Last update 01 Nov 2024
Direclidine
Last update 01 Nov 2024
Overview
Basic Info
Drug Type Small molecule drug |
Synonyms |
Target |
Mechanism M4 receptor agonists(Muscarinic acetylcholine receptor M4 agonists) |
Therapeutic Areas |
Active Indication |
Inactive Indication- |
Originator Organization |
Active Organization |
Inactive Organization |
Drug Highest PhasePhase 2 |
First Approval Date- |
Regulation- |
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Structure
Molecular FormulaC19H30N4O2 |
InChIKeyHEJAEKBVOZHTRA-UWUNEBHHSA-N |
CAS Registry1803346-98-6 |
Related
4
Clinical Trials associated with DireclidineA Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of NBI-1117568 in Adults With Schizophrenia Who Warrant Inpatient Hospitalization
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, multi-arm, multi-stage inpatient study designed to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of NBI-1117568 compared with placebo in adult subjects with a primary diagnosis of schizophrenia, who are experiencing an acute exacerbation or relapse of symptoms.
Start Date04 Oct 2022 |
Sponsor / Collaborator |
Phase 1, Randomised, Open-label, 3-period Crossover, Single Dose Study in Healthy Subjects, to Assess Relative Bioavailability From an Oral Capsule of HTL0016878 Citrate Salt Versus an Oral Solution of HTL0016878 Hydrochloride Salt
This is a randomised, open-label, 3-period, crossover single dose study to assess the relative bioavailability of two formulations of HTL0016878: an oral solution of HCl salt form (the reference product) and an oral capsule containing citrate salt (the test product); and of the effect of food on the pharmacokinetics of the capsule formulation.
Start Date27 Jul 2021 |
Sponsor / Collaborator |
A Phase 1, Open-label, Randomised, Single-centre, Single Oral Dose Study to Determine the Concentration of HTL0016878 in Cerebrospinal Fluid and Plasma in Healthy Male Subjects Following Dosing With HTL0016878 Oral Solution
A Phase 1, open-label, randomised, single oral dose study to determine the concentration of HTL0016878 in CSF and plasma in healthy male subjects following dosing with HTL0016878 10 mg or 20 mg oral solution
Start Date26 Sep 2018 |
Sponsor / Collaborator |
100 Clinical Results associated with Direclidine
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100 Translational Medicine associated with Direclidine
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100 Patents (Medical) associated with Direclidine
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31
News (Medical) associated with Direclidine30 Oct 2024
INGREZZA® (valbenazine) Third Quarter Net Product Sales of $613 Million Representing 26% Year-Over-Year Growth
INGREZZA
® (valbenazine) 2024 Net Product Sales Guidance Raised to $2.30 - $2.32 Billion
Board Authorizes $300 Million Share Repurchase Plan
SAN DIEGO, Oct. 30, 2024 /PRNewswire/ -- Neurocrine Biosciences, Inc. (Nasdaq: NBIX) today announced its financial results for the third quarter ended September 30, 2024 and provided an update on its 2024 financial guidance.
"With continued INGREZZA growth across the tardive dyskinesia and Huntington's disease chorea indications, FDA Priority Review for crinecerfont in congenital adrenal hyperplasia, a deep neuroscience focused pipeline and a strong balance sheet, we are confident in our ability to help more patients than ever before," said Kyle W. Gano, Ph.D., Chief Executive Officer of Neurocrine Biosciences.
William Rastetter, Chairman of the Board of Directors of Neurocrine Biosciences, said, "The share repurchase authorization reflects the Board's confidence in Neurocrine's significant value creation potential. Importantly, the new share repurchase authorization preserves our flexibility to drive sustained growth through investments in INGREZZA and the anticipated launch of crinecerfont, while also advancing our diverse pipeline and maintaining our strong balance sheet."
Financial Highlights
INGREZZA Net Product Sales Highlights
INGREZZA third quarter 2024 net product sales were $613 million and grew 26% compared to the third quarter 2023
Year-over-year growth driven by strong underlying patient demand and improvement in gross-to-net dynamics
Other Key Financial Highlights
Differences in third quarter 2024 GAAP and Non-GAAP operating expenses compared with third quarter 2023 were driven by:
Increased R&D expense in support of an expanded and advancing portfolio including investments in muscarinic compounds, gene therapy programs, and second generation VMAT2 inhibitors. Third quarter 2024 R&D expense includes $39 million for development milestones achieved under collaborations with Nxera Pharma UK Limited (Nxera, formerly known as Sosei Heptares) and Voyager Therapeutics, Inc. (Voyager).
Increased SG&A expense includes incremental investment in crinecerfont-related headcount, crinecerfont-related pre-launch activities, and continued investment in INGREZZA, including the recent expansion of our psychiatry and long-term care sales teams in September 2024.
Third quarter 2024 GAAP net income and earnings per share were $130 million and $1.24, respectively, compared with $83 million and $0.82, respectively, for third quarter 2023
Third quarter 2024 Non-GAAP net income and earnings per share were $189 million and $1.81, respectively, compared with $156 million and $1.54, respectively, for third quarter 2023
Differences in third quarter 2024 GAAP and Non-GAAP net income compared with third quarter 2023 driven by:
Higher INGREZZA net sales and improved operating margin
Third quarter 2024 includes $17 million loss from changes in fair values of equity investments compared with $40 million loss for third quarter 2023 (Non-GAAP adjustment)
Third quarter 2024 includes $39 million of expense for development milestones achieved under collaborations with Nxera and Voyager
At September 30, 2024, the Company had cash, cash equivalents and marketable securities totaling approximately $1.9 billion
A reconciliation of GAAP to Non-GAAP financial results can be found in Table 3 and Table 4 at the end of this news release.
Recent Developments
Kyle W. Gano, Ph.D. appointed Chief Executive Officer effective October 11, 2024.
Announced the Company's Board of Directors has authorized a $300 million share repurchase plan. The Company subsequently intends to enter into a $300 million accelerated share repurchase transaction in the coming days, subject to market conditions, which will constitute the entirety of the authorized share repurchase plan.
Announced positive topline data for the Phase 2 study of NBI-1117568, a first-in-class, orally active, highly selective investigational M4 agonist, in development as a potential treatment for schizophrenia. The successful completion of the Phase 2 study triggered a $35 million milestone payment to Nxera in the third quarter of 2024. We expect to advance NBI-1117568 into Phase 3 development in the first half of 2025, which would trigger an additional $15 million milestone payment to Nxera upon initiation of the Phase 3 study.
Presented KINECT
®-HD2 interim data at the 2024 MDS International Congress of Parkinson's Disease and Movement Disorders demonstrating robust and sustained improvements in chorea associated with Huntington's Disease through week 104 irrespective of antipsychotic use.
Announced the ERUDITE™ Phase 2 study of luvadaxistat (NBI-1065844) in cognitive impairment associated with schizophrenia (CIAS) did not meet its primary endpoint. In addition, we provided Takeda Pharmaceutical Company Limited with written notice of termination of the license agreement to develop and commercialize luvadaxistat and NBI-1065846. The termination is anticipated to be effective in April 2025.
Provided Idorsia Pharmaceuticals Ltd. with written notice of termination of the license agreement to develop and commercialize NBI-827104 in epileptic encephalopathy with continuous spike and wave during sleep. The termination is anticipated to be effective in January 2025.
Raised 2024 Net Sales Guidance and Updated Expense Guidance
Conference Call and Webcast Today at 8:00 AM Eastern Time
Neurocrine Biosciences will hold a live conference call and webcast today at 8:00 a.m. Eastern Time (5:00 a.m. Pacific Time). Participants can access the live conference call by dialing 800-225-9448 (US) or 203-518-9708 (International) using the conference ID: NBIX. The webcast and accompanying slides can also be accessed at approximately 8:00 a.m. Eastern Time on Neurocrine Biosciences' website under Investors at . A replay of the webcast will be available on the website approximately one hour after the conclusion of the event and will be archived for approximately one month.
About Neurocrine Biosciences
Neurocrine Biosciences is a neuroscience-focused, biopharmaceutical company with a simple purpose: to relieve suffering for people with great needs, but few options. We are dedicated to discovering and developing life-changing treatments for patients with under-addressed neurological, neuroendocrine, and neuropsychiatric disorders. The company's diverse portfolio includes FDA-approved treatments for tardive dyskinesia, chorea associated with Huntington's disease, endometriosis* and uterine fibroids*, as well as a robust pipeline including multiple compounds in mid- to late-phase clinical development across our core therapeutic areas. For three decades, we have applied our unique insight into neuroscience and the interconnections between brain and body systems to treat complex conditions. We relentlessly pursue medicines to ease the burden of debilitating diseases and disorders, because you deserve brave science. For more information, visit neurocrine.com, and follow the company on LinkedIn, X (Formerly Twitter) and Facebook. (*in collaboration with AbbVie)
NEUROCRINE BIOSCIENCES, NEUROCRINE and YOU DESERVE BRAVE SCIENCE are registered trademarks of Neurocrine Biosciences, Inc. The Neurocrine logo is a trademark of Neurocrine Biosciences, Inc.
Non-GAAP Financial Measures
In addition to the financial results and financial guidance that are provided in accordance with accounting principles generally accepted in the United States (GAAP), this press release also contains the following Non-GAAP financial measures: Non-GAAP R&D expense, Non-GAAP SG&A expense, and Non-GAAP net income and net income per share. When preparing the Non-GAAP financial results and guidance, the Company excludes certain GAAP items that management does not consider to be normal, including recurring cash operating expenses that might not meet the definition of unusual or non-recurring items. In particular, these Non-GAAP financial measures exclude: non-cash stock-based compensation expense, charges associated with convertible senior notes, vacated legacy campus facility costs, net of sublease income, non-cash amortization expense related to acquired intangible assets, acquisition and integration costs, changes in fair value of equity security investments, changes in foreign currency exchange rates and certain adjustments to income tax expense. These Non-GAAP financial measures are provided as a complement to results provided in accordance with GAAP as management believes these Non-GAAP financial measures help indicate underlying trends in the Company's business, are important in comparing current results with prior period results and provide additional information regarding the Company's financial position. Management also uses these Non-GAAP financial measures to establish budgets and operational goals that are communicated internally and externally and to manage the Company's business and evaluate its performance. The Company provides guidance regarding combined R&D and SG&A expenses on both a GAAP and a Non-GAAP basis. A reconciliation of these GAAP financial results to Non-GAAP financial results is included in the attached financial information.
Forward-Looking Statements
In addition to historical facts, this press release contains forward-looking statements that involve a number of risks and uncertainties. These statements include, but are not limited to, statements related to: the benefits to be derived from our products and product candidates; the value our products and/or our product candidates may bring to patients; the continued success of INGREZZA; our financial and operating performance, including our future revenues, expenses, or profits; our collaborative partnerships; expected future clinical and regulatory milestones; the timing of the initiation and/or completion of our clinical, regulatory, and other development activities and those of our collaboration partners; and our intention to enter into an accelerated share repurchase transaction, including the expected dollar amounts and the timing of the transaction. Among the factors that could cause actual results to differ materially from those indicated in the forward-looking statements are: our future financial and operating performance; risks and uncertainties associated with the commercialization of INGREZZA; risks that the crinecerfont New Drug Applications (NDAs) may not obtain regulatory approval, such approval may be delayed, or may not receive the benefits associated with priority review; risks related to the development of our product candidates; risks associated with our dependence on third parties for development, manufacturing, and commercialization activities for our products and product candidates, and our ability to manage these third parties; risks that the FDA or other regulatory authorities may make adverse decisions regarding our products or product candidates; risks that clinical development activities may not be initiated or completed on time or at all, or may be delayed for regulatory, manufacturing, or other reasons, may not be successful or replicate previous clinical trial results, may fail to demonstrate that our product candidates are safe and effective, or may not be predictive of real-world results or of results in subsequent clinical trials; risks that the potential benefits of the agreements with our collaboration partners may never be realized; risks that our products, and/or our product candidates may be precluded from commercialization by the proprietary or regulatory rights of third parties, or have unintended side effects, adverse reactions or incidents of misuse; risks associated with government and third-party regulatory and/or policy efforts which may, among other things, impose sales and pharmaceutical pricing controls on our products or limit coverage and/or reimbursement for our products; risks associated with competition from other therapies or products, including potential generic entrants for our products; constraints, volatility, or disruptions in the capital markets or other factors affecting our ability to enter into or complete an accelerated share repurchase transaction; and other risks described in our periodic reports filed with the SEC, including our Quarterly Report on Form 10-Q for the quarter ended September 30, 2024. Neurocrine Biosciences disclaims any obligation to update the statements contained in this press release after the date hereof other than as required by law.
SOURCE Neurocrine Biosciences, Inc.
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Phase 2License out/inFinancial StatementExecutive Change
23 Sep 2024
iStock/
Evgeny Gromov
As the FDA prepares to render a verdict on BMS’ closely watched schizophrenia drug,
BioSpace
takes a closer look at the late-stage pipeline for this neuropsychiatric disorder.
A new era of schizophrenia treatment could be on the horizon as Bristol Myers Squibb awaits the FDA’s decision on the company’s recently acquired drug KarXT. If approved, KarXT would represent the
first novel approach
for schizophrenia in several decades.
“What we’re on the cusp of is the first approval for a brand new, novel mechanism of action,” Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told
BioSpace
.
Schizophrenia is a neuropsychiatric disorder comprising positive symptoms relating to psychosis as well as negative symptoms such as social withdrawal and lack of motivation, in addition to cognitive symptoms. It affects
more than 3.5 million
people across the U.S., with the treatment market expected to top
$7 billion
by 2028, according to The Business Research Company.
First-generation antipsychotics made their debut in the 1960s and 1970s, Suvannevejh said. They were then followed by second-generation antipsychotics. Both work by targeting the dopamine and serotonin receptors, he explained.
KarXT, which came into BMS’ possession with the $14 billion
acquisition
of Karuna Therapeutics in December 2023, belongs to a class called muscarinic receptor acting modulators. Unlike existing schizophrenia treatments, KarXT does not directly block dopamine receptors. Instead, it works through the dual activation of the M1 and M4 muscarinic acetylcholine receptors in the central nervous system, a mechanism shown to improve positive, negative and cognitive symptoms in schizophrenia without the side effects associated with antipsychotics.
Antipsychotics can induce excessive sleepiness and weight gain, among other adverse effects, which can lead to discontinuation, Suvannevejh said. The muscarinic class, on the other hand, has shown “best in class efficacy” and “potentially best in class safety and tolerability. . . . That’s why we think there is a lot of pent-up demand for this new class of drugs.”
Following behind KarXT in the schizophrenia pipeline are several drugs targeting the positive, negative and cognitive symptoms of the disease via the muscarinic pathway and others.
BioSpace
takes a closer look at five of these investigational therapies.
Neurocrine Biosciences
NBI-1117568
A recent readout from a Phase II trial of Neurocrine’s NBI-1117568, an oral muscarinic M4 selective agonist, sparked further interest in the schizophrenia space—though few accolades from investors.
While the candidate improved symptoms of schizophrenia, it did so only at the lowest dose tested, Neurocrine
reported
. Specifically, NBI-1117568 met the trial’s primary endpoint, improving the positive and negative symptoms of the psychiatric disease, at the 20-mg dose after six weeks. The severity of the disorder was also improved at this dose level. All other doses—30 mg, 40 mg and 60 mg—failed to meet the trial’s primary endpoint.
Investors were unimpressed, and the company’s shares dropped 20% following the results, due partly to a lower Positive and Negative Syndrome Scale (PANSS) score than its competitors.
Neurocrine plans to move forward with a Phase III trial in early 2025, according to a
press release
announcing the results.
AbbVie
Emraclidine
Like KarXT and NBI-1117568,
emraclidine
targets the M4 receptor.
AbbVie
came into possession of emraclidine
when it
acquired
Cerevel in December 2023 for $8.7 billion in a deal that
closed
Aug. 1.
Emraclidine
is currently in
Phase II development
. However, Suvannevejh said the studies have been designed as “potentially registrational” as they are much larger than average Phase II trials.
“Because of the strong data we’ve seen with drugs like KarXT . . . I think the expectation [for emraclidine] is you should also expect to see very good efficacy and equally, if not more importantly, very good safety and tolerability,” he added.
A Phase Ib trial of emraclidine in adults with schizophrenia demonstrated a “clinically meaningful and statistically significant improvement” in PANSS total score at six weeks, according to a
press release
announcing the trial’s publication in
The Lancet
.
Reviva Pharmaceuticals
Brilaroxazine
Taking a different tack, Reviva Pharmaceuticals is developing brilaroxazine, a serotonin-dopamine signaling modulator, for schizophrenia.
“Schizophrenia is primarily caused by imbalance of [the] serotonin and dopamine signaling cascade,” Laxminarayan Bhat, founder, president and CEO of Reviva, told
BioSpace
. An effective treatment is expected to balance the levels of these neurochemicals by directly or indirectly modulating both dopamine and serotonin signaling cascades, he explained. “The difference with our drug with respect to dopamine signaling cascade is we have more potent activity for D4, [which is] highly expressed in the frontal cortex” and implicated in the negative and cognitive symptoms of schizophrenia, Bhat said.
Reviva
announced
topline results from the pivotal Phase III RECOVER trial of brilaroxazine in October 2023. The treatment met the trial’s primary endpoint, showing a “statistically significant and clinically meaningful” 10.1-point reduction in PANSS total score vs. placebo after four weeks when dosed at 50 mg. Brilaroxazine at this dose also elicited reductions in all major symptom domains and secondary endpoints, according to Reviva. The drug was “generally well-tolerated” with a side effect pro to placebo at both the 50 mg and 15 mg doses.
In April, the company
announced
it had reached alignment with the FDA on a registrational Phase III program for brilaroxazine where two positive four-week studies plus a year-long safety study could support a new drug application. Topline data from a one-year open-label extension are expected in the fourth quarter of this year.
Boehringer Ingelheim
Iclepertin
Boehringer Ingelheim
is developing
iclepertin
, a glycine transporter 1 (GlyT1) inhibitor, to treat the cognitive symptoms associated with schizophrenia.
GlyT1
is thought to play an important role in regulating both inhibitory and excitatory neurotransmission.
Iclepertin is Boehringer’s lead small molecule candidate for schizophrenia—the company is also working on a digital therapeutic for negative symptoms—and is currently being studied in three large, randomized, controlled studies, which are expected to read out in 2025, according to Mike Jablonski, vice president of clinical development and medical affairs at Boehringer.
The cognitive symptoms of schizophrenia, which include poor memory, low attention span and forgetfulness, are “often overlooked,” Jablonski told
BioSpace
. “Even if [the] positive symptoms are controlled through antipsychotic utilization, that doesn’t address the cognitive symptoms,” he said, calling this a real unmet need.
Boehringer delved deeper into the schizophrenia space in March,
inking
a deal worth up to $732 million with Sosei Heptares (now Nxera Pharma) to address the positive, negative and cognitive symptoms of the disease. Under this deal, the German multinational has the exclusive option to license Sosei Heptares’ portfolio of GPR52 agonists.
Alto Neuroscience
ALTO-101
Alto Neuroscience is also targeting cognitive symptoms with ALTO-101, a novel inhibitor of phosphodiesterase 4 (PDE4) enzymes,
disruptions in which
potentially play a role in schizophrenia.
“PDE4 is an enzyme that breaks down cAMP, an intracellular signaling molecule important for cognition and neuroplasticity, which has long been of interest for its putative pro-cognitive and antidepressant effects,” Amit Etkin, founder and CEO of Alto, told
BioSpace
in an email.
Alto kicked off a
Phase II study
of ALTO-101 in June 2024, intending to enroll approximately 70 individuals between 21 and 55 years of age with schizophrenia and “a demonstrable level of cognitive impairment.” Topline data are expected in the second half of 2025.
In a Phase I study, the candidate demonstrated positive effects on cognition and electroencephalography (EEG) measures relevant to cognitive function, according to Alto. A transdermal formulation of ALTO-101 achieved greater systemic drug exposure than an oral version of the drug, the company reported. Transdermal ALTO-101 will be tested in the Phase II trial.
Clinical ResultPhase 2Phase 3AcquisitionPhase 1
13 Sep 2024
William Blair analysts said they “viewed luvadaxistat development as high risk.”
Neurocrine Biosciences’ schizophrenia program pivot has failed. The biotech was unable to replicate the cognition signal it saw in an earlier midphase study, prompting it to stop development of luvadaxistat.San Diego-based Neurocrine in-licensed the DAAO inhibitor luvadaxistat and other R&D programs from Takeda for $120 million upfront in 2020. The next year, a phase 2 trial of luvadaxistat missed its primary endpoint. However, while the candidate failed to improve schizophrenia symptoms on the PANSS scale, Neurocrine did track a significant improvement on secondary endpoints that looked at cognition.The secondary endpoint wins persuaded Neurocrine to run a second phase 2 trial that largely replicated the design of the earlier study. The key difference was the use of the Brief Assessment of Cognition in Schizophrenia as the primary endpoint. Neurocrine included another cognition scale as a secondary goal.This time around, the biotech failed to replicate the cognitive data seen in the earlier trial. Neurocrine said the failure was partly caused by “the large variability seen in the cognitive measures across the population studied and a potential imbalance in the baseline characteristics of subjects enrolled across the treatment arms.” Rather than try to address those issues in a third trial, the biotech has decided to stop development of the drug candidate and focus its resources on other assets. Specifically, Neurocrine plans to pump the money into phase 3 studies of NBI-1117568 for schizophrenia and NBI-1065845 for major depressive disorder.Neurocrine’s share price fell 2% to below $119 in premarket trading, a muted reaction that likely reflects expectations for the program. William Blair analysts said they “viewed luvadaxistat development as high risk” in a note published in response to the failed trial. Neurocrine was open about the risks in the run-up to the readout, too.“Cognitive impairment associated with schizophrenia has been a very, very challenging area. It's about as high risk as you could get, in my view, and there's not a lot known about clinical development in this space because there's such a few number of companies that have worked here,” Kyle Gano, Ph.D., chief business development and strategy officer at Neurocrine, said at a Wells Fargo event last week.There are no FDA-approved treatments for cognitive impairment associated with schizophrenia. Biogen, Roche and Pfizer have studied candidates in the setting but no longer have any active trials. Recognify Life Sciences, an atai Life Sciences company, is running a phase 2 trial that is scheduled to end this year, according to ClinicalTrials.gov.
Phase 2
100 Deals associated with Direclidine
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R&D Status
10 top R&D records. to view more data
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| Indication | Highest Phase | Country/Location | Organization | Date |
|---|---|---|---|---|
| Schizophrenia | Phase 2 | US | 04 Oct 2022 | |
| Alzheimer Disease | Phase 2 | GB | 30 Jan 2022 |
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Clinical Result
Clinical Result
Indication
Phase
Evaluation
View All Results
| Study | Phase | Population | Analyzed Enrollment | Group | Results | Evaluation | Publication Date |
|---|
Phase 2 | 210 | Placebo | (nzocnuqthn) = rankopljlg syosvjxplj (cxgcufeoml ) | Positive | 28 Aug 2024 | ||
NBI-1117568 20 mg QD | (nzocnuqthn) = hmqomsmyfd syosvjxplj (cxgcufeoml ) |
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