Cracks In Promising Treatments For Monkeypox—TPOXX And Jynneos

As the above photo illustrates, there has been urgent demand for treatments for monkeypox and access to medications despite inadequate data to support the efficacy and potential side effects of treatment. The rapid spread of monkeypox and its disfiguring, extraordinarily painful lesions has driven the urgency in providing treatment.

We are beginning to see cracks in this approach, both with vaccination and treatment with tecovirimat (TPOXX).

TPOXX

The FDA authorized the use of TPOXX through expanded access use, aka compassionate use. It had only been approved for use against smallpox, and that was based on the “animal rule” since testing on people would have been unethical. We have no data on its efficacy.

There has been a furor because, although the US had supplies of TPOXX in the Strategic National Stockpile, it was extraordinarily difficult and burdensome[ link] for physicians to access the antiviral for their patients.

TPOXX inhibits a viral protein called VP37, preventing the virus from reproducing^⁠. It works similarly on other orthopoxviruses (e.g., smallpox and vaccinia), and monkeypox.

A major problem with TPOXX, the FDA noted, is that it has a low threshold for resistance developing. Fierce Pharma noted the FDA is now urging “judicious” use of TPOXX. They are concerned that the drug is only one mutation away from becoming useless—and then we will have no treatments. One type of mutation was already seen in California, leading to false negative diagnostic tests in three patients.

The new guidance recommends TPOXX only for people with serious disease or at risk for the same, which they detail. They caution against treating generally healthy patients who could receive pain medication alone. If we’re not careful, we’ll squander our only antiviral drug to resistance, just as we have lost many antibiotics.

There are more than 22,000 monkeypox cases thus far in the US since May 6^th’s’ first report, but cases are slowing. One death and two cases of encephalomyelitis, a serious neurologic complication with inflammation of the brain and spinal cord, have been reported.

Clinical trials on the efficacy of TPOXX have just begun. The trials will also be looking for adverse effects and viral mutations.

Vaccines:

The other potential strategy for dealing with monkeypox is vaccination to prevent disease.

There are two vaccines, the newer Jynneos and the older ACAM2000; both were developed against the threat of smallpox. The latter is only used in military recruits as it is a live vaccinia virus, so it has significant side effects in immunocompromised individuals. It was expected that ACAM2000 would provide good protection against monkeypox.

A recent report in the Emerging Infectious Diseases journal describes a 34-year-old gay man who had been vaccinated in the military eight years ago. He presented to a sexually transmitted infections clinic with ulcerated sores on his penis and generally feeling unwell. PCR testing and subsequent cultures confirmed monkeypox. So the patient had a mild breakthrough infection despite prior vaccination. The authors caution that the public should be warned, “Vaccine should complement, not replace, public health campaigns that aim to minimize high-risk health behaviors.”

Jynneos is a safer vaccine and does not have the same risks as the live ACAM2000 vaccine. It causes mild muscle pain, headache, fatigue, nausea, and chills. The urgent problem with Jynneos is that we have no good data on its efficacy and a very limited supply. We don’t know that the Jynneos vaccine prevents infection, though have seen that it reduces the severity of disease.

Because of the drug shortage, the FDA has elected to allow vaccination with 1/5^th of the standard dose injected into the skin, where it is more immunogenic (produces a better immune response). One small study supports this “dose-sparing” route of administration.

If this approach fails—and we won’t know for some time—the monkeypox epidemic may worsen. There are already problems reported as the intradermal injections require special needles and training to administer correctly.

If Jynneos dilutions prove ineffective or cases rapidly increase, the ACAM2000 vaccinations will likely be used more broadly as our only option.

By giving vaccines (or medicines) through emergency use, we also fail to gather as much data as we would with a clinical trial. It will likely take much longer to collect good information about the treatments, such as with TPOXX, too.

One of the other problems is vast disparities in access to vaccination by race, location, language, and other factors. While Blacks make up 38% of cases, they have received just 12% of the doses. We saw the same pattern with access to Covid vaccines.

The biggest injustice thus far is that, once again, well-to-do countries of Europe and North America have gobbled up available antivirals and vaccines, just as we did with Covid. If we had paid attention to monkeypox earlier, when it was endemic in Africa, we wouldn’t be in crisis mode now. We might have done appropriate studies and treated Africans, controlling the infection at its origin.

When will we learn to do better?