Parkinson’s Drug Nuplazid showed early Red Flags

The Parkinson’s drug Nuplazid showed early red flags. It’s approval by the FDA came with significant reservations from many of the reviewers who voted 12-2 to recommend FDA approve it for sale. A March 28, 2016 story came out just as Nuplazid gained FDA approval. It was titled “Parkinson’s Drug Nuplazid could reduce hallucinations, but at what cost?” It was a fair question then, and it looks prescient now. The real cost of Nuplazid seems clearer by the day. A reported 500 deaths have now been linked with the drug, though ultimate causation questions remain.

MSNBC reported that Nuplazid’s maker, Acadia, saw its stock plunge 22% in April 2018 when the FDA announced that it was reexamining drug.  An FDA spokeswoman told MSNBC the agency is conducting an evaluation of Nuplazid.

An Acadia spokesman, however, said the FDA review does not mean the agency has determined Nuplazid has a new risk, and that FDA has not suggested doctors stop prescribing the drug or that patients stop taking it.

Nuplazid was a hopeful drug for some people with Parkinson’s Disease who experience hallucinations. Parkinson’s can, for some, come with debilitating psychosis. Half of the million or so Americans diagnosed with Parkinson’s can experience hallucinations, illusions, and delusions. Symptoms are usually benign, but they can sometimes be very destructive.

Psychiatric disturbances often result from standard Parkinson’s drugs. That can leave patients choosing between physical and emotional stability. In desperation, some might try meds not designed for their condition.

In 2016, an advisory panel to the FDA voted 12-2 in favor of approving Acadia Pharmaceuticals’ Nuplazid, which was specifically designed for Parkinson’s psychosis. The FDA does not have to follow the panel’s advice, but it usually does, and it did in this case.

Nuplazid costs far more than existing antipsychotics, which are mostly used to treat schizophrenia and are available as generics. StatNews reported that in the votal trial behind Acadia’s marketing application, Nuplazid showed only modest improvements over placebo. It was also tested in a way that makes it difficult to compare against other treatments. (One might ask: Why?)

Nevertheless, physicians involved in the trial, some of who had financial ties to Acadia, stood by Nuplazid.

A neurologist at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Dr. Jeffrey Cummings, said he was struck by some of the patients’ “dramatic” responses, but he also acknowledged “families will also respond to placebos, and that’s why we don’t approve drugs based on anecdotal reports.” Dr. Cummings has taken consulting fees from Acadia. He called it “a pretty impressive study.”

Dr. Joseph Friedman, chief of the Butler Hospital Movement Disorders Program, also received consulting fees from Acadia in the past. Dr. Friedman also participated in the Nuplazid study. He noted that fear drives many Parkinson’s patients. He said patients can “start to worry about losing their mind.”

A smaller subset of patients suffers from paranoid delusions, most typically involving the fear that the person’s spouse is cheating on them. Studies have shown that psychosis, more than any other reason, causes Parkinson’s patients to move to nursing homes.

In an effort to help Parkinson’s patients with drugs, doctors often try to lower dosages of conventional Parkinson’s medications. These work to control tremors and other movement problems by targeting the same neurotransmitters in the brain that can also trigger psychosis.

The most common alternative is to give antipsychotic medications that are FDA-approved for treating schizophrenia or bipolar disorder but not Parkinson’s. Some doctors believe antipsychotics like Seroquel or Clozaril have some effect on Parkinson’s psychosis. Some doctors think they can also help ease anxiety and sleeplessness. But clinical studies have not shown any effect on Parkinson’s psychosis.

Nuplazid (also known as pimavanserin) was approved by the FDA in the middle of this already-dicey situation. Hope for Nuprazid rested mostly on a single Phase 3 trial lasting just six weeks.

Nuplazid Maker sponsored own studies
That trial was paid for by Acadia. It focused on 199 Parkinson’s patients. Half were given placebo, the other half Nuplazid. The Lancet reported that Nuplazid treatment showed a 37 percent improvement on a nine-point clinical scale, compared to a 14 percent improvement for those on placebo. It’s very hard to translate those numbers into any real concrete notion of the drug’s safety and effectiveness.

Another study participant with financial ties to Acadia, Dr. William Ondo, admitted that it is impossible to say whether that result shows Nuplazid is better than other kinds of antipsychotics. Director of movement disorders at the Houston Methodist Neurological Institute, Dr. Ondo has sat on Acadia’s scientific advisory board.

Nuplazid had failed to demonstrate a benefit in two previous Phase 3 trials. Both included international as well as US patients, which, according to Dr. Cummings, skewed the results. He claimed that people in other cultures carry different definitions of hallucinations.

The previous trials also evaluated the drug using the so-called Scale for the Assessment of Positive Symptoms, or SAPS, a traditional measure to gauge the extent of schizophrenia symptoms.

Acadia adapted that scale to better gauge the effectiveness in combating Parkinson’s psychosis specifically. Acadia adapted that scale to measure the sorts of hallucinations and delusions people experience with the neurodegenerative disease. The modified scale allegedly helped Acadia show Nuplazid was better than placebo at controlling symptoms in Parkinson’s patients. But since the Parkinson’s version of the scale hasn’t been used to test other drugs, some question the tool’s clinical validity.

Nuplazid uses a novel molecular approach. Other antipsychotic medications target both the dopamine and serotonin pathways in the brain; so they can interact with drugs that help regulate movement disorders Parkinson’s patients can suffer. By contrast, Nuplazid targets only the brain’s serotonin receptors. That may be why it was not found to worsen motor symptoms.

Nuplazid Side Effects
Since Nuplazid hit the market, many people have reported significant Nuplazid side effects. In all the Phase 3 trials of Nuplazid, 8.1 percent of patients on the drug experienced severe side effects, while only 4.8 percent who received placebo reported side effects. Symptoms included irregular heart rhythms, muscle injury, weight loss.

FDA: One adverse event for every two who benefit
The FDA noted in its own documents that for every two patients expected to achieve “much improved” status from taking Nuplazid, one patient experiences a serious adverse event.

Parkinson’s patients with psychosis can suffer abominably, as can their families and caregivers. But any answer for terrible suffering must not come with a price tag so high that it may be worse than the suffering itself. At this moment in time, it appears that Nuplazid may cause more problems than it solves.