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Data shows L1-79 offers a statistically significant improvement compared to placebo in socialization, as well as the investigator- and parent-rated global impression scales The change over placebo may be one of the largest statistically significant effects observed with the Vineland-3 Socialization standard score for a medication in autism NEW YORK, July 30, 2024 (GLOBE NEWSWIRE) -- Yamo Pharmaceuticals, a clinical stage pharmaceutical company, announced today positive topline results of its Phase 2 clinical trial evaluating the effects of L1-79 in adolescents and young adults with autism spectrum disorder (ASD). The data demonstrated a statistically significant improvement with L1-79 compared to placebo on the Vineland Adaptive Behavior Scale (Vineland-3) Socialization standard score (difference compared to placebo: 7.09, p-value = 0.02) during the first 12-weeks of the study. The Vineland-3 Socialization Domain is a well-established standardized assessment tool that looks at a person’s coping skills, ability to engage in play, and leisure and interact with others. In addition, other endpoints, such as the Clinical Global Impression of Severity of Illness (CGI-S) and the Caregiver Global Impression of Change of 3 Most Bothersome Symptoms of ASD (CGI-3P), demonstrated statistically significant improvements with L1-79 compared to placebo, corroborating the Vineland-3 findings. L1-79 was generally safe and well tolerated. There were no serious adverse events or adverse events leading to withdrawal from the trial with L1-79. “It is very encouraging to see a more than seven-point improvement in the Socialization Domain of the Vineland-3,” said J. Thomas Megerian, MD, PhD, Yamo’s Chief Medical Officer. “We believe that this is one of the largest statistically significant effects observed to-date with a medication in ASD on the Vineland-3 Socialization standard score, representing a clinically meaningful improvement in one of the core domains of function affected by ASD. The Company is eager to meet with the FDA to discuss Phase 3 plans, as well as to file for Breakthrough Therapy designation.” “We are excited to receive these results in the hope to offer patients and their families a treatment option that can impact the core symptoms of ASD,” said Chuck Bramlage, Yamo’s Chief Executive Officer. About L1-79Evidence suggests that dysfunction in the catecholaminergic system may play a role in the core symptoms of ASD. L1-79 is a tyrosine hydroxylase inhibitor expected to modulate the catecholaminergic pathways, and thereby improve the core ASD symptoms. L1-79 was granted Fast Track designation by the FDA in May of 2018. About the StudyThis Phase 2, multi-center, randomized, chronic-dosing (12-week) clinical trial was a two-period placebo-controlled crossover trial that enrolled 58 adolescent and young adults with ASD. Patients were randomized 1:1 to one of two active treatment groups: L1-79 200 mg or 300 mg. On day one of Period 1, participants in each dosing group were randomized to receive either L1-79 or placebo BID for 12-weeks. Following the conclusion of Period 1, participants underwent a six-week washout period and then crossed over into Period 2, in which each participant that received placebo in Period 1 received L1-79 and vice versa BID for another 12-weeks. Please refer to study identifier NCT05067582 at www.clinicaltrials.gov for additional clinical trial details. About Autism Spectrum DisorderAutism spectrum disorder or autism refers to a group of complex neurodevelopment disorders that is defined in the Diagnostic and Statistics Manual of Mental Disorders V (DSM-5) by “difficulties in social communication and social interaction, and restricted and repetitive behavior, interests or activities.” In the U.S., it is estimated that 1 in 36 children have ASD, with boys being 3.8 times more likely to be diagnosed than girlsi. Symptoms of repetitive and characteristic patterns of behavior and difficulties with social-communication and interaction start early in childhood and continue throughout a person’s life. While the causes of ASD are not known, research suggests that both genes and environment play important roles. Since the severity, specific types of symptoms, and causes of ASD vary between individuals, it is referred to as a “spectrum’ disorder.” Currently there are no approved pharmacological therapies which address the core symptoms of ASD. About Yamo PharmaceuticalsYamo Pharmaceuticals is a clinical stage pharmaceutical company founded in 2015 to develop L1-79, a novel therapy with the potential to improve the core symptoms of ASD. Yamo Pharmaceuticals is a privately held company. More information may be found at www.yamopharma.com. Safe Harbor StatementThis press release contains “forward-looking statements” concerning the development and commercialization of Yamo Pharmaceuticals’ products, the potential benefits and attributes of such products, and Yamo Pharmaceuticals expectations regarding its prospects. Forward-looking statements are subject to risks, assumptions and uncertainties that could cause actual future events or results to differ materially from such statements. These statements are made as of the date of this press release. Actual results may vary. Yamo Pharmaceuticals undertakes no obligation to update any forward-looking statements for any reason. Contact DataInvestor and Media ContactsChuck Bramlage, CEOcbramlage@yamopharma.com Eugene Prahin, CFOeprahin@yamopharma.com(212) 610-1570 i Maenner MJ, Warren Z, Williams AR, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020. MMWR Surveill Summ 2023;72(No. SS-2):1–14.

During pregnancy, the effects of therapeutical doses of amphetamine have been investigated on birth outcomes in humans. However, a thorough investigation of the mechanisms underlying the long-term effects of embryonal exposure to addictive doses of amphetamine remains largely unexplored. Using a tiny worm, researchers have revealed the underlying mechanisms of embryonal exposure to methamphetamine (Meth) and amphetamines, a psychostimulant used to treat a variety of brain dysfunctions. Amphetamine is a psychostimulant that has been used to treat a variety of brain dysfunctions. However, it is a highly abused drug. In fact, amphetamine and amphetamine-derived compounds such as methamphetamine (Meth) are among the most abused psychostimulants in the world. The neurological effects caused by acute or chronic use of amphetamine have been broadly investigated and several studies have shown that proteins involved in the synthesis, storage, release and reuptake of dopamine (DA), a neurotransmitter that plays a role as in the "reward" center, are either direct targets of or are indirectly affected by these drugs. During pregnancy, the effects of therapeutical doses of amphetamine have been investigated on birth outcomes in humans. However, a thorough investigation of the mechanisms underlying the long-term effects of embryonal exposure to addictive doses of amphetamine remains largely unexplored. Using a tiny worm, C. elegans, Florida Atlantic University researchers are the first who investigate the underlying mechanisms within the embryo after exposure to high concentrations of amphetamines, uncovering their long-lasting effects. For the study, researchers examined whether exposure to high doses of amphetamine throughout embryogenesis causes changes in the expression and function of two major dopaminergic proteins, tyrosine hydroxylase (TH) and vesicular monoamine transporter (VMAT). TH and VMAT both play important roles in the synthesis, storage and release of dopamine -- critical for various brain functions and behaviors. Results of the study, published in the International Journal of Molecular Sciences, show that following exposure to high doses of amphetamine during embryogenesis, the expression of specific genes in the dopaminergic system (dopamine transporter, TH and VMAT) is altered in adult C. elegans via epigenetic mechanisms. These modifications in gene and, consequently, proteins expression cause behavioral changes in adult animals such that animals that received amphetamine during embryogenesis were more susceptible to amphetamine-induced behaviors. "The dopaminergic response to amphetamines and the mechanisms underlying histone methylation are highly conserved across diverse species, which is why we used C. elegans to examine the long-term effects caused by embryonal exposure to amphetamines," said Lucia Carvelli, Ph.D., senior author and an associate professor of neuroscience, FAU Harriet L. Wilkes Honors College and a member of the FAU Stiles-Nicholson Brain Institute. "Importantly, although we used C. elegans as a model system, our goal is to understand how amphetamine works in humans." One advantage of the model the researchers used is that C. elegans embryos can develop outside the uterus and in the absence of maternal care. "Our results were not influenced by possible amphetamine-induced epigenetic or behavioral modifications passed through maternal care, but they are a direct consequence of biological alterations at the embryo," said Carvelli. Behavioral data from the research show that, following embryonic exposure to amphetamine, adult animals exhibit an increased response to amphetamines. This suggests that the altered expression of TH and VMAT caused by continuous exposure to amphetamines during embryogenesis generates animals that are hypersensitive to amphetamines. "Since our results are in agreement with data showing that mice overexpressing TH exhibit enhanced amphetamine-induced behaviors, and that rats chronically treated with amphetamine exhibit a long-lasting increase in striatal reuptake of dopamine, our findings establish C. elegans as an efficient and inexpensive model to study the long-lasting physiological modifications caused by prenatal exposure to amphetamine," said Carvelli. Study co-authors are Tao Ke, Ph.D., a post-doctoral researcher in the Carvelli lab; Kate E. Poquette, an undergraduate FAU student; and Sophia L. Amro Gazze, a student at FAU High School. This research was funded by the National Institute on Drug Abuse, National Institutes of Health (grant No. DA042156), awarded to Carvelli.

Pictured: A child covering his ears over a neuron background/Taylor Tieden for BioSpace With the prevalence of autism on the rise in the U.S., the biopharma industry is making a concerted effort to develop new treatments to alleviate the challenges associated with the neurological condition. Diagnoses of autism spectrum disorder (ASD) rose from 1 in 54 in 2016 to 1 in 36 in 2020, according to the Centers for Disease Control and Prevention. However, efforts by the biopharma industry to find treatments have also accelerated; more than 100 drugs are in trial or have completed studies, according to the autism news site Spectrum. But despite this significant push, challenges remain when it comes to developing a successful treatment for ASD. R&D Hurdles Remain One of the biggest hurdles involves measuring the condition precisely. Paul Wang, the director of clinical research associates and a senior clinical research scientist at the Simons Foundation, said that unlike in cancer, where specific metrics such as survival can be measured, or diabetes, where blood sugar can be precisely tracked, measuring improvements in autism is more of an “open question.” “Up to this point, the best things that we have are surveys and questionnaire rating scales, and . . . for kids and for those who have a more severe impairment, they can’t respond to those rating scales themselves,” Wang told BioSpace. “It depends on a parent’s impression or clinicians’ impression, and there’s always going to be a lot of imprecision and noisiness around that.” Additionally, Michael Tranfaglia, medical director and chief scientific officer at the FRAXA Research Foundation—an organization dedicated to finding treatments for Fragile X syndrome, the most common inherited cause of autism—told BioSpace that, despite ongoing research, the specific genetic mutations or factors causing ASD have yet to be determined. The heterogeneity of the condition poses another challenge, Tranfaglia said. Selective serotonin reuptake inhibitors (SSRIs) have been tested for ASD, but the results were “very disappointing” for this reason. “It was really hard to show that [SSRIs] worked in autism because we got a whole mixed bag of results.” He noted that there were subgroups of patients who appeared to have a “dramatically positive response,” while others got worse, and still others had no response at all. Wang agreed that one drug or treatment will not help 100% of individuals with ASD. Because of this, he said there has been a reluctance by most of the larger pharmaceutical companies to go into the ASD treatment space. Autism Candidates in the Clinic One large pharma bucking this trend is Roche. The company is investigating the small molecule alogabat, a highly selective positive allosteric modulator of the GABAA α5 receptor, which is expressed in brain regions that are key to ASD. Roche is investigating the molecule’s efficacy, safety and tolerability in an ongoing Phase II study for patients aged 15–45, a company spokesperson told BioSpace in an email, adding that alogabat has been safe and well tolerated so far. “No approved pharmacological treatment exists for the core social communication and social interaction deficits or restricted and repetitive behaviors of ASD, and this disorder continues to be an area of high-unmet medical need,” the spokesperson said. In Westchester County, New York, Curemark is on a mission to develop new therapies for neurodegenerative and neuro-developmental disorders, including ASD. Founder and CEO Joan Fallon told BioSpace that when autism was first emerging in the 1980s and 1990s, she noticed that affected patients were not eating very much protein. Investigating further, she found that children with ASD could not digest protein due to low enzyme activity. This spurred Fallon to launch Curemark in 2007. The company’s lead asset, an enzyme called CM-AT, aims to enhance protein digestion, restoring the essential amino acids in children to boost neurological performance. In November 2023, Curemark published long-term data from a clinical study of CM-AT in JAMA. Curemark reported that the trial, which investigated the irritability/agitation subscale of the Aberrant Behavior Checklist (ABC-I), showed a statistically significant difference for individuals taking CM-AT after 12 and 36 weeks. “What we saw in our trials gives me a lot of hope that the children can change, and there can be a sustained change for them over time,” Fallon said. Curemark is in the process of submitting a Biologics License Application for CM-AT and beginning more clinical trials. Also based in New York, Yamo Pharmaceuticals is developing L1-79, a tyrosine hydroxylase inhibitor that aims to improve communication and socialization in individuals with ASD by modulating the catecholaminergic pathways associated with the disorder. Yamo kicked off a Phase II trial in 2022 and is expecting results by early August. CEO Chuck Bramlage told BioSpace that two previous trials have shown “positive results.” Bramlage, the former CEO of Pearl Therapeutics, said he joined Yamo to get back to working in a therapeutic area with a massive unmet need, especially for children. “I feel bad for the parents of children with autism because they’ve been told a lot of things that would work, and nothing has,” he said. Still others are investigating existing medicines as potential treatments for ASD. Tarrytown, New York–based PaxMedica is studying PAX-101 (suramin), a therapy for human African trypanosomiasis, or African sleeping sickness, for autism. An over abundance of purines in cells can offset hemostasis and cause an overproduction of cellular adenosine triphosphate. Suramin targets extra purines with the aim of reducing the symptoms of ASD, PaxMedica CEO Howard Weisman told BioSpace. The company posted results from a 14-week proof-of-concept study of 44 ASD patients who completed the study in the Annals of General Psychiatry last year. Weisman said the results were “encouraging” and noted that PAX-101 was well-tolerated. Preclinical assets for ASD are also showing promise. Calgary-based Marvel Biosciences posted interim results of a study of MB-204, a derivative of an adenosine A2A receptor antagonist used to treat Parkinson’s disease, in early March. The study found that a single oral dose of MB-204 restored social deficits and enhanced certain social interaction behaviors to normal levels in an autism mouse model. Mark Williams, president and chief science officer at Marvel, told BioSpace that based on this result, the company is planning for Phase I study, which it expects to initiate in 2025. “I’m very hopeful that if we’re right, it’s possible that after a short course of therapy, you might see dramatic behavioral changes with people on a drug like [MB]-204,” he said. While these clinical and preclinical data are encouraging, Wang said it will take time to get autism treatments across the line. “The brain is the most complex organ in the body, and we just don’t understand it completely,” Wang said. Despite this, he expressed optimism that progress is being made toward a greater understanding of ASD, and said he is hopeful that “we will eventually get to the point where we have helpful supports.” Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.