FDA flags Guillain-Barré risks for GSK, Pfizer RSV shots, but just one will need safety trial

Both Pfizer and GSK’s upcoming respiratory syncytial virus (RSV) vaccines had instances of Guillain-Barré syndrome in clinical trials. And yet the FDA is only recommending that one of them conduct a new post-marketing study to assess the risk.

Just Pfizer—which is seeking approval for RSVpreF, to be known as Abrysvo if approved—has been asked to submit a plan for a follow-up trial, which the company has offered to do in briefing documents (PDF) released ahead of an FDA advisory committee meeting. GSK has for the time being avoided the after-approval work and detailed the risk in its pharmacovigilance plan, which the FDA is assessing.

The companies will spend the next two days at the FDA’s Vaccines and Related Biological Products Advisory Committee meeting. Pfizer is in the hot seat first and GSK will present tomorrow. Ahead of the meeting, the FDA released its briefing documents that details what both pharmas will have to defend to secure an approval recommendation. Both are seeking approval for RSV vaccines in a tight race to market.

Guillain-Barré syndrome (GBS) is a rare neurological disorder that causes your immune system to attack part of the peripheral nervous system, which is located outside the brain and spinal cord. Most people eventually recover, but the condition can lead to paralysis and even the inability to breathe independently in severe cases. The condition can happen to anyone but vaccinations can increase the risk. 

In Pfizer’s phase 3 study 1013, one 66-year-old male recipient with a history of high blood pressure was hospitalized on day seven post-vaccination for a heart attack and underwent angioplasty. On day eight, the patient began experiencing lower back pain and later lower extremity weakness, which is a hallmark of GBS. The condition was later confirmed with tests, but the diagnosis was eventually updated to chronic inflammatory demyelinating polyneuropathy. Symptoms were resolving as of the data cutoff, about six months after emerging. Pfizer referred to this as a “life-threatening event” in its briefing documents.

The investigator determined the case of GBS was possibly related to the study after conferring with the patient’s neurologist. Pfizer, however, noted that the event occurred just a day after the heart attack and angioplasty, calling that timing a “confounding factor.”

There was also a severe case of Miller Fisher syndrome, a variant of GBS, where a 66-year-old woman with type 2 diabetes had to be hospitalized after symptoms emerged eight days post-vaccination. The woman experienced severe fatigue, unstable movements, poor muscle control and other symptoms. The case had resolved by three months without treatment.

Since Miller Fisher syndrome is so rare, the investigator concluded with the other clinical evidence that there was a reasonable possibility that the event was related to the study participation. Pfizer noted there was some evidence missing to make this determination and said the condition was preceded by upper respiratory infection symptoms.

The FDA, however, agreed with the investigators that the GBS cases were likely related to the study and called GBS an important potential risk in the briefing docs.

The FDA noted (PDF) that non-fatal serious adverse events were balanced between the placebo group and vaccine recipients at 2.3%, even with the instances of GBS. There were two total cases of GBS including the Miller Fisher syndrome event in 19,942 people who were vaccinated.

The normal rate of GBS is about 1.5 to three cases per 100,000, according to the FDA. So Pfizer will be asked to include it and other immune-mediated demyelinating conditions in a pharmacovigilance plan to warn of an important potential risk. The company will have to submit a proposal for a study to assess the risk of GBS. Pfizer will also have to report all instances of GBS regardless of how serious and will need to submit an analysis of the cases.

Pfizer detailed plans for that study in its pharmacovigilance plan, promising to conduct a trial in the older adult population. The company will also examine the risk of Abrysvo vaccination in immunocompromised older adults.

In the case of GSK’s RSVPreF3-AS01, to be known as Arexvy if approved, a 78-year-old woman in the phase 3 study 004 began exhibiting symptoms of GBS nine days after receiving the vaccine. She experienced lower and upper limb weakness, difficulty walking and respiratory weakness. She was hospitalized and treated for the condition, leaving the hospital six months after vaccination. Testing was not conducted to confirm the GBS diagnosis but GSK noted that the occurrence was "within the risk window for [GBS] as a vaccine-related reaction."

There were no cases of GBS in GSK’s study 006 or any other studies conducted with RSVPreF3-AS01 to date, meaning the incidence was one in 15,000 vaccines.

This event was considered to be related to vaccination by the investigators and the FDA (PDF). GSK included a warning of potential immune-mediated disease in its pharmacovigilance plan, noting that GBS is an important potential risk. The rate of these events was balanced at 0.3% for the vaccine group and the placebo arm of the trial. GSK will also conduct routine pharmacovigilance activities, including reporting adverse events and examining postmarketing safety data.

The FDA is reviewing the pharmacovigilance plan at the moment and will provide further guidance on any actions needed at a later time, but a post-marketing study was not requested.