Disruptive, Impulse Control, and Conduct Disorders

After coming up short in a phase 3 trial for the second time, Otsuka has discontinued development of AVP-786. The drug was under investigation as a therapy for agitation that can accompany Alzheimer's disease. Otsuka Pharmaceutical is packing up an Alzheimer’s disease med after a phase 3 study failed to move the needle on measures of agitation associated with dementia.   The results were originally issued in February, with Otsuka reporting that AVP-786 did not achieve the primary endpoint that measured a change in baseline on a rating scale of agitation compared with placebo. The therapy had been under development through Otsuka’s U.S. subsidiaries for agitation associated with dementia due to Alzheimer's. At the time, Otsuka did not have full details of the study to present. In announcing the termination of AVP-786 today, the Japanese pharma is still keeping those details under wraps. AVP-786 has traveled a bumpy path through the clinic, including failing a different phase 3 trial in 2019. That disappointment for the NMDA receptor antagonist came just months after Otsuka posted positive results for AVP-786 in a separate phase 3 trial. Otsuka acquired AVP-786 from CNS specialist Avanir Pharmaceuticals in a 2015 buyout worth $3.5 billion. Also coming in that deal was Nuedexta, a treatment approved in 2010 for pseudobulbar affect (PBA), a rare disorder that causes outbursts of laughing or crying that accompany some neurological conditions. Nuedexta uses the same chemical compound—dextromethorphan hydrobromide and quinidine sulfate—as AVP-786. Otsuka also investigated AVP-786 in early-stage trials for intermittent explosive disorder, schizophrenia and traumatic brain injury.

Pictured: Collage of a brain and stem cells/Taylor Tieden for BioSpace Could stem cell therapies make the Parkinsonian brain generate dopamine again? Some companies, including BlueRock Therapeutics and International Stem Cell Corporation, are banking on it. Parkinson’s disease is currently treated with dopamine replacement agents, but the efficacy of these drugs is limited and they come with challenging side effects. Some in the stem cell field say these new therapies, though early-stage, could ultimately be a better, safer option. In a March 2024 report, GlobalData touted the “early promise” of cell therapies to address the motor and non-motor symptoms of Parkinson’s disease with minimal adverse effects. ‘Resetting the Clock’ With more than 10 million people around the world living with Parkinson’s disease, the treatment market is currently valued at $5.56 billion and is expected to reach $6.63 billion by 2029. A progressive disease of the nervous system, Parkinson’s is characterized by the degradation of neurons in the part of the brain that controls movement. The loss of these neurons slows the production of dopamine, leading to a combination of motor symptoms, including writhing movements, resting tremors and muscle stiffness, which can be lessened with levodopa and dopamine-agonists—drugs that behave like dopamine. The disease also brings non-motor symptoms, including depression, hyposmia, dysphasia and psychosis. Levodopa is currently the “gold standard” treatment for Parkinson’s. Although it provides a dopamine kick, the drug is laden with severe adverse effects, including hallucinations, dyskinesia and loss of impulse control. These side effects can occur a dopamine response is stimulated in several parts of the brain through medication, Agnete Kirkeby, a stem cell scientist at Lund University and the University of Copenhagen, told BioSpace. Levodopa also provides only a small window of relief for patients, Kirkeby said. In an emailed statement to BioSpace, GlobalData analysts Lorraine Palmer and Christie Wong said early clinical trials of stem cell transplantation in Parkinson’s have shown a reduction in motor and non-motor symptoms. “However, the subject size of these clinical trials have been small and were not powered to measure statistical significance,” they said, adding that large-scale, pivotal trials will be required to investigate how safely and how well the therapies work. “Currently, there are no therapies which recover lost dopaminergic neurons so if cell therapies do end up meeting their hopes of replacing dopaminergic neurons,” they could be market changers, Palmer and Wong said. During her postdoctoral days at Lund, Kirkeby, along with her supervisor, designed a method to grow transplantable dopamine cells from embryonic stem cells. “When we transplant the cells, we transplant [them] to a very particular region of the brain that is involved in motor control,” she explained. Kirkeby is currently leading a preclinical study of STEM-PD sponsored by Lund, a stem-cell therapy intended to replace lost dopamine neurons in the brains of Parkinson’s patients. Cambridge, Mass.–based BlueRock Therapeutics, a Bayer subsidiary, is also developing a stem cell–based therapy, called bemdaneprocel. “You can think about it almost like you’re resetting the clock for those people who live with Parkinson’s disease by providing them cells, which have the potential to integrate and re-establish some of the neural networks and circuitry in that part of the brain,” Ahmed Enayetallah, head of development at BlueRock, told BioSpace. Cell Therapies for Parkinson’s in the Pipeline There are currently seven stem cell therapies for Parkinson’s disease in Phase I clinical trials or later. Three of these—sponsored by BlueRock, Celavie Biosciences and International Stem Cell Corporation—have completed and published results. In the Phase I trial of bemdaneprocel, neuronal progenitor stem cells derived from donors were transplanted into 12 patients, whose progress was monitored for 18 months. During the first year, the patients were treated with immunosuppressive drugs. The cells survived and bemdaneprocel was tolerated by patients throughout the trial period, Enayetallah said, even after immunosuppression was discontinued. The trial met multiple clinical endpoints and broadened the window at which the patients experienced relief from disease symptoms, he added. Unlike with current treatments, Enayetallah said, there were no reported cases of dyskinesia or other adverse events except gastrointestinal bleeding and seizure, which he attributed to the surgical procedure and not the therapy itself. Having a one-time treatment for Parkinson’s disease would be a paradigm shift, Enayetallah said. Another therapy, ISC-hpNSC, is in development by California-based International Stem Cell Corporation. Upon completion of a Phase I trial, patients’ ON-Time—a period where Parkinson’s medications like levodopa bring about good motor control—increased by 65% over two years, and OFF-Time decreased by 55% within the same period, the company reported in June 2021. The cells were well-tolerated with no serious adverse events. With therapies such as these, Kirkeby said it is possible that the cells could overgrow and generate too many cells in the brain, but so far, neither trials of STEM-PD nor bemdaneprocel have recorded this adverse effect. And while stem cell therapies are currently aimed at relieving the motor symptoms of Parkinson’s, Enayetallah said bemdaneprocel’s trial results hint at improved quality of life and psychiatric outcomes. Kirkeby also indicated that her lab is working on stem cell therapies that would target non-motor symptoms such as cognitive impairment. Enayetallah noted that therapeutic development in Parkinson’s is “incredibly challenging” and plagued with the highest failure rates in drug development. However, he said, the results of BlueRock’s Phase I trial are a significant step toward bringing a “transformational therapy” to patients. “Cell therapy in neurology is something that hasn’t been explored to that extent before. We’re paving the road here.” Patience Asanga is a Nigeria-based freelance science journalist who writes about the environment, biotechnology and life sciences.

Findings to be presented at 2024 American Academy of Neurology annual conference between April 13-18 in Denver, CO PRINCETON, N.J., April 12, 2024 /PRNewswire/ -- Kyowa Kirin, Inc., an affiliate of Kyowa Kirin Co., Ltd. (Kyowa Kirin, TSE: 4151), a global specialty pharmaceutical company based in Japan, will announce findings from an updated systematic literature review (SLR) and meta-analysis comparing the safety of NOURIANZ® (istradefylline) in relation to other levodopa adjunctive therapies for patients with Parkinson's Disease (PD).1,2 NOURIANZ is an adenosine receptor antagonist used with levodopa/carbidopa to treat adults with PD experiencing "off" episodes, the return of Parkinson's symptoms between medication doses. The findings will be presented at the American Academy of Neurology (AAN) 2024 Annual Meeting, during a poster presentation on Monday, April 15, from 5:30 – 6:30 PM MDT. Parkinson's disease is a progressive, neurodegenerative disease characterized by motor symptoms such as tremors, rigidity, slow movement, and postural instability. Within 5 years of starting levodopa/carbidopa treatment, half of people living with PD begin to experience "off" time, including problems with movement.3 Adjunctive therapies may be used to treat these episodes but are often hampered by safety and tolerability issues that limit their clinical utility.1 "With the growing landscape of adjunctive therapies for Parkinson's disease, it is important for physicians to have data that demonstrates the relative risk profiles of these treatment options," said lead author Yasar Torres-Yaghi, MD, MedStar Georgetown University Hospital. "These data provide useful information on safety and tolerability of these therapies, an important factor for physicians when choosing an appropriate adjunctive therapy for patients experiencing "off" episodes." About the Study Researchers updated a previously published SLR with an additional 20 randomized controlled trials from Jan 1, 2010, to April 15, 2019, evaluating adjunctive therapies in patients with PD. The study analyzed data from a total of 57 randomized clinical trials involving 11,517 patients. Interventions included COMT inhibitors, monoamine oxidase type B (MAO-B) inhibitors, dopamine agonists (DAs), istradefylline, and amantadine ER. A pair-wise meta-analysis was conducted to calculate summary odds ratios (OR) and 95% confidence intervals (CI). Bucher indirect comparisons were used to generate estimates of relative safety, and information on study design, eligibility criteria, and baseline characteristics were extracted for heterogeneity assessment. About NOURIANZ® NOURIANZ is an adenosine receptor antagonist indicated as an adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson's disease (PD) experiencing "off" episodes. It is not known if istradefylline is safe and effective in children.4 Important Safety Information Warnings and Precautions Dyskinesia: NOURIANZ in combination with levodopa may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical trials, 1% of patients treated with either NOURIANZ 20 mg or 40 mg discontinued treatment because of dyskinesia, compared to 0% for placebo. Hallucinations / Psychotic Behavior: Because of the potential risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with NOURIANZ. Consider dosage reduction or discontinuation if a patient develops hallucinations or psychotic behaviors while taking NOURIANZ. Impulse Control / Compulsive Behaviors: Patients treated with NOURIANZ and one or more medication(s) for the treatment of Parkinson's disease (including levodopa) may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges. In clinical trials, 1 patient treated with NOURIANZ 40 mg was reported to have impulse control disorder, compared to no patient on NOURIANZ 20 mg or placebo. DRUG INTERACTIONS The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 mg once daily. Avoid use of NOURIANZ with strong CYP3A4 inducers. SPECIAL POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ADVERSE REACTIONS The most common adverse reactions with an incidence ≥5% and occurring more frequently than with placebo were dyskinesia (15%, 17%, and 8%), dizziness (3%, 6%, and 4%), constipation (5%, 6%, and 3%), nausea (4%, 6%, and 5%), hallucination (2%, 6%, and 3%), and insomnia (1%, 6%, and 4%) for NOURIANZ 20 mg, 40 mg, and placebo, respectively. You are encouraged to report suspected adverse reactions to Kyowa Kirin, Inc. at 1-844-768-3544 or FDA at 1-800-FDA-1088 or . Please click to see full Prescribing Information for Nourianz. About Kyowa Kirin Kyowa Kirin aims to discover and deliver novel treatments with life-changing value. As a Japan-based Global Specialty Pharmaceutical Company, we have invested in drug discovery and biotechnology innovation for more than 70 years and are currently working to engineer the next generation of antibodies and cell and gene therapies with the potential to help patients with high unmet medical needs, focusing on bone/mineral, intractable hematological diseases/hemato oncology, and rare diseases. A shared commitment to our values, to sustainable growth, and to making people smile unites us across the globe. You can learn more about the business of Kyowa Kirin at: kkna.kyowakirin.com References Torres-Yaghi Y., Qian, J. et al. (2024). Comparative Safety of Istradefylline Among Parkinson's Disease Adjunctive Therapies: A Systematic Review and Meta-Analysis of Randomized Controlled Studies. Data presented at the 2024 American Academy of Neurology Annual Meeting, April 13-18, 2024, Denver, CO. Stowe R et al. Movement disorders. 2011;26(4):587-98 Hickey, P., & Stacy, M. (2011). Available and Emerging Treatments for Parkinson's Disease: A Review. Drug Design, Development and Therapy, 5, 241-254. doi:10.2147/DDDT.S11836 NOURIANZ. Prescribing Information. Kyowa Kirin Inc. Princeton, NJ. SOURCE Kyowa Kirin