Author: Youakim, James M ; An, Di ; Marsh, Eric D ; Berry-Kravis, Elizabeth M ; Glaze, Daniel G ; Benke, Timothy A ; Bishop, Kathie M ; Peters, Sarika U ; Neul, Jeffrey L ; Percy, Alan K

BACKGROUND:

Trofinetide was approved by the US Food and Drug Administration for the treatment of Rett syndrome (RTT) in March 2023. Benefiting the ability to communicate in RTT is often identified as the most important caregiver goal for new therapies. This analysis reports the communication-related end points from the phase 3 LAVENDER study of trofinetide in RTT.

METHODS:

Females with RTT, aged five to 20 years, were randomized 1:1 to trofinetide or placebo for 12 weeks. Secondary efficacy end points related to communication were based on change from baseline to week 12 and included the caregiver-rated Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite score (key secondary end point; scores ranged from 0 to 26 [higher scores indicated better communication]) and novel clinician rating scales (0 [normal] to 7 [severe impairment]) measuring the ability to communicate choices nonverbally (RTT-COMC) and verbally (RTT-VCOM).

RESULTS:

Trofinetide demonstrated a statistically significant difference versus placebo for the CSBS-DP-IT Social Composite score (least squares mean [LSM] difference = 1.0; 95% confidence interval [CI], 0.3 to 1.7; P = 0.0064; Cohen's d effect size = 0.43) and a nominally significant difference for the RTT-COMC (LSM difference: -0.3; 95% CI, -0.6 to -0.0; P = 0.0257; Cohen's d effect size = 0.36). As expected, there was no difference for the RTT-VCOM.

CONCLUSIONS:

Significant treatment benefit for trofinetide versus placebo was observed in scales measuring the ability to communicate. These scales may be appropriate for future clinical studies in RTT and other neurodevelopmental disorders.

01 Mar 2024·Clinical therapeutics

A Physiologically Based Pharmacokinetic Modeling Approach to Assess the Potential for Drug Interactions Between Trofinetide and CYP3A4-Metabolized Drugs

Article

Author: Darwish, Mona ; Youakim, James M ; Lukacova, Viera ; Owen, Joel S ; Bradley, Heather ; Darling, Inger

PURPOSE:

Trofinetide is the first drug to be approved by the US Food and Drug Administration for use in the treatment of patients with Rett syndrome, a multisystem disorder requiring multimodal therapies. Cytochrome P450 (CYP) 3A4 metabolizes >50% of therapeutic drugs and is the CYP isozyme most commonly expressed in the liver and intestines. In vitro studies suggest the concentration of trofinetide producing 50% inhibition (IC₅₀) of CYP3A4 is >15 mmol/L; that concentration was much greater than the target clinical concentration associated with the maximal intended therapeutic dose (12 g). Thus, trofinetide has a low potential for drug-drug interactions in the liver. However, there is potential for drug-drug interactions in the intestines given the oral route of administration and expected relatively high concentration in the gastrointestinal tract after dose administration.

METHODS:

Using a validated physiologically based pharmacokinetic (PBPK) model, deterministic and stochastic simulations were used for assessing the PK properties related to exposure and bioavailability of midazolam (sensitive index substrate for CYP3A4) following an oral (15 mg) or intravenous (2 mg) dose, with and without single-dose and steady-state (12 g) coadministration of oral trofinetide.

FINDINGS:

Following coadministration of intravenous midazolam and oral trofinetide, the PK properties of midazolam were unchanged. The trofinetide concentration in the gut wall was >15 mmol/L during the first 1.5 hours after dosing. With the coadministration of oral midazolam and trofinetide, the model predicted increases in fraction of dose reaching the portal vein, bioavailability, C_max, and AUC_inf of 30%, 30%, 18%, and 30%, respectively.

IMPLICATIONS:

In this study that used a PBPK modeling approach, it was shown that CYP3A4 enzyme activity in the liver was not affected by trofinetide coadministration, but trofinetide was predicted to be a weak inhibitor of intestinal CYP3A4 metabolism after oral administration at therapeutic doses.

01 Mar 2024·European journal of medicinal chemistry

Exploring structural determinants of neuroprotection bias on novel glypromate conjugates with bioactive amines

Article

Author: Costa-Almeida, Hugo F ; Pereira, David M ; Costa, Vera M ; García-Mera, Xerardo ; Correia, Xavier Cruz ; Rodríguez-Borges, José E ; Correia da Silva, Daniela ; Silva-Reis, Sara C ; Sampaio-Dias, Ivo E

Neurodegenerative disorders of the central nervous system (CNS) such as Alzheimer's and Parkinson's diseases, afflict millions globally, posing a significant public health challenge. Despite extensive research, a critical hurdle in effectively treating neurodegenerative diseases is the lack of neuroprotective drugs that can halt or reverse the underlying disease processes. In this work, we took advantage of the neuroprotective properties of the neuropeptide glycyl-l-prolyl-l-glutamic acid (Glypromate) for the development of new peptidomimetics using l-pipecolic acid as a proline surrogate and exploring their chemical conjugation with relevant active pharmaceutical ingredients (API) via a peptide bond. Together with prolyl-based Glypromate conjugates, a total of 36 conjugates were toxicologically and biologically evaluated. In this series, the results obtained showed that a constrained ring (l-proline) at the central position of the peptide motif accounts for enhanced toxicological profiles and biological effects using undifferentiated and differentiated human neuroblastoma SH-SY5Y cells. Additionally, it was shown that biased biological responses are API-dependent. Conjugation with (R)-1-aminoindane led to a 38-43% reduction of protein aggregation induced by Aβ_25-35 (10 μM), denoting a 3.2-3.6-fold improvement in comparison with the parent neuropeptide, with no significative difference between functionalization at α and γ-carboxyl ends. On the other hand, the best-performing neuroprotective conjugate against the toxicity elicited by 6-hydroxydopamine (6-OHDA, 125 μM) was obtained by conjugation with memantine at the α-carboxyl end, resulting in a 2.3-fold improvement of the neuroprotection capacity in comparison with Glypromate neuropeptide. Altogether, the chemical strategy explored in this work shows that the neuroprotective capacity of Glypromate can be modified and fine-tuned, opening a new avenue for the development of biased neurotherapeutics for CNS-related disorders.

News (Medical) associated with Trofinetide

18 Jun 2024

·www.biospace.com

Acadia Pharmaceuticals Presents DAYBUE™ (trofinetide) Real-World Evidence and Additional Data in Rett Syndrome at the 2024 International Rett Syndrome Foundation (IRSF) Annual Scientific Meeting

SAN DIEGO--(BUSINESS WIRE)-- Acadia Pharmaceuticals, Inc. (Nasdaq: ACAD) today announced that interim data from the open-label real-world LOTUS™ study will be presented at the 2024 International Rett Syndrome Foundation (IRSF) Annual Scientific Meeting, being held this week in Westminster, Colorado. LOTUS is an ongoing, caregiver-reported study evaluating the efficacy and tolerability outcomes in patients with Rett syndrome treated with DAYBUE™ (trofinetide). “These interim data from the LOTUS study reinforce that the clinical effectiveness of DAYBUE in the real-world setting is consistent with results observed in the DAYBUE Phase 3 clinical trial program and further characterize what Rett syndrome symptom improvements may look like to caregivers,” said Ponni Subbiah, M.D., M.P.H., Senior Vice President, Global Head of Medical Affairs and Chief Medical Officer. “These initial findings also illustrate caregivers’ strategies to manage gastrointestinal tolerability in the real world and underscore the value of education and effective implementation of diarrhea management strategies to help families improve the patient experience.” Six-month interim findings evaluating DAYBUE in 101 Rett syndrome patients with an age range of two to 60 years old from the Phase 4, observational, prospective study showed caregivers of more than two-thirds of enrolled participants reported improvements at Month 1 in at least one Rett syndrome symptoms category. This was measured using the Behavioral Improvement Questionnaire (BIQ) developed by Acadia in consultation with Rett experts and caregivers. The most consistently reported improvements over six months were nonverbal communication (58.5%), alertness (51.2%) and social interaction/connectedness (40.2%). Additionally, diarrhea and formed/normal stool were both common, as measured by the Gastrointestinal (GI) Health Questionnaire also developed by Acadia for this study. Some participants reported initiating therapy on doses less than half of the FDA approved dose and increasing over several weeks; the majority of patients were on >90% of labeled dose by week 10. The results of this six-month follow-up are limited by lack of placebo arm, missing data and the online nature of this study. Participants are being enrolled in the LOTUS study for at least 12 months from initiation of DAYBUE treatment, with the option to extend participation for an additional 12 months. This interim analysis of LOTUS data will be presented at the IRSF Scientific Meeting, as well as new findings from health economics and outcomes research in Rett syndrome care and encore data from DAYBUE open-label extension and clinical trial program studies. IRSF Poster Presentations, Tuesday, June 18, 5pm MDT-7pm MDT: Assessing experiences with trofinetide for Rett syndrome: interviews with caregivers of patients in LAVENDER™, LILAC-1™, and LILAC-2™ studies Real-world benefits and tolerability of trofinetide for the treatment of Rett Syndrome: the LOTUS study Prevalence of respiratory clinical outcomes among patients with Rett syndrome: analysis of real-world data in the United States Trofinetide for the treatment of Rett syndrome: long-term safety and efficacy results from the open-label LILAC-2 study Prevalence of epilepsy in individuals with Rett syndrome–a real-world evidence analysis Prevalence of respiratory comorbidities among patients with Rett syndrome Prevalence of nutritional deficiency, underweight status and gastrostomy among patients with Rett syndrome: an analysis of electric health record (EHR) data About Rett Syndrome Rett syndrome is a rare, complex, neurodevelopmental disorder that may occur over four stages and affects approximately 6,000 to 9,000 patients in the U.S., with approximately 5,000 patients currently diagnosed according to an analysis of healthcare claims data.1-4 A child with Rett syndrome exhibits an early period of apparently normal development until six to 18 months, when their skills seem to slow down or stagnate. This is typically followed by a duration of regression when the child loses acquired communication skills and purposeful hand use. The child may then experience a plateau period in which they show mild recovery in cognitive interests, but body movements remain severely diminished. As they age, those living with Rett may continue to experience a stage of motor deterioration which can last the rest of the patient’s life.3 Rett syndrome is typically caused by a genetic mutation on the MECP2 gene.5 In preclinical studies, deficiency in MeCP2 is thought to lead to impairment in synaptic communication, and the deficits in synaptic function may be associated with Rett manifestations.5-7 Symptoms of Rett syndrome may also include development of hand stereotypies, such as hand wringing and clapping, and gait abnormalities.8 Most Rett patients typically live into adulthood and require round-the-clock care.2,9 About DAYBUE™ (trofinetide) Trofinetide is a synthetic analog of the N-terminal tripeptide of insulin-like growth factor 1. The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown. In animal studies, trofinetide has been shown to increase branching of dendrites and synaptic plasticity signals.10 Important Safety Information for DAYBUE™ (trofinetide) Warnings and Precautions Diarrhea: In a 12-week study and in long-term studies, an aggregate of 85% of patients treated with DAYBUE experienced diarrhea. In those treated with DAYBUE, 49% either had persistent diarrhea or recurrence after resolution despite dose interruptions, reductions, or concomitant antidiarrheal therapy. Diarrhea severity was of mild or moderate severity in 96% of cases. In the 12-week study, antidiarrheal medication was used in 51% of patients treated with DAYBUE. Patients should stop taking laxatives before starting DAYBUE. If diarrhea occurs, patients should notify their healthcare provider, consider starting antidiarrheal treatment, and monitor hydration status and increase oral fluids, if needed. Interrupt, reduce dose, or discontinue DAYBUE if severe diarrhea occurs or if dehydration is suspected. Weight Loss: In the 12-week study, 12% of patients treated with DAYBUE experienced weight loss of greater than 7% from baseline, compared to 4% of patients who received placebo. In long-term studies, 2.2% of patients discontinued treatment with DAYBUE due to weight loss. Monitor weight and interrupt, reduce dose, or discontinue DAYBUE if significant weight loss occurs. Adverse Reactions: The common adverse reactions (≥5% for DAYBUE-treated patients and at least 2% greater than in placebo) reported in the 12-week study were diarrhea (82% vs 20%), vomiting (29% vs 12%), fever (9% vs 4%), seizure (9% vs 6%), anxiety (8% vs 1%), decreased appetite (8% vs 2%), fatigue (8% vs 2%), and nasopharyngitis (5% vs 1%). Drug Interactions: Effect of DAYBUE on other Drugs DAYBUE is a weak CYP3A4 inhibitor; therefore, plasma concentrations of CYP3A4 substrates may be increased if given concomitantly with DAYBUE. Closely monitor when DAYBUE is used in combination with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities. Plasma concentrations of OATP1B1 and OATP1B3 substrates may be increased if given concomitantly with DAYBUE. Avoid the concomitant use of DAYBUE with OATP1B1 and OATP1B3 substrates for which a small change in substrate plasma concentration may lead to serious toxicities. Use in Specific Population: Renal Impairment DAYBUE is not recommended for patients with moderate or severe renal impairment. DAYBUE is available as an oral solution (200 mg/mL). Please read the accompanying full Prescribing Information, also available at DAYBUE.com About Acadia Pharmaceuticals Acadia is advancing breakthroughs in neuroscience to elevate life. For 30 years we have been working at the forefront of healthcare to bring vital solutions to people who need them most. We developed and commercialized the first and only FDA-approved drug to treat hallucinations and delusions associated with Parkinson’s disease psychosis and the first and only FDA-approved drug for the treatment of Rett syndrome. Our clinical-stage development efforts are focused on Prader-Willi syndrome, Alzheimer’s disease psychosis and multiple other programs targeting neuropsychiatric symptoms in central nervous system disorders. For more information, visit us at Acadia.com and follow us on LinkedIn and Twitter. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements other than statements of historical fact and can be identified by terms such as “intends,” “may,” “will,” “should,” “could,” “would,” “expects,” “plans,” “anticipates,” “believes,” “estimates,” “projects,” “predicts,” “potential” and similar expressions (including the negative thereof) intended to identify forward-looking statements. Forward-looking statements contained in this press release, include, but are not limited to, statements about: (i) the clinical benefits of DAYBUE and continued statistically significant efficacy observed in the DAYBUE Phase 3 clinical trial program, (ii) the safety and tolerability pro DAYBUE and anticipated Rett syndrome symptom improvements, and (iii) the timing and outcome of future results from, and continued enrollment and possible participation extensions in, the real world, observational LOTUS study. Forward-looking statements are subject to known and unknown risks, uncertainties, assumptions and other factors that may cause our actual results, performance or achievements to differ materially and adversely from those anticipated or implied by our forward-looking statements. Such risks, uncertainties, assumptions and other factors include, but are not limited to: our ability to continue to successfully commercialize DAYBUE, the timing, enrollment and results of ongoing and future clinical trials and our ability to continue to stay in compliance with applicable laws and regulations. Given the risks and uncertainties, you should not place undue reliance on these forward-looking statements. For a discussion of these and other risks, uncertainties, assumptions and other factors that may cause our actual results, performance or achievements to differ, please refer to our quarterly report on Form 10-Q for the period ended March 31, 2024 filed with the Securities and Exchange Commission on May 9, 2024, as well as our subsequent filings with the Securities and Exchange Commission from time to time. The forward-looking statements contained herein are made as of the date hereof, and we undertake no obligation to update them after this date, except as required by law. References 1 Acadia Pharmaceuticals Inc., Data on file. RTT US Prevalence. March 2022. 2 Fu C, Armstrong D, Marsh E, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatrics Open. 2020; 4: 1-14. 3 Kyle SM, Vashi N, Justice MJ. Rett syndrome: a neurological disorder with metabolic components. Open Biol. 2018; 8: 170216. 4 Acadia Pharmaceuticals Inc., Data on file. 5 Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999; 23(2): 185-188. 6 Fukuda T, Itoh M, Ichikawa T, et al. Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. J Neuropathol Exp Neurol. 2005; 64(6): 537-544. 7 Asaka Y, Jugloff DG, Zhang L, et al. Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis. 2006; 21(1): 217-227. 8 Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010; 68(6): 944-950. 9 Daniel C, Tarquinio DO, Hou W, et al. The changing face of survival in Rett syndrome and MECP2-related disorders. Pediatr Neurol. 2015; 53(5): 402-411. 10 Acadia Pharmaceuticals Inc., Data on file.

Clinical ResultPhase 3Drug Approval

27 May 2024

·www.prnewswire.com

Neuren Phase 2 trial shows significant improvements in Pitt Hopkins syndrome

Highlights: Statistically significant improvement from baseline assessed by both clinicians and caregivers in all four efficacy measures specifically designed for Pitt Hopkins syndrome (Wilcoxon signed rank test p<0.05) Clinician and caregiver global efficacy measures showed a level of improvement considered clinically meaningful: - Clinical Global Impression of Improvement (CGI-I) - mean score of 2.6, with 9 out of 11 children showing improvement assessed by clinicians - Caregiver Overall Impression of Change (CIC) – mean score of 3.0, with 8 out of 11 children showing improvement assessed by caregivers Improvements were seen in clinically important aspects of Pitt Hopkins syndrome, including communication, social interaction, cognition and motor abilities NNZ-2591 was safe and well tolerated, with no serious or severe adverse events and no meaningful trends in laboratory values or other safety parameters during treatment Second positive Phase 2 trial result further strengthens confidence in NNZ-2591's potential relevance for multiple neurodevelopmental disorders MELBOURNE, Australia, May 27, 2024 /PRNewswire/ -- Neuren Pharmaceuticals (ASX: NEU) today announced top-line results from its Phase 2 clinical trial of NNZ-2591 in children with Pitt Hopkins syndrome (PTHS). Statistically significant improvement from baseline was observed by both clinicians and caregivers from treatment, across all 4 efficacy measures that were specifically designed to assess the core characteristics of PTHS. There are no approved treatments for PTHS despite its severely debilitating impact on the lives of patients, as well as their parents and siblings. Neuren CEO Jon Pilcher commented "We are very excited about the results of this first clinical trial in Pitt Hopkins patients. This underserved community has such urgent unmet need and we can now continue towards our goal of developing a first approved treatment. We are very grateful to the people in the Pitt Hopkins community and at the trial sites in the United States who enabled the successful completion of this extremely challenging, but groundbreaking trial." Elliott Sherr, M.D., Ph.D., Professor of Neurology and Pediatrics at the University of California San Francisco, and Director, Brain Development Research Program was an investigator in the trial. Dr Sherr commented: "I am optimistic about the results in the PTHS specific measures. The mechanism of action of NNZ-2591 supports this response seen in PTHS and its potential in other highly impactful neurodevelopmental disorders." Dr. Nancy Jones, Neuren Vice President of Clinical Development commented: "The consistent results on the PTHS specific assessments affirm the need for syndrome specific measurements in severe neurodevelopmental disorders where measures that were developed for broader populations may not be as appropriate. Neuren appreciates the collaboration of Dr. Cassandra Newsom, Associate Professor at the University of Alabama, Birmingham (an investigator in the trial), the Pitt-Hopkins Research Foundation, and others who contributed to the development of these important measures." Study design The open label Phase 2 trial in 16 children aged 3 to 17 years (mean age 9 years) at five hospitals in the United States examined safety, tolerability, pharmacokinetics and efficacy over 13 weeks of treatment with NNZ-2591. NNZ-2591 was administered to all subjects as an oral liquid dose twice daily, with escalation in two stages up to the target dose of 12 mg/kg during the first 6 weeks of treatment, subject to independent review of safety and tolerability data. The study commenced with at least 4 weeks of screening and observation to thoroughly define baseline characteristics prior to treatment, followed by the treatment period of 13 weeks. A follow-up assessment was made 2 weeks after the end of treatment. The primary endpoints of this first trial in children with PTHS were safety, tolerability and pharmacokinetics. Secondary endpoints included four efficacy measures specifically designed for PTHS assessed by clinicians and by caregivers, as well as ten efficacy measures that were not designed for use in PTHS but have been used in other neurodevelopmental conditions. Safety and tolerability NNZ-2591 was well tolerated and demonstrated a good safety profile. All Treatment Emergent Adverse Events (TEAEs) were mild to moderate and most were considered not related to study drug. There were no Serious TEAEs and no meaningful trends in laboratory values, electrocardiogram (ECG) or other safety parameters were observed during treatment. 11 subjects completed the trial. One subject discontinued because they were unable to complete the safety monitoring procedures required by the study protocol. Four subjects discontinued due to TEAEs, all of which resolved. For two of those subjects the TEAEs (COVID-19 and mild vomiting/diarrhea/lethargy) were considered not related to study drug and for two subjects the TEAEs (moderate constipation/self-injury/abdominal distention/fatigue and mild sleep disorder/constipation) were considered related to study drug. Efficacy The mean improvement from baseline was statistically significant (Wilcoxon signed rank test p<0.05) for each of the four efficacy measures that were specifically designed for Pitt Hopkins syndrome, whether calculated for the subjects that completed the study (n=11), or including discontinued subjects (n=15). Changes from baseline were not statistically significant for the efficacy measures that were not designed for use in PTHS but have been used in other neurodevelopmental conditions. Results for efficacy measures specifically designed for Pitt Hopkins syndrome The results for the global measures rated by both clinicians and caregivers showed a level of improvement considered clinically meaningful. 9 out of 11 children that completed the trial showed improvement measured by the PTHS Clinical Global Impression of Improvement (CGI-I), an assessment by the clinician of the child's overall status compared with baseline. The mean CGI-I score was 2.6. Five children received a score of either 1 ("very much improved") or 2 ("much improved"). 8 out of 11 children that completed the trial showed improvement measured by the PTHS Caregiver Overall Impression of Change (CIC), an assessment by the caregiver of the child's overall status compared with baseline. The mean CIC score was 3.0. Four children received a score of 2 ("much improved"). 6 out of 11 children that completed the trial showed improvement measured by the PTHS Clinical Global Impression of Severity (CGI-S), an assessment by the clinician of the child's overall severity of illness, compared with the assessment at baseline. The CGI-S score improved from 6 to 5 for 3 children and from 5 to 4 for 3 children. 8 out of 11 children that completed the trial showed improvement measured by the Caregiver Top 3 Concerns overall score, an individualised assessment by the caregiver of their child's most concerning symptoms. Language/Communication was the most commonly chosen concern. Detailed results are available in the full announcement and investor presentation: About Pitt Hopkins syndrome Pitt Hopkins syndrome (PTHS) is a neurodevelopmental condition caused by the loss of one copy or a mutation of the TCF4 gene on chromosome 18. The incidence of PTHS has been estimated at between 1 in 34,000 and 1 in 41,000 people. Characteristics of PTHS are a range of developmental delay with moderate-to-severe intellectual disability and behavioral differences, hyperventilation and/or breath-holding while awake, seizures, gastrointestinal issues, lack of speech, sleep disturbance, stereotypic hand movements and distinctive facial features. Some individuals with PTHS are diagnosed with autism. Further information about PTHS is available at: About Neuren Neuren is developing new drug therapies to treat multiple serious neurological disorders that emerge in early childhood and have no or limited approved treatment options. Recognising the urgent unmet need, all programs have been granted "orphan drug" designation in the United States. Orphan drug designation provides incentives to encourage development of therapies for rare and serious diseases. DAYBUE™ (trofinetide) is approved by the US Food and Drug Administration (FDA) for the treatment of Rett syndrome in adult and pediatric patients two years of age and older. Neuren has granted an exclusive worldwide licence to Acadia Pharmaceuticals Inc. for the development and commercialisation of trofinetide. Neuren's second drug candidate, NNZ-2591, is in Phase 2 development for multiple neurodevelopmental disorders, with positive results achieved in Phase 2 clinical trials in Phelan-McDermid syndrome and Pitt Hopkins syndrome. ASX Listing Rules information This announcement was authorized to be given to the ASX by the board of directors of Neuren Pharmaceuticals Limited, Suite 201, 697 Burke Road, Camberwell, VIC 3124 Forward-looking Statements This announcement contains forward-looking statements that are subject to risks and uncertainties. Such statements involve known and unknown risks and important factors that may cause the actual results, performance or achievements of Neuren to be materially different from the statements in this announcement. SOURCE Neuren Pharmaceuticals Ltd

Clinical ResultOrphan DrugPhase 2Drug ApprovalLicense out/in

08 May 2024

·www.biospace.com

Acadia Pharmaceuticals Reports First Quarter 2024 Financial Results and Operating Overview

- First quarter NUPLAZID® (pimavanserin) net product sales of $129.9 million - First quarter DAYBUE™ (trofinetide) net product sales of $75.9 million SAN DIEGO--(BUSINESS WIRE)-- Acadia Pharmaceuticals Inc. (Nasdaq: ACAD) today announced its financial results for the first quarter ended March 31, 2024. “In the first quarter of 2024, Acadia delivered net product sales of $205.8 million, representing 74% revenue growth year over year, primarily due to the addition of our second commercial product, DAYBUE for the treatment of Rett syndrome, combined with growth in market share of NUPLAZID for the treatment of Parkinson’s disease psychosis,” said Steve Davis, Chief Executive Officer. “In addition, we are executing on our plans to bring DAYBUE to markets outside the U.S., continuing to enroll our late-stage trials in Prader-Willi syndrome and Alzheimer’s disease psychosis, and utilizing our financial strength to support our early-stage pipeline and business development opportunities.” Company Updates Seven posters accepted for presentation at the International Rett Syndrome Foundation’s Scientific Meeting to be held on June 18-19, 2024. These will include, among other topics, two encore presentations discussing outcomes from LILAC-2™, as well as findings from exit interviews with caregivers of individuals living with Rett syndrome who participated in the DAYBUE clinical trials supporting its approval. The company will also present a poster with additional real world patient and caregiver experiences from an analysis of an ongoing post marketing observational study. The Journal of Alzheimer’s Disease published favorable results from a Phase 3b trial evaluating the safety and tolerability of NUPLAZID (pimavanserin) in patients with neuropsychiatric symptoms related to neurodegenerative diseases 60 years of age and older. NUPLAZID was well-tolerated in this elderly, frail population, with a similar rate of treatment-emergent adverse events to the placebo group and did not impact motor or cognitive function versus placebo. Appointed Elizabeth H.Z. Thompson, Ph.D. as Executive Vice President, Head of Research and Development. Dr. Thompson joined Acadia’s executive leadership team. Financial Results Revenues Total revenues, comprised of net product sales from NUPLAZID and DAYBUE were $205.8 million for the three months ended March 31, 2024. Net product sales of NUPLAZID were $129.9 million for the first quarter of 2024, an increase of 10% as compared to $118.5 million for the first quarter of 2023. The increase in net product sales of NUPLAZID was due to 6% sell in growth and a 4% net price benefit in 2024 compared to 2023. Net product sales of DAYBUE were $75.9 million for the first quarter of 2024. There were no net product sales of DAYBUE in the first quarter of 2023. Research and Development Research and development expenses for the first quarter of 2024 were $59.7 million, compared to $69.1 million for the same period of 2023. The decrease in research and development expenses was mainly due to trofinetide commercial supply build that was expensed in the first quarter of 2023, prior to FDA approval. Post-approval inventory expenditures are expensed as part of cost of goods sold. Selling, General and Administrative Selling, general and administrative expenses for the first quarter of 2024 were $108.0 million, compared to $101.2 million for the same period of 2023. The increase in selling, general and administrative expenses was primarily driven by annualization of DAYBUE expenses as well as foundational investments to commercialize trofinetide outside the U.S. Net Income (Loss) For the first quarter of 2024, Acadia reported net income of $16.6 million, or $0.10 per common share, compared to a net loss of $43.0 million, or $0.27 per common share, for the same period in 2023. Net income for the three months ended March 31, 2024 included $14.8 million of non-cash stock-based compensation expense. Net loss for the three months ended March 31, 2023 included $14.7 million of non-cash stock-based compensation expense. Cash and Investments At March 31, 2024, Acadia’s cash, cash equivalents and investment securities totaled $470.5 million, compared to $438.9 million at December 31, 2023. Full Year 2024 Financial Guidance Acadia is reiterating all of its 2024 guidance provided on February 27, 2024. DAYBUE net product sales guidance in the range of $370 to $420 million. NUPLAZID net product sales guidance in the range of $560 to $590 million. R&D expense in the range of $305 to $325 million. SG&A expense in the range of $455 to $480 million. Conference Call and Webcast Information Acadia will host a conference call to discuss the first quarter 2024 results today, Wednesday, May 8, 2024 at 1:30 p.m. PT/4:30 p.m. ET. The conference call will be available on Acadia’s website, Acadia.com, under the investors section and will be archived there until June 7, 2024. The conference call may also be accessed by registering for the call here. Once registered, participants will receive an email with the dial-in number and unique PIN number to use for accessing the call. About NUPLAZID® (pimavanserin) Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors. These receptors are thought to play an important role in neuropsychiatric disorders. In vitro, pimavanserin demonstrated no appreciable binding affinity for dopamine (including D2), histamine, muscarinic, or adrenergic receptors. Pimavanserin was approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis by the U.S. Food and Drug Administration in April 2016 under the trade name NUPLAZID. About DAYBUE™ (trofinetide) Trofinetide is a synthetic version of a naturally occurring molecule known as the tripeptide glycine-proline-glutamate (GPE). The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown. Trofinetide was approved for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older by the U.S. Food and Drug Administration in March 2023 under the trade name DAYBUE. About Acadia Pharmaceuticals Acadia is advancing breakthroughs in neuroscience to elevate life. For 30 years we have been working at the forefront of healthcare to bring vital solutions to people who need them most. We developed and commercialized the first and only FDA-approved drug to treat hallucinations and delusions associated with Parkinson’s disease psychosis and the first and only FDA-approved drug for the treatment of Rett syndrome. Our clinical-stage development efforts are focused on Prader-Willi syndrome, Alzheimer’s disease psychosis and multiple other programs targeting neuropsychiatric symptoms in central nervous system disorders. For more information, visit us at Acadia.com and follow us on LinkedIn and Twitter. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements other than statements of historical fact and can be identified by terms such as “may,” “will,” “should,” “could,” “would,” “expects,” “plans,” “anticipates,” “believes,” “estimates,” “projects,” “predicts,” “potential” and similar expressions (including the negative thereof) intended to identify forward-looking statements. Forward-looking statements contained in this press release, include, but are not limited to, statements about: (i) our business strategy, objectives and opportunities, including support for our early-stage pipeline and business development opportunities; (ii) plans for, including timing, development and progress of commercialization or regulatory timelines for, NUPLAZID, DAYBUE (both within and outside the U.S.) and our product candidates; (iii) benefits to be derived from and efficacy of our products, including the potential advantages of NUPLAZID and DAYBUE; (iv) the timing and conduct of our clinical trials, including continued enrollment of our clinical trials in Prader-Willi syndrome and Alzheimer’s disease psychosis, and the timing and content of our presentations regarding our clinical trials; and (v) our estimates regarding our future financial performance, profitability or capital requirements, including our full year 2024 financial guidance. Forward-looking statements are subject to known and unknown risks, uncertainties, assumptions and other factors that may cause our actual results, performance or achievements to differ materially and adversely from those anticipated or implied by our forward-looking statements. Such risks, uncertainties and other factors include, but are not limited to: our dependency on the continued successful commercialization of NUPLAZID and DAYBUE and our ability to maintain or increase sales of NUPLAZID or DAYBUE; our plans to commercialize DAYBUE outside the U.S.; the costs of our commercialization plans and development programs, and the financial impact or revenues from any commercialization we undertake; our ability to obtain necessary regulatory approvals for our product candidates and, if and when approved, market acceptance of our products; the risks associated with clinical trials and their outcomes, including risks of unsuccessful enrollment and negative or inconsistent results; our dependence on third-party collaborators, clinical research organizations, manufacturers, suppliers and distributors; the impact of competitive products and therapies; our ability to generate or obtain the necessary capital to fund our operations; our ability to grow, equip and train our specialized sales forces; our ability to manage the growth and complexity of our organization; our ability to maintain, protect and enhance our intellectual property; and our ability to continue to stay in compliance with applicable laws and regulations. Given the risks and uncertainties, you should not place undue reliance on these forward-looking statements. For a discussion of these and other risks, uncertainties and other factors that may cause our actual results, performance or achievements to differ, please refer to our quarterly report on Form 10-Q for the quarter ended March 31, 2024 as well as our subsequent filings with the Securities and Exchange Commission from time to time, including our annual report on Form 10-K for the year ended December 31, 2023. The forward-looking statements contained herein are made as of the date hereof, and we undertake no obligation to update them after this date, except as required by law. ACADIA PHARMACEUTICALS INC. CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (in thousands, except per share amounts) (Unaudited) Three Months Ended March 31, 2024 2023 Revenues Product sales, net $ 205,831 $ 118,462 Total revenues 205,831 118,462 Operating expenses Cost of product sales (1)(2) 22,951 1,667 Research and development (2) 59,679 69,144 Selling, general and administrative (2) 107,991 101,235 Total operating expenses 190,621 172,046 Income (loss) from operations 15,210 (53,584 ) Interest income, net 5,506 3,800 Other income 286 4,845 Income (loss) before income taxes 21,002 (44,939 ) Income tax expense (benefit) 4,447 (1,918 ) Net income (loss) $ 16,555 $ (43,021 ) Earnings (net loss) per share: Basic $ 0.10 $ (0.27 ) Diluted $ 0.10 $ (0.27 ) Weighted average common shares outstanding: Basic 164,798 162,263 Diluted 166,623 162,263 (1) Includes license fees and royalties (2) Includes the following stock-based compensation expense Cost of product sales, license fees and royalties $ 153 $ 168 Research and development $ 4,093 $ 3,972 Selling, general and administrative $ 10,504 $ 10,565 ACADIA PHARMACEUTICALS INC. CONDENSED CONSOLIDATED BALANCE SHEETS (in thousands) March 31, 2024 December 31, 2023 (unaudited) Assets Cash, cash equivalents and investment securities $ 470,520 $ 438,865 Accounts receivable, net 94,701 98,267 Interest and other receivables 5,378 4,083 Inventory 61,936 35,819 Prepaid expenses 42,761 39,091 Total current assets 675,296 616,125 Property and equipment, net 4,370 4,612 Operating lease right-of-use assets 54,280 51,855 Intangible assets, net 110,204 65,490 Restricted cash 5,770 5,770 Long-term inventory 4,707 4,628 Other assets 476 476 Total assets $ 855,103 $ 748,956 Liabilities and stockholders’ equity Accounts payable $ 19,332 $ 17,543 Accrued liabilities 311,265 236,711 Total current liabilities 330,597 254,254 Operating lease liabilities 49,189 47,800 Other long-term liabilities 11,273 15,147 Total liabilities 391,059 317,201 Total stockholders’ equity 464,044 431,755 Total liabilities and stockholders’ equity $ 855,103 $ 748,956

Clinical ResultDrug ApprovalFinancial StatementPhase 3Executive Change

100 Deals associated with Trofinetide

External Link

KEGG	Wiki	ATC	Drug Bank
-	Trofinetide	-	DB06045

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Rett Syndrome	US	ACADIA Pharmaceuticals, Inc.	10 Mar 2023

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Nervous System Diseases	NDA/BLA	-	ACADIA Pharmaceuticals, Inc.	-
Brain Concussion	Phase 2	US	Neuren Pharmaceuticals Ltd.	01 Sep 2014
Fragile X Syndrome	Phase 2	US	Neuren Pharmaceuticals Ltd.	01 Jan 2014
Brain Injuries, Traumatic	Phase 2	US	Neuren Pharmaceuticals Ltd.	01 Apr 2010

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04988867 (DAFFODIL, AAN2024) Manual	Phase 2/3	Rett Syndrome	12	Trofinetide	lkyjiqfucy(qlxiilfjrs) = Diarrhea (80.0%) and vomiting (53.3%) were the most common TEAEs, all of mild/moderate severity. mvihqpntml (kwxuyrplai ) View more	Positive	13 Apr 2024
AAN2024 Manual	Not Applicable	Rett Syndrome	325	Trofinetide	ayltrmwhde(neosglxmkx) = geoqlrvwwo erhonwagcj (uiownekzty )	Positive	13 Apr 2024
NCT04279314 (CTgov)	Phase 3	Rett Syndrome	154	Trofinetide	kkdtnwgryt(mqsxblooti) = pazkofdpcy fgtvmbbpqc (vqqekuhfir, mrqvddjctr - yuozaaiwpp) View more	-	11 Apr 2024
NCT04181723 (CTgov)	Phase 3	Rett Syndrome	187	Trofinetide (Drug - Trofinetide)	bkmgqauzle(spbwvktmgj) = grdreplzhc hsjnftxatm (qzmmnavozy, jgryrgmyxx - yceetcedtp) View more	-	08 Apr 2024
				Placebo (Placebo)	bkmgqauzle(spbwvktmgj) = ruobyobatd hsjnftxatm (qzmmnavozy, oilqfnbxqc - jnmyzqwzng) View more
LAVENDER study (AAN2023)	Phase 3	Rett Syndrome	-	Trofinetide	uexuqqxqxb(bfxbcwyilv): P-Value = 0.0257 View more	Positive	25 Apr 2023
				Placebo
NCT04181723 (FDA) Manual	Phase 3	Rett Syndrome	187	DAYBUE	uwmoprhxmf(wmegrwqixc) = yzvocpnxwr benkgxcjob (opvsxxcqil, 0.08) View more	Positive	10 Mar 2023
				placebo	uwmoprhxmf(wmegrwqixc) = npqnosbord benkgxcjob (opvsxxcqil, 0.06) View more

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