (89% and 100%) occurred within 4 weeks of stopping treatment. The average time to relapse was 15 days.
During the entire study period, new symptoms of CMV infection developed in 6% in each group of subjects, and 11% of patients in each group died.
Among the most common adverse reactions in the maribavir and control groups were: impaired taste (in 46% of patients vs. 4%), nausea (21% vs. 22%), diarrhea (19% vs. 21%), vomiting (14% vs. 16%), and fatigue (12% vs. 9%).
Treatment was discontinued due to adverse events in 13% of patients in the maribavir group and 32% in the control group (due to neutropenia in 9% of patients, acute renal failure in 5%).
Expert Comments
The development of maribavir has been going on for more than two decades, and during that time, a decent amount of data on its safety and efficacy has been accumulated. GlaxoSmithKline, which invented it, has been testing this molecule since 1996 in the treatment of cytomegalovirus retinitis in patients with human immunodeficiency virus (HIV) infection. The rapid ascent of highly active antiretroviral therapy (HAART), which restores the protective power of the immune system, has wiped out cases of CMV retinitis, and so in August 2001, maribavir was shelved.
In August 2003, ViroPharma licensed maribavir from GlaxoSmithKlein and began studying it to prevent CMV after transplantation. However, it did not work: as it later turned out, the prescribed dose of maribavir was insufficient. After the dose was increased, everything came to fruition: maribavir proved that it could manage the treatment of CMV infection.
The FDA’s Advisory Committee raised a number of questions during its discussion of maribavir’s New Drug Application (NDA). Thus, the experts complained about the design of the SOLSTICE pivotal clinical trial, which was open, and therefore did not exclude the risks of bias in the data collected. However, conducting a double-blind study comparing maribavir to placebo would have been difficult. First, it would be unethical, since the life-threatening nature of CMV infection suggests immediate treatment, not the prescription of a dummy. Second, three of the four control antiviral drugs (ganciclovir, foscarnet, cidofovir) are administered by intravenous infusion, whereas maribavir is offered in an oral formulation, and bitter to the taste. Third, one of the side effects of maribavir is a change or worsening of taste, which has not been observed with other antiviral drugs, which, by the way, show greater toxicity.
The experts noted the lack of diversity in the patients invited to the study: there were no infants or children. Despite SOLSTICE’s age criterion for participation of at least 12 years old, none of the subjects were younger than 18 years old. Moreover, the majority of patients were male, with a median age of 50 years.
The experts complained that Takeda had not tested maribavir in cases of nonrefractory or nonresistant CMV infection, and they also recommended that maribavir be tested for interactions with other drugs used in post-transplant conditions and to monitor the level of CMV resistance to maribavir treatment.
Still, at the end, FDA experts were unanimous in their support for approving maribavir because of the critical need for new drugs to curb CMV infection.
The regulator ordered Takeda to conduct a series of post-marketing studies.
So, the Japanese pharmaceutical giant needs to determine the gB subtype of cytomegalovirus in each of the SOLSTICE participants. The bottom line is that CMV can be represented by different variants due to the polymorphism of its gene gpUL55, which encodes glycoprotein B (gB). Different CMV genotypes affect the pathogenesis, manifestation and course of infection in different ways.
Takeda should also perform a phenotypic analysis of the efficacy of maribavir against cytomegalovirus with certain substitutions in its genome (pUL97, pUL27, pUL54 proteins) that can cause resistance to treatment.
Finally, Takeda has already launched clinical trial NCT02927067 phase 3 (randomized, double-blind, active-controlled, multicenter, international) comparing maribavir with valganciclovir in the treatment of CMV infection after hematopoietic stem cell transplantation.
Extras
Livtencity (maribavir). Prescribing information. US. [PDF]
Maribavir. FDA presentation. AdCom. October 7, 2021. [PDF]
Maribavir. Takeda Pharmaceutical presentation. AdCom. October 7, 2021. [PDF]
Maribavir. Takeda Pharmaceutical briefing document. AdCom. October 7, 2021. [PDF]