Molnupiravir for COVID-19

On 1 March 2022, molnupiravir became the first COVID-19 antiviral to be available on the Pharmaceutical Benefits Scheme (PBS). Molnupiravir is provisionally approved for the treatment of adults with COVID-19 who are at increased risk of hospitalisation or death.

To qualify for PBS-subsidised therapy, patients must meet all of the following criteria:

• Test positive for SARS-CoV-2 (either via polymerase chain reaction (PCR) test OR a rapid antigen test (RAT) verified by a medical practitioner);
• Have at least one sign or symptom attributable to COVID-19;
• Must not require hospitalisation at the time of prescribing; and
• Treatment must be initiated within five days of symptom onset.

In terms of population, patients must be:

• 65 years of age or older with two additional risk factors for severe disease;
• 50 years of age or older, identify as Aboriginal or Torres Strait Islander and have two additional risk factors for severe disease;
• 75 years of age or older with one additional risk factor for severe disease; or
• 18 years of age or older and at risk of progression to severe disease due to moderate to severe immunocompromise.

Molnupiravir is not PBS-subsidised for pre-exposure or post-exposure prophylaxis.

Risk factors

For the purposes of PBS subsidy, risk factors include:

• Having received less than two doses of a SARS-CoV-2 vaccine;
• Residing in a residential aged care or residential disability care facility;
• Neurological conditions (e.g. stroke, dementia);
• Respiratory compromise (e.g. chronic obstructive pulmonary disease, moderate or severe asthma requiring inhaled steroids, bronchiectasis);
• Congestive heart failure (NYHA Class II or greater);
• Obesity (BMI greater than 30 kg/m²);
• Diabetes Types I and II, requiring medication for glycaemic control;
• Renal failure;
• Cirrhosis; and
• Lack of, or reduced, access to higher-level healthcare (resides in an area of geographic remoteness classified by the Modified Monash Model as Category 5 or above).

Full details of the PBS restrictions are available on the PBS website.

Efficacy

Molnupiravir is a nucleoside analogue with activity against various viruses, including SARS-CoV-2. Following metabolism, it distributes into cells where it can be incorporated into viral RNA. This inhibits viral replication due to an accumulation of errors in the viral genome.

The safety and efficacy of molnupiravir were evaluated in a double-blind Phase III trial of at-risk unvaccinated adults diagnosed with COVID-19. Patients were randomly assigned to receive 800mg of molnupiravir or placebo twice daily for five days. The primary efficacy end point was the incidence of hospitalisation or death at day 29. At the interim analysis, this risk was lower in the molnupiravir group compared to the placebo group (7.3% versus 14.1%). One death was reported in the molnupiravir group and nine in the placebo group. Recruitment into the trial was stopped early due to these positive results. However, the efficacy shown in the final analysis was significantly lower at 6.8% for molnupiravir, compared to 9.7% for placebo. This translates to an adjusted relative risk reduction of 30% for molnupiravir compared to placebo (3% absolute reduction in risk).

There are many potential factors that may have contributed to this observed reduction in efficacy between the interim and final analyses, including regional differences in hospitalisation practices and capacity. In addition, the proportion of patients infected with the Delta variant increased significantly between the interim and final analyses, which may have affected the results. The efficacy of molnupiravir against the Omicron variant is not known.

Administration

Molnupiravir therapy should be initiated as soon as possible after a diagnosis of COVID-19, and within five days of symptom onset. It is administered orally, with a recommended dose of 800mg every 12 hours for five days. Each capsule contains 200mg of molnupiravir; doses may be taken with or without food. No dose adjustments are recommended for patients with renal or hepatic impairment.

Neither molnupiravir nor its metabolite inhibits or induces major drug metabolising enzymes or transporters. Although formal drug interaction trials have not been conducted, the potential for interactions is considered unlikely.

Adverse effects

The most frequently reported adverse effects considered to be related to the trial regimen were diarrhoea, nausea, and dizziness. However, rates of these adverse effects were similar to those seen in the placebo group. COVID-19 pneumonia was reported as an adverse effect in 6.3% of the molnupiravir group, compared to 9.6% of the placebo group. Worsening of COVID-19 was also reported in 7.9% of molnupiravir-treated patients and 9.8% of the placebo group.

As a new medication, molnupiravir is included in the Black Triangle Scheme. All potential adverse reactions should be reported to the Therapeutic Goods Administration (TGA).

Vaccination status

There is currently a lack of data on the efficacy of molnupiravir in partially or fully vaccinated patients as clinical trials were conducted in unvaccinated individuals. However, as vaccination confers a lower risk of deterioration, molnupiravir is considered unlikely to provide significant treatment benefits in immunocompetent patients who have received three vaccine doses.

The Pharmaceutical Benefits Advisory Committee (PBAC) considers receipt of zero or only one vaccine dose a risk factor for severe disease. While vaccine protection is not complete and does wane over time, the greatest risk of severe infection is currently found in patients who have received less than two doses of a COVID-19 vaccine.

The PBS criteria allow vaccinated older adults to access subsidised therapy if they have other risk factors for severe disease. For moderately to severely immunocompromised adults, subsidised access is not dependent upon vaccination status.

Place in therapy

The National COVID-19 Clinical Evidence Taskforce Living Guidelines recommend molnupiravir when other treatments (such as nirmatrelvir plus ritonavir) are not suitable or available.

Paxlovid® (nirmatrelvir plus ritonavir) is another orally administered antiviral for COVID-19. While there is currently no head-to-head trial evidence to compare its safety and efficacy with molnupiravir, studies suggest that Paxlovid® may offer a greater magnitude of benefit. Paxlovid® demonstrated an 88.9% relative reduction in the risk of hospitalisation or death (5.8% absolute risk reduction).

However, some factors may affect the appropriateness of Paxlovid® for individual patients, including:

• Paxlovid® is not currently subsidised on the PBS. This may limit the ability to initiate therapy in a timely manner;
• Paxlovid® has many clinically significant drug interactions due to its action as an inhibitor and substrate of the CYP3A enzyme (no interactions have been identified for molnupiravir);
• Paxlovid® requires dose adjustment in moderate renal impairment and is contraindicated in severe renal impairment (no dose adjustments required for molnupiravir); and
• Paxlovid® is contraindicated in severe hepatic impairment (hepatic impairment unlikely to affect exposure to molnupiravir).

Conclusions

Antiviral therapies that reduce the risk of COVID-19 progression may play a vital role in reducing hospitalisation and death, thereby easing pressure on the health system. As these therapies are most effective when initiated early, it is encouraging to see an oral agent readily available on the PBS. However, the availability of molnupiravir and other targeted therapies should not be considered a substitute for vaccination against COVID-19. Vaccination remains crucial for protecting individuals and the community.

The treatment of COVID-19 is a rapidly expanding area of research. The National COVID-19 Clinical Evidence Taskforce Living Guidelines are continually updated in response to new evidence. This resource can be freely accessed online for the latest recommendations.