It could reduce hallucinations, but at what cost? New Parkinson’s drug raises questions

March 28, 2016  By BOB TEDESCHI @bobtedeschi

EROS DERVISHI FOR STAT

Most people associate Parkinson’s with tremors and other motor symptoms. But for some, the disease gives rise to something more terrifying, and much more hidden: psychosis.

As many as half of the million or so Americans with Parkinson’s experience hallucinations, illusions, and delusions — symptoms that are typically benign, but sometimes deeply destructive.

In a cruel twist, these psychiatric disturbances often result from standard Parkinson’s drugs, leaving patients to choose between physical and emotional stability, or try medications that aren’t designed for the condition.

On Tuesday, an advisory panel to the Food and Drug Administration will review a new antipsychotic drug — Acadia Pharmaceuticals’ Nuplazid — that’s specifically designed for Parkinson’s psychosis.

If approved, the treatment would offer an important new option for those battling the disorder, said Dr. Rachel Dolhun, a spokesperson for the Michael J. Fox Foundation for Parkinson’s Research. “We’re in kind of a quandary here with our current therapies.”

But that hope is tempered by significant uncertainty surrounding the drug’s cost and its effectiveness.

Nuplazid, if given the FDA go-ahead, would undoubtedly cost far more than existing antipsychotics, which are mostly used to treat schizophrenia and are available as generics. In the pivotal trial behind Acadia’s marketing application, Nuplazid showed only modest improvements over placebo, and was tested in a way that makes it difficult to compare against other treatments.

Physicians involved in the trial stand by the drug, nonetheless.

Dr. Jeffrey Cummings, a neurologist at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said he was struck by some of the patients’ “dramatic” responses.

“Of course, families will also respond to placebos, and that’s why we don’t approve drugs based on anecdotal reports,” said Cummings, who has taken consulting fees from Acadia. “But when families are saying this really made a difference for his life and our lives together, for me it was a pretty impressive study.”

Parkinson’s psychosis usually occurs in the latter stages of the disease, and generally involves nonthreatening visual hallucinations. Cynthia Hatfield, a 72-year-old former banker living in Westerly, R.I., several times a week sees a calico cat resembling one she’d actually owned many years ago, and which her children named “Mushroom.” For years, her hallucinations included a menagerie of small animals.

“Chipmunks and little squirrels and cats, and a little mouse would come out every once in a while,” she said. “I actually enjoy seeing them.”

But even pleasant visions can have disturbing connotations for Parkinson’s patients who aren’t prepared for them.

“If they don’t know and they haven’t been warned, they can get very upset and start to worry” about losing their mind, said Dr. Joseph Friedman, chief of the Butler Hospital Movement Disorders Program, who received consulting fees from Acadia in the past.

The stakes are higher for those who experience frightening hallucinations.

“It’s a little scary sometimes,” said Cheryl Kingston, a Los Angeles writer who has wrestled with Parkinson’s disease for more than 20 years. She recently called 911 because she was convinced that a moose was trying to break through her door to attack her.

We’re in kind of a quandary here with our current therapies.”DR. RACHEL DOLHUN, MICHAEL J. FOX FOUNDATION

Diane Sagen has been caring for her 77-year-old husband, Jay, since he was first diagnosed with Parkinson’s nine years ago. His hallucinations and delusions have grown worse in recent years, to the point where he often believes she is not his wife. “It just kind of wears you out,” said Sagen, a therapist in Irvine, Calif.

A smaller subset of patients suffers from paranoid delusions, most typically involving the fear that the person’s spouse is cheating on them. Such patients can stubbornly cling to these delusions, and are often too embarrassed to discuss the situation with doctors.

It’s an intractable issue, as the spouse is usually the patient’s primary, or sole, caregiver. Studies have shown that psychosis, more than any other reason, causes Parkinson’s patients to move to nursing homes.

To avoid this fate, doctors will often try to dial down conventional Parkinson’s medications, which work to control tremors and other movement problems by targeting the same neurotransmitters in the brain that can also trigger psychosis. That’s clearly a fraught approach for those with advancing physical symptoms.

The most common alternative: giving antipsychotic medications that are FDA-approved for treating schizophrenia or bipolar disorder, but not Parkinson’s. Doctors believe antipsychotics like Seroquel or Clozaril have some effect on Parkinson’s psychosis, and can help ease anxiety and sleeplessness as well, but clinical studies have failed to show an effect on Parkinson’s psychosis.

Thus the high hopes for Nuplazid (which is also known as pimavanserin), even if those hopes rest on a somewhat shaky foundation, largely composed of a single Phase 3 trial lasting six weeks.

The trial, which was paid for by Acadia, focused on 199 Parkinson’s patients, with half given placebo and the other half Nuplazid. As reported in the Lancet, Nuplazid treatment resulted in a 37 percent improvement on a nine-point clinical scale, compared to a 14 percent bump for those taking placebo.

Is that better than other kinds of antipsychotics? It’s impossible to say, according to Dr. William Ondo, director of movement disorders at the Houston Methodist Neurological Institute, who participated in the study and has sat on Acadia’s scientific advisory board.

Nuplazid failed to demonstrate a benefit in two previous Phase 3 trials. Both included international patients, as well as those from the United States. That skewed the results, Cummings said, because patients in other cultures have differing definitions of hallucinations.

The previous trials also evaluated the drug using the so-called Scale for the Assessment of Positive Symptoms, or SAPS, which is traditionally used to measure the extent of schizophrenia symptoms.

To better gauge the effectiveness in combating Parkinson’s psychosis specifically, Acadia adapted that scale to measure the sorts of hallucinations and delusions experienced by people with the neurodegenerative disease. The modified scale ultimately helped the company show that Nuplazid was better than placebo at controlling symptoms in Parkinson’s patient. But the Parkinson’s version of the scale hasn’t been used when testing other drugs, leading some to question the tool’s clinical validity.

Part of the intrigue surrounding Nuplazid involves its novel molecular approach. Other antipsychotic medications target both the dopamine and serotonin pathways in the brain, and so can interact with drugs that help regulate the movement disorders that burden Parkinson’s patients. Nuplazid, in contrast, targets only the brain’s serotonin receptors — which is perhaps why it was not found to worsen motor symptoms.

“This represents a new pharmacologic paradigm,” Acadia wrote in briefing documents released last week ahead of Tuesday’s advisory committee meeting. (The company declined to comment for this story.)

Significant side effects do exist, however. Totaling across all the Phase 3 trials of Nuplazid, including the two that failed to show a clinical benefit, 8.1 percent of the patients who took the Acadia drug experienced severe side effects, compared to 4.8 percent of those who received placebo. These symptoms included irregular heart rhythms, muscle injury, and weight loss.

In its own briefing documents, the FDA noted that for every two patients who are expected to achieve “much improved” status as a result of Nuplazid, one patient experiences a serious adverse event.

The FDA advisory committee of outside experts will vote on Tuesday on whether they think the benefits of Nuplazid outweigh its risk. The agency does not have to follow the panel’s advice, but it usually does. A final regulatory decision will be made by May 1.

If greenlighted, cost remains a major question for Nuplazid. A price has not been set, but analysts are expecting significant demand for the drug — to the point where some are projecting worldwide sales to top $1 billion or more.

Given the burden of psychosis on Parkinson’s patients and caregivers, it is little surprise that they would eagerly pay for a treatment that might improve their quality of life. Others, for whom the hallucinations are less disturbing, will more likely skip the drug if it comes with a high price tag and even a small chance of side effects.

Bob Tedeschi can be reached at tedeschi@statnews.com 
Follow Bob on Twitter @bobtedeschi 

https://www.statnews.com/2016/03/28/parkinsons-psychosis-nuplazid/