dm+d

Unassigned

New Medicines

NuplazidParkinson's disease-associated psychosis

Information

Nuplazid
New molecular entity
Acadia
Acadia

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Launched
Apr 21Acadia continue to focus on expanded the indications for Nuplazid in the US. Development for other markets, including Europe, depends on the success of their US operations. No specific plans announced so far [28].
Apr 20Acadia still has not announced plans for EU/UK filing although it is not ruled out in their latest annual report [27].
Apr 19Acadia still have not announced a revised estimate for when they will file in the EU [26].
Nov 18No information available in company annual report on plans for EU filings; concern expressed over Brexit and consequential risks in UK [25].
Jun 18FDA approves a new 34mg capsule formulation and a 10mg tablet of pimavanserin for treatment of patients, living with hallucinations and delusions associated with PD psychosis. These two new formulations will be available by mid-August [24].
May 18Acadia deferred submission of an MAA to the EMA because of their continuing development of pimavanserin in indications other than in PD psychosis, and the time-limited data exclusivity currently granted by the EMA that commences on first approval of a product in Europe. Availability of Nuplazid in the EU is dependent on success in development for other indications in the US [22].
Jun 17Acadia corporate goals include pursuing and engaging in potential business development opportunities and advancing worldwide plans for pimavanserin [19].
May 17Acadia states in its 2016 annual report that it has decided to defer submission of an MAA to the EMA and do not yet have a revised estimate of when we will make that filing [18].
Jan 17Acadia plans to establish one or more strategic alliances to commercialise pimavanserin outside of the US [17].
May 16Launched in the US for Parkinson´s disease-associated psychosis [17].
May 16Approved in US [16].
Mar 16US FDA Psychopharmacologic Drugs Advisory Committee has voted 12 to 2 in favour of approval. Advisory Committee recommendations are normally followed by the FDA, which will make a final decision on approval by 1st May [15].
Oct 15FDA grans priority for review status. A decision is expected by may 2016 [14].
Sep 15ACADIA Pharmaceuticals announced it has submitted a New Drug Application (NDA) to the US FDA seeking approval for NUPLAZID™ (pimavanserin) for psychosis associated with Parkinson’s disease [13].
Mar 15Company announce that it had shifted it´s plan to submit NDA to the second half of 2015 [12].
Sep 14The FDA has granted Breakthrough Therapy designation to NUPLAZID™ (pimavanserin) for the treatment of Parkinson’s disease psychosis. There are plans to submit the NDA to the FDA near the end of this year. [11]
Apr 13The FDA has agreed that the data from the pivotal PIII -020 study, together with supportive data from other studies are sufficient to support the filing of a New Drug Application (NDA) for the treatment of Parkinson’s disease psychosis. ACADIA will no longer conduct the PIII -021 study that was planned as a confirmatory trial and was scheduled to start later this month. The company plan to file in the US in late 2014 [9]
Jul 10New PIII trial started [4].
May 09Currently being investigated in 2 PIII studies (1).

Category

Selective 5-HT2A inverse agonist
Up to 40% of patients with PD may develop psychotic symptoms, commonly visual hallucinations and delusions (1)
Parkinson's disease-associated psychosis
Oral

Trial or other data

Sep 18The FDA announced completion of its safety review of Nuplazid (pimavanserin). Based on analysis of all available data, the FDA did not identify any new or unexpected safety findings with Nuplazid, or findings inconsistent with the established safety profile currently described in the drug label. The FDA’s conclusion thus remains unchanged that the drug’s benefits outweigh its risks for patients with hallucinations and delusions of Parkinson’s disease psychosis [23].
Apr 18In the US, the FDA is conducting a safety evaluation after reports of side effects, including deaths, raised questions about its approval. Acadia has issued a statement: "we remain confident in the efficacy and safety of NUPLAZID that supported its approval by the FDA and stand firmly behind it" [20,21].
Feb 14PIII 020 Study published in Lancet 2014 Feb 8; 383: 533
Nov 13Data published from pivotal Phase III -020 Study in the November 1, 2013 online issue of The Lancet [10]
Mar 13Acadia Pharmaceutcials announces detailed results from the pivotal PIII -020 study.Pimavanserin met the primary endpoint by demonstrating highly significant antipsychotic efficacy on the 9-item SAPS-PD scale (p=0.001). Pimavanserin also met secondary endpoints for motoric tolerability as measured using Parts II and III of the Unified Parkinson´s Disease Rating Scale (UPDRS), the Clinical Global Impression Severity (CGI-S) scale (p<0.001), the Clinical Global Impression Improvement (CGI-I), scale (p=0.001), and a CGI-I responder analyses (p=0.002). The CGI-I responder results showed that approximately twice as many subjects in the pimavanserin treatment arm vs. placebo were rated as very much improved or much improved at the conclusion of the study. In addition, pimavanserin demonstrated significant improvements using the full 20-item SAPS scale and each of the separate hallucinations and delusions domains in supportive analyses. Statistically significant benefits were also observed in exploratory measures of nighttime sleep, daytime wakefulness, and caregiver burden [8].
Dec 12Following positive results from a PIII study, Acadia has won finance for a PIII confirmatory study [7].
Nov 12Acadia Pharmaceuticals announces successful top-line results from its pivotal PIII trial evaluating efficacy, tolerability & safety of pimavanserin in pts with PDP. Pimavanserin met the primary endpoint with a 5.79 point improvement in psychosis at day 43 vs. a 2.73 point improvement for placebo on SAPS-PD (difference 3.06 points; p=0.001). Pimavanserin also met the key secondary endpoint for motoric tolerability as measured using Parts II & III of the Unified PD Rating Scale, (UPDRS). These results were further supported by a highly significant improvement in the secondary efficacy measure, the Clinical Global Impression Improvement (CGI-I) scale (p=0.001). In addition, clinical benefits were observed in all exploratory efficacy measures with significant improvements in nighttime sleep, daytime wakefulness & caregiver burden. Most common adverse events were urinary tract infection (11.7% placebo vs. 13.5% Pima vanserin) & falls (8.5% vs. 10.6%, respectively). AEs were generally mild to moderate. The only serious AEs that occurred in more than one pt were UTI (1 vs. 3) & psychotic disorder (0 vs. 2), respectively. 90% of pts who completed the clinical phase of this trial elected to roll over into the ongoing open-label safety extension study [6].
Oct 10Acadia Pharmaceuticals and Biovail have ended the collaboration agreement on pimavanserin. Acadia has regained all rights to pimavanserin and plans to continue PIII studies for Parkinson´s, but won´t pursue development for Alzheimer´s or schizophrenia [5].
Oct 09Acadia and Biovail have decided to conduct a third PIII trial for PDP even though a previous PIII study failed last month. They will use the findings from the failed study along with the data from a second, ongoing PIII study to design the third trial, due to start H1 2010. The study will use a 40mg dose of pimavanserin [3].
Sep 09Pimavanserin failed to achieve the primary endpoint of antipsychotic efficacy according to the top-line results from the first pivotal PIII trial in 298 patients with Parkinson´s disease psychosis (PDP). The 6-week study randomized patients to one of three arms (pimavanserin 10 mg or 40 mg, or placebo, daily) while remaining on stable doses of their existing anti-Parkinson´s therapy. The primary endpoint was measured using the hallucinations and delusions domains of the Scale for the Assessment of Positive Symptoms (SAPS). There was a marked reduction in SAPS scores in all arms: 5.9 points in the placebo arm, 5.8 points in the 10 mg pimavanserin arm, and 6.7 points in the 40 mg pimavanserin arm. Statistical significance was not achieved in either pimavanserin arm primarily due to the larger than expected improvement in placebo-treated patients. Pimavanserin met the secondary endpoint of motoric tolerability as measured using the Unified Parkinson´s Disease Rating Scale (UPDRS) and was well tolerated, with the frequency of adverse events generally similar across all study arma [2].

Evidence based evaluations

NuplazidDementia-associated psychosis

Information

Nuplazid
Licence extension / variation
Acadia
Acadia

Development and Regulatory status

Phase II Clinical Trials
Phase II Clinical Trials
Not approved
Aug 21Acadia announces it completed a Type A end of review meeting regarding the FDA complete response letter (CRL) for the sNDA for pimavanserin for the treatment of hallucinations and delusions associated with DRP. The FDA reiterated their stated position in the CRL, that pimavanserin should be studied by individual subgroups of dementia, and advised that the best path forward is to conduct an additional clinical study in each of the subgroups for which Acadia seeks approval. However, the FDA also indicated that they are open to having another meeting to discuss additional analyses from the HARMONY and -019 studies in support of a potential resubmission without an additional clinical study [15].
Mar 21Acadia announce they have received notification from the US FDA stating that the agency has identified deficiencies that preclude discussion of labeling and post-marketing requirements/commitments at this time. The company plans to work with the FDA to learn the nature of the deficiencies and seek to resolve them. It is not clear whether the agreed PDUFA action date of April 3 2021 will now be met [13].
Jul 20US FDA accept sNDA for pimavanserin to treat dementia patients with hallucinations and delusions; a decision is expected 3/4/21 [12].
Sep 19Acadia plan to meet with FDA in 2020 regarding submission of a sNDA [10].
Oct 17US FDA grants Breakthrough Therapy Designation to pimavanserin for dementia-related psychosis [6].

Category

Selective 5-HT2A inverse agonist
Behavioural signs, such as aggression, psychomotor agitation and psychosis (hallucinations and delusions), are very common in patients with Alzheimers disease, especially in the late stages of the disease [2]
Dementia-associated psychosis
Oral

Trial or other data

Jul 21PIII HARMONY RCT (n=351) was stopped early for efficacy, patients who had response to treatment (n=217) had lower risk of relapse with continuation of drug than with discontinuation (13% vs. 28%, placebo; HR 0.35; 95% CI, 0.17 to 0.73; p=0.005) [14].
Dec 19In PIII HARMONY study (n=392) patients had average baseline of moderate to severe psychosis as per Scale for Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D). Nuplazid patients saw their SAPS-H+D score improve by 63% and 75.2%, respectively [11].
Sep 19ACADIA Pharmaceuticals announce PIII Harmony study meets primary endpoints. Results from a planned interim analysis reported a statistically significant longer time to relapse of psychosis with pimavanserin vs placebo resulting in an early halt of the trial [9].
Nov 18PIII HARMONY trial (NCT03325556) is still recruiting patients in the US; timescales unchanged [8].
Dec 17PIII HARMONY trial (NCT03325556) is recruiting patients in the US. Collection of primary outcome data due to complete Mar 2020 [7].
Oct 17PIII HARMONY trial to evaluate the efficacy and safety of pimavanserin for treatment of hallucinations and delusions associated with dementia-related psychosis starts. The trial will be conducted globally and will enrol approximately 360 patients. Primary endpoint is time to relapse in the double-blind period. ACADIA believes that positive results from one PIII study together with supportive data from prior studies could serve as the basis of a supplementary New Drug Application [6].
Dec 16a further PII trial is in progress in the US (NCT02992132) assessing efficacy in treatment of agitation and aggression in patients with AD; estimated enrolment is 432 and estimated primary completion date June 2019 [5].
Dec 16Acadia announce positive top-line results from PII trial (NCT02035553) - at six weeks, the primary outcome (Neuropsychiatric Inventory - Nursing Home Version, NPI-NH) score was statistically significantly better in the pimavanserin group vs. the placebo group (3.76 point improvement from baseline vs. 1.93 points for placebo; p=0.0451). In the secondary outcome of scores at 12 weeks, the improvement was maintained in the treatment group but the difference did not statistically separate from placebo [4].
Dec 15Remains in PII development currently [3]
Nov 13Phase II feasibility trial initiated to examine the efficacy and safety of pimavanserin as a treatment for patients with Alzheimer’s disease psychosis (ADP) [1]

NuplazidSchizophrenia, predominant negative symptoms - adjunctive treatment

Information

Nuplazid
Licence extension / variation
Acadia
Acadia

Development and Regulatory status

None
Phase III Clinical Trials
Phase II Clinical Trials

Category

Selective serotonin 5HT2A agonist
Schizophrenia affects around 1 in every 100 people over the course of their life [2].
Schizophrenia, predominant negative symptoms - adjunctive treatment
Oral

Nuplazid Major depressive disorder - adjunctive treatment to standard antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI)

Information

Nuplazid
Licence extension / variation
Acadia
Acadia

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Jul 20Acadia Pharmaceuticals discontinue development of pimavanserin for adjunctive major depressive disorder due to negative results from PIII CLARITY study [4].

Category

Selective 5-HT2A selective agonist
Annually, 5% of adults have an episode of depression. About one in four women and one in ten men will develop depression severe enough to require treatment at some time in their lives. Most depressive states are at the mild-to-moderate end of the spectrum and it is these that are mainly seen in primary care [1].
Major depressive disorder - adjunctive treatment to standard antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI)
Oral

Trial or other data

Jul 20Acadia announce PIII CLARITY studies fail to meet primary endpoint. Pimavanserin 34 mg, given once-daily as an adjunctive treatment to standard antidepressant therapy was associated with a mean reduction of 9.0 in HAMD-17 total score vs 8.1 for placebo (p=0.296) [4].