Acadia Pharmaceuticals Inc. started the week with a double win: preparations to launch its lead product, Nuplazid (pimavanserin), and a first FDA approval in the indication: treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP).

Nuplazid also becomes the first drug approved by the FDA that preferentially targets 5-HT2A receptors. The selective serotonin inverse agonist also avoids activity at dopamine and other receptors commonly targeted by antipsychotics, enabling clinicians to treat the relevant symptoms without affecting a patient's motor function.

In 2014, the FDA gave the oral drug breakthrough therapy designation to treat hallucinations and delusions associated with PDP.

"We never want to lose sight of the fact that there's a very significant unmet need in the PDP space," Steve Davis, Acadia's president and CEO, told BioWorld Today. "Parkinson's disease psychosis tends to be much more prevalent in the advanced stages of the disease. Controlling the motor symptoms of Parkinson's is always a very delicate balance, especially when you have psychosis layered on top of that. Having a drug that's approved for the treatment of Parkinson's disease psychosis that doesn't interfere with motor therapies represents a very meaningful advancement for these patients."

Managing PDP has required clinicians to decrease Parkinson's dopaminergic agents or to add "atypical" antipsychotic medications, either of which might worsen the disease, according to Rachel Dolhun, a movement disorders specialist and vice president of medical communications for the Michael J. Fox Foundation for Parkinson's Research.

"You were in this quandary of treating the symptoms of psychosis but potentially worsening the motor symptoms," Dolhun told BioWorld Today. Pimavanserin offers clinicians a new tool to fix that dilemma.

Up to half of patients with PD may eventually develop PDP, according to Dolhun. The disruptive behaviors and associated physical dysfunction associated with PDP often force family members to place a loved one with Parkinson's in long-term care settings, she added.

The drug's approval was largely expected after members of the FDA's Psychopharmacologic Drugs Advisory Committee (adcom) gave it a solid endorsement in March, despite qualms about serious adverse events (SAEs) in the treatment group. (See BioWorld Today, March 30, 2016.)

At the time, FDA reviewer Paul Andreason acknowledged that Nuplazid "presents us with a bit of a dilemma as regulators, because on one hand we have evidence that the drug is superior to placebo and at various levels of exploring clinical efficacy, it continues to be superior to placebo."

And, as H.C. Wainwright analyst Andrew Fein observed following the adcom, the FDA was hard-pressed to draw firm conclusions regarding the observations about SAEs, "which could not be distinguished from what is normally seen in this patient population, or related to a specific drug-related mechanism or premonitory signal."

Moreover, FDA briefing documents about the drug noted that "PDP has been associated with nursing home placement, which itself has been associated with increased morbidity and mortality for these patients; therefore, a drug to prevent psychosis in this population without worsening motor function would, indeed, represent an important treatment advance." (See BioWorld Today, March 28, 2016.)

The drug came with a black box warning about increased mortality in elderly patients with dementia-related psychosis – wording that Leerink Partners analyst Paul Matteis queried on Acadia's conference call Monday morning. In response, Davis said the warning was designed to ensure that the drug was approved to treat all PDP patients – no matter their age – but not dementia-related psychosis unrelated to hallucinations and delusions associated with PDP.

However, approval to treat hallucinations and delusions associated with PDP is an indication that's "appropriately broad and clear to physicians," Serge Stankovic, Acadia's executive vice president and head of research and development, said on the call. "Hallucinations and delusions are the hallmark symptom of PDP. Referring explicitly to these symptoms in the indication enables us to speak clearly to physicians using language that they instantaneously associate with their patients' symptoms," without regard to stage of disease, symptom severity or dementia status, he added.

Specificity of the indication compared to more general PDP is a function of the Scale for Assessment of Positive Symptoms-Parkinson's Disease, or SAPS-PD, measure used in the pivotal phase III Study -020 of Nuplazid "and shouldn't have a material adverse impact on the addressable market," agreed Piper Jaffray analyst Charles Duncan in a research note.

"The label really only excludes formal thought disorders and measures of bizarre behavior, which are more of a hallmark in schizophrenia," Duncan wrote. "We would also argue specificity of the indication sets a regulatory precedent for approvals in new neurodegenerative disease indications based on newly established neuropsych scales such as the SAPS-PD; the FDA clearly wants to stay close to the phase III population and clinical data when outlining approval labels."

In Study -020, Nuplazid reduced the frequency and severity of psychotic symptoms compared to placebo on the SAPS-PD without impairing motor function, leading to a new drug application (NDA) filing last year. The most common adverse reactions were peripheral edema and confusional state. (See BioWorld Today, Sept. 4, 2015.)

Nuplazid also was shown to prolong QT interval, leading to a caution on the label regarding use with certain high-risk patients or patients taking other medications that may prolong the interval, including certain anti-arrhythmic, antipsychotic and antibiotic drugs.

"We were encouraged that this small but consistent prolongation was not a point of focus at the [adcom] and has now not resulted in a barrier to approval," Duncan wrote.

'WE HAVE A VERY SIGNIFICANT LIFE CYCLE PLAN'

As part of its post-marketing commitments, San Diego-based Acadia agreed to conduct a randomized withdrawal trial – essentially, an extension of the phase III study – to expand the safety database for Nuplazid and to ascertain an appropriate dosage during concomitant treatment with CYP3A4 inhibitors.

Although the company is keeping pricing close to the vest as it prepares for Nuplazid's launch next month, expectations for the drug are high, according to Thomson Reuters Cortellis, which forecast sales of more than $1.6 billion in 2021. Acadia also is advancing the drug in Alzheimer's disease psychosis, where a phase II study is underway, plans to initiate a study in Alzheimer's disease agitation by mid-year and has other indications in mind.

"We have a very significant life cycle plan that we're now executing against," Davis said. "We'll be making a significant investment in the molecule to explore where it might be useful for the treatment of other related conditions."

That said, the company's first priority is a successful launch, he emphasized. Acadia's market research suggests payers are on board, with Medicare Part D plans expected to dominate the payer mix, followed by commercial insurers and Medicaid.

Acadia said it identified approximately 11,000 key physicians who treat PDP and last week hired 132 neuroscience sales specialists who will call mainly on movement disorder specialists and psychiatrists, working under a field management team of 12 regional sales reps and six account managers who have been in place at the company since March 2015.

As part of the drug's launch, Acadia plans to introduce a program, called NUPLAZIDconnect, to provide patients and caregivers with financial assistance or access to Nuplazid, including assistance with prior authorizations. The company established a distribution network of four specialty pharmacies and two specialty distributors and also plans "an extensive sampling program" to familiarize physicians with the product.

Acadia plans to submit filings for Nuplazid to the EMA by mid-year but hasn't yet made a decision on partnering ex-U.S.

"Now is not the time to partner, if we do ultimately do that," Davis told analysts. "But it is the kind of thing that we will continue exploring as we move forward. And in due course, as we get closer to approvals outside of the U.S., we will make a determination whether the best result for us is to partner in one or more partnerships outside of the U.S. or launch the drug ourselves. We are preparing for both."

Acadia's shares (NASDAQ:ACAD) didn't get much of an FDA approval bounce on Monday, opening 5 percent higher but dropping into negative territory before regaining some ground to close at $33 for a gain of 70 cents. More than 7.8 million shares changed hands, or about 2.5 times the company's three-month moving average.

Some investor malaise may be related to the track record for Nuplazid, which has been in development for more than 13 years. In 2003, Acadia raised $25 million in a private placement to take the candidate (then ACP-103) into a phase II proof-of-concept trial for treatment-induced PDP in patients who required antipsychotic treatment but could not tolerate D2 receptor antagonism and the motor liabilities associated with most antipsychotic drugs. By 2006, the company was prepping for a pivotal trial in PDP, which began a year later. But in 2009, the drug failed to hit its primary endpoint in the first of two pivotal studies in PDP. (See BioWorld Today, Sept. 2, 2009.)

In 2012, after tweaking the study design, the drug met all of the endpoints in Study -020. The FDA then sweetened the pot for Acadia by deciding the company did not need to conduct an additional phase III study before submitting the NDA. (See BioWorld Today, Nov. 28, 2012, and April 12, 2013.)

But J.P. Morgan analyst Cory Kasimov sounded reassuring in his research note, predicting gradual but steady uptake for Nuplazid in a "relatively delicate patient population" where physicians might test the product with partial doses to explore patient tolerance.

"For these reasons, we forecast sales of ~$8M in 2016 growing to nearly $400M by 2020," Kasimov wrote, predicting the product will be priced at approximately $17,500 per year. "Ultimately, we do believe the PDP market is large enough to support a blockbuster product with ~$1B in annual sales, but physicians will obviously have to grow very comfortable with Nuplazid's benefit/risk profile to attain these levels."

And in terms of strategic value, it's "difficult to ignore 100 percent worldwide ownership of a now approved CNS drug with potential line extensions," he added.

Nuplazid has various layers of composition of matter patents into 2028, according to Davis, and Hatch-Waxman provisions should extend the drug into 2030 in the U.S. Ex-U.S., composition of matter patent expiries begin about five years earlier, but drugs launched outside the U.S. still enjoy 10-year exclusivity from launch date, he pointed out.

Approval of a medication to treat a condition that wasn't even recognized until recently could, itself, bring more PDP patients to treatment earlier, Dolhun suggested.

"Many times patients and their families aren't even aware of [PDP] or don't bring it up to their doctors," she pointed out. "Now that we have a medication specifically indicated for it, that may raise more awareness about the fact that this is part of Parkinson's, in many cases, and there's something we can do about it."