The Seropeutics Story

Seropeutics is an early-stage pharmaceutical company that is advancing breakthrough therapies to treat the orphan indication Fragile X syndrome. We are positioned to deliver two first-in-class drug candidates for clinical development within 12 months of program funding. The lead from our first platform, SERx – 519, is directed at the core Fragile X symptoms that occur in most patients (repetitive behaviors, social deficits, anxiety, cognitive dysfunction); and our second platform candidate, SERx – 480, is focused on the other symptoms that appear frequently in Fragile X syndrome (attention deficit, hyperactivity, psychosis/mania). Both platforms target brain serotonin receptors, an area of intense research over the last two decades. Currently, 18 serotonin receptors are known, several of which have been the targets of commercially successful therapies. What distinguishes Seropeutics is the identification of two distinct, first-in-class chemotypes that selectively modulate novel combinations of serotonin receptors. The unique serotonin receptor activities we have achieved offers the potential to bring efficacious treatments forward for Fragile X syndrome, while dramatically reducing risk of side effects. Seropeutics intends on filing separate INDs for both candidates in 2017 and will seek orphan status for both programs.

Fragile X Syndrome

Fragile X syndrome is the most common monogenetic form of autism spectrum disorder (ASD). In addition to core ASD symptoms such as repetitive stereotypical behaviors and deficits in social functioning, there is cognitive impairment and anxiety in Fragile X syndrome. In addition, hyperactivity, attention deficit, psychosis/mania, hypersensitivity to sensory stimuli, and/or increased seizure potential also may be evident. The cause of Fragile X syndrome involves an inherited mutation in the fragile X mental retardation 1 gene (FMR1) that results in gene silencing, and the loss of FMR1 protein expression that is critical for normal neuronal function. Fragile X syndrome is typically diagnosed at 2 to 3 years based on symptoms and confirmed by genetic analysis—well after significant neuronal impairment has occurred.

There are no approved drugs for treating the core symptoms of Fragile X syndrome. Depending on the patient, anti-anxiety agents or serotonin selective reuptake inhibitors (SSRIs) can mitigate some of the behaviors that accompany Fragile X syndrome; however, limited efficacy may be achieved and side effects are a frequent issue. Drugs that effectively treat Fragile X syndrome, designated as an orphan disease, represent a major unmet need for afflicted children and older patients.

Therapeutic Strategies for CNS Disorders

The most common approach for treating any CNS disorder, including Fragile X syndrome, involves modulation of the complex array of neurotransmitters and receptors that are in homeostasis in the healthy human brain, but become unbalanced in a disease state. The neurotransmitter serotonin (5-hydroxytryptamine, 5HT) and its 18 receptors play a central role in normal brain function. This critical system has been the focus of decades-long drug research that has yielded commercially successful drug classes for treating depression, anxiety, migraine, and other CNS disorders. Importantly, it is now known that disruption in serotoninergic neurotransmission plays a prominent role in Fragile X syndrome. However, there were two big challenges in pursuing this approach: identifying which serotonin receptors and associated functions need to be modulated to treat Fragile X symptoms, and then developing drug molecules that selectively impact only those receptors’ functional activities. Previous work in this area has shown that selective receptor modulation is very difficult to achieve. Lack of such selective receptor function modulation is a problem with virtually all current CNS drugs, which leads to a wide range of significant side effects.

‘Threading the Needle’ in Achieving Selective Receptor Function Modulation

Seropeutics is an early-stage company that is taking a targeted approach in the development of drugs to treat Fragile X syndrome with the goal of ‘threading the needle’ with respect to achieving high target selectivity and appropriate function, with minimal off-target receptor binding that can lead to side effects. Our strategy has been to use structure-based drug design to develop selective modulators of key serotonin (5HT) receptors believed to be involved in Fragile X syndrome and test them in validated animal models for predicting therapeutic efficacy. What have emerged from our program are two distinct, first-in-class drug series that selectivity modulate the activity of unique combinations of serotonin receptor subtypes.

SERx – 500 Series

Our SERx – 500 series chemotype has a unique profile with 5HT1A, 5HT2C, and 5HT7 receptor partial agonist activity. Our lead compound, SERx – 519, is highly effective in decreasing repetitive behaviors and motor stereotypy, and increasing social functioning in multiple Fragile X syndrome and autism mouse models, suggesting efficacy in treating core Fragile X symptoms. Partial activation of 5HT1A receptors alleviates stereotyped (repetitive) behaviors and social anxiety, while partial activation of 5HT2C and 5HT7 receptors produces pro-cognitive effects. Importantly, we have achieved this high 5HT1A/2C/7 selective activation with minimal effects at other receptors, which represents a unique receptor modulation profile—no other drug class achieves this. We anticipate that our lead will have minimal side effects, such as suppression of locomotor activity, sedative/stimulant activity, or cognitive impairment seen with other drugs.

SERx – 400 Series

We have also developed a SERx – 400 series that exhibits a different, but complementary, pharmacological profile that has potential for treating additional symptoms that often accompany Fragile X syndrome and other autistic disorders. Our SERx – 400 series selectively enhances 5-HT2C signaling while reducing 5-HT2A/2B signaling. As with our SERx – 500 series, this represents a first-in-class pharmacological profile and we believe that our SERx – 400 lead, SERx – 480, has potential to address cognitive dysfunction, attention deficit, hyperactivity, and psychosis associated with Fragile X syndrome and autism. We anticipate that SERx – 480 will not produce the sedative or weight gain side effect that typically accompany other antipsychotic drugs frequently used in Fragile X patients.

Preclinical evaluation of our SERx – 500 and SERx – 400 series has confirmed that both platforms have favorable pharmacological profiles: they selectively modulate serotonin receptor activities with minimal off-target effects, demonstrate therapeutic efficacy and safety in animal models with oral dosing; there is available extensive PK/metabolic profiling data; there is no toxicity observed in preclinical models. In addition, the necessary chemistry is in place for scale-up to support advanced studies of both candidates. Seropeutics has broad intellectual property rights to both series with multiple issued patents, applications and anticipated filings.

Seropeutics Strategic Plan

Seropeutics intends on advancing its SERx – 500 and SERx – 400 lead compounds for treating their respective target Fragile X symptoms. Based on work done to date, we are positioned to file INDs for both candidates approximately 12 months after program funding. We have completed preliminary CMC work and will advance to next steps required for an IND submission. In parallel, we have engaged top KOLs for clinical trial design based on objective measurable endpoints to ensure reliable and efficient assessment of therapeutic efficacy.  Seropeutics is also working with external partners to develop the best strategy for achieving orphan drug status for both of our Fragile X therapeutic candidates.