Giuliana Grossi

Craig Granowitz, MD, Vice President and Chief Medical Officer, Lexicon Pharmaceuticals

 LX9211 has gained traction throughout September with 

 at PAINWeek 2022 National Conference on Pain Management and IASP World Congress on Pain. The therapeutic cadidate has displayed promising results for the treatment of neuropathic pain without any involvement in the opioid pathway.

The clinical trial (RELIEF-DPN 1) utilized a unique study design while investigators evaluating its impact on patients with 

. The full framework and analysis of the resutls will also be presented at Arrowhead's Annual Pain Therapeutics Summit in Washington DC on November 14. 

Craig Granowitz, MD, Chief Medical Officer and Senior Vice President of Lexicon Pharmaceuticals was excited to discuss the potential that LX9211 has on pain management, an area of medicine that has been impeded by various obstacles for decades. 

"Most of the other agents had been identified through serendipity—these were agents that had already been established for other uses and then were identified in a post marketing, or in a later stage of development, as potentially having an impact on pain," Granowitz explained in an interview with 

Part of what differentiates the drug candidate from current treatments is the intentional approach of its development and the 15-year journey which has showed a distinct pain state separating LX9211 from other approved neuropathic pain agents.

"If you look at the story of LX9211, that actually started based on a knockout mouse model that identified a phenotype of pain resistance, and then developing an understanding of that knockout gene, the mechanism of that gene, and then developing a specific oral inhibitor of that gene that mimicked the phenotype initially seen in mice," he continued. "Then bringing that forward into humans, demonstrating that this particular drug candidate can be delivered safely and effectively."

The pathway of neuropathic pain is very complex, and while current treatments like gabapentin and tricyclic antidepressants provide relief, Granowitz said that they come with a liability of adverse events. Furthermore, the complications associated with opioid use has been apparent in long-term opioid patients and on a societal level, as well. 

"We found in that, that this alpha adrenergic, what's called the off adrenergic neuron pathway, which sort of runs from the periphery of your body into the spinal cord, was specifically inhibited by this LX9211 compound through a gene target called AAK1," he said. "Now, this is the first and most advanced AAK1 that's in development."

Adaptor-associated protein kinase 1 (AAK1) inhibitors have been investigated before, but Granowitz explained that LX9211 is the only one active at this time. He's hopeful that the promising results demonstrated by this research "re-energizes" other neuropathic pain programs that were previously done, to take a closer look at the neuropathic pathway of pain

"Nothing creates change in a field like having a successful drug," he said. "We see that over and over again, is that one innovation breaks a dam open, and that there's a lot of additional innovation, and then there's significant movement forward in a field."

Articles

Dr. Craig Granowitz of Lexicon Pharmaceuticals details the success of the LX9211 clinical trial for painful diabetic neuropathy and the unique study design.

Novel Pain Therapy Addresses the Complex Pathway of Painful Diabetic Neuropathy

Sleep chronotypes are known to indicate various circadian-mediated metabolic and horomonal profiles, but a team of investigators aimed to further understand how the different chronotypes are affected by resting and exercise fuel use as it relates to insulin sensitivity. 

Those with early chronotypes have a tendency for insulin sensitivity due in part to their physical activity. However, the interaction between the chronotype variations in resting and/or exercise fuel oxidation and insulin action was not previously understood, according to investigators. 

"Collectively, this work highlights and supports chronotype as a potential risk factor related to type 2 diabetes and cardiovascular disease risk," the team wrote.

The investigation was led by Steven K. Malin, PhD, Department of Kinesiology and Health, Rutgers Uniersity, and the investigators used the Morningness-Eveningness Questionnaire (MEQ) and included invidividuals with metabolic syndrome according to the adults with metabolic syndrome (ATP III) criteria to classify early chronotypes and late chronotypes. 

The cross-sectional study included a total of 51 adults who were separated into a chronotype category and then assessed to determine if there were impacts related to each chronotype. Participating individuals had a sedentary lifestyle with less than 60 minutes each week of structured exercise, did not smoke, have cardiovascular disease, respiratory complications, known metabolic disease (such as type II diabetes, non-alcoholic fatty liver disease, etc.), or cancer (within the last 5 years). 

This study was part of a larger clinical trial in which all individuals had metabolic syndrome classified by ATP III guideline. 

Anyone using medication that affected substrate metabolism, blood flow or insulin sensitivity were excluded. Those who met the criteria underwent an electrocardiogram (resting/exercise), clinical biochemistries, as well as a medical examination.

The early chronotype group consisted of 24 adults, 19 were women, with the average age of 54.2 years, and 27 adults, with 23 women, were included in the late chronotype group with the average age of 55.3 years. While the demographics of the groups were similar, investigators found that those in the early chronotype had less sedentary behavior and more physical activity during the morning and midday than those who were categorized as late chronotypes, which correlated with some related measures.

When compared with the late chronotype, a higher measure of maximum oxygen intake during exercise (VO2 max), non-oxidative glucose disposal (NOGD), and resting fat oxidation (FOX) was observed in the early chronotype. During exercise, both chronotypes showed an increase in carbohydrate (CHO) reliance, though the early chronotype used more fat.

The key findings of the investigation indicated that adults with metabolic syndrome in the early chronotype utilize more fat as energy when engaing in fasted and moderate-high exercise compared with adults with a late chronotype. Overall, during high intensity exercise investigators observed elevated exercise fat oxidation was associated with non-oxidative glucose metabolism. 

"These findings occur independent of workload, suggesting that chronotype may be characterized by unique alterations in metabolism. Indeed, late chronotype participants were more sedentary and had lower aerobic fitness than early chronotypes. Interestingly, more light physical activity was positively related to metabolic insulin sensitivity, and higher fitness was related to increased exercise fat oxidation," investigators concluded.

Early chronotype with metabolic syndrome favours resting and exercise fat oxidation in relation to insulin-stimulated non-oxidative glucose disposal

"Collectively, this work highlights and supports chronotype as a potential risk factor related to type 2 diabetes and cardiovascular disease risk," investigators wrote.

How Insulin Sensitivity and Fat Oxidation Relate to Early, Late Sleep Chronotype

Experiencing a nightmare is a common phenomenom, particularly among the general adolescent population. Various consequences have been linked to nightmares and can have a severe impact on 

, even leading to increased risk of suicide.

The experience has been characterized as dysphoric, frightening, or disturbing dreams that can inflict intense irritability and lead to 

. As the prevalence of nightmares experienced by an individual increases, so does their vulnerability for 

, daytime sleepiness, anxiety and depressive symptoms, post-traumatic stress disorder (PTSD), behavioral problems, and impaired psychosocial function.

While previous evidence has shown that adults with major depressive disorder (MDD), bipolar disorders, or schizphrenia encounter this dysphoric dream state more frequently than the general population, there's a lack of evidence when it comes to adolescents with MDD.

Insomnia, Nightmares & Depression in Adolescents

Investigators including Shuang-Jiang Zhou; Jing-Xu Chen, Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School,  aimed to amend the gap in literature regarding nightmare prevalence among adolescents with major depressive disorder. The team conducted a large-scalem cross-sectional investigation in outpatient centers at 4 large psychiatric hospitals in China from January-October 2021. 

Participating individuals were between the ages of 12-18 years old with a diagnosis of major depressive disorder according to the DSM-IV who were not receiving any treatment at the time of their depressive episode. Those with significant physical illness, another mental illness, substance abuse or dependency, were pregnant, or had undergone treatment with electroconvulsive therapy in that last month were excluded. The healthy control group was matched by gender and age with no personal or family history of mental illness.

The analysis measures consisted of insomnia, daytime sleepiness, nightmare frequency, nightmare distress, depression severity, anxiety severity, and suicide risk. 

The Relationship Between Nightmares & Suicide Risk

Findings revealed that the group with depression had a higher proportion of insomnia and suicide risk, as well as an increased frequency of nightmares compared with the control group.

Of the adolescents with depression, 67.5% experienced nightmares within the previous month, which was compared with 28.7% among the control group. On a weekly basis, the rate for the control group was 6%, while the rate among the adolescents with depression was 28.7%. Both sets of relationships were deemed statistically significant. 

A statistically significant association was identified between suicide risk and nightmare frequency. Suicide risk was present in 38.1% of the group with depression, and of that subpopulation, 51.6% experienced frequent nightmares which was a significantly higer rate than those without risk of suicide. 

Investigators also observed that the suicide risk was higher among adolescents in a recurrent depressive episode compared to those experiencing their first. Severe nightmare distress in those at risk for suicide (54.7%) was notable compared to those without suicide risk (24.3%).

"In conclusion, the current study, which included a large clinical population, provides evidence that nightmares occur frequently among adolescent patients with MDD," investigators wrote.

"Furthermore, the results of this study demonstrate that nightmare distress is independently associated with an increased risk of suicide. These findings may have important implications for further research on night-suicide mechanisms and for identifying individuals who are at a risk of suicide by asking about nightmare distress. Since nightmares are potentially modifiable, and the clinical efficacy of psychotherapy is well documented, intervention programs aimed at addressing nightmare-related distress may play an important role in preventing suicide among adolescents with MDD."

Nightmare Distress as a Risk Factor for Suicide Among Adolescents with Major Depressive Disorder

Various consequences have been linked to nightmares and can have a severe impact on mental health, even leading to increased risk of suicide.

Higher Risk of Suicide Observed in Adolescents Suffering from Nightmare Distress

New evidence from a Mount Sinai study suggested that consistent lack of 

 has negative effects on immune stem cells and increases the risk of inflammatory disorders and 

. And while it might be thought that a period of inadequate sleep can be amended by catching up on sleep, findings indicated that the cellular effects can’t be reversed.

This study is the first to demonstrate the relationship between sleep and DNA within the immune cells–particularly, that sleep alters the structure of this DNA. Consistently cutting sleep short, even for 90 minutes a night, can lead to increased vulnerability to disease and negative impacts.

“This is important because it is yet another key observation that sleep reduces inflammation and, conversely, that sleep interruption increases inflammation,” Filip Swirski, PhD, Director of the Cardiovascular Research Institute at Icahn Mount Sinai, and lead investigator, said in a 

. “This work emphasizes the importance of adults consistently sleeping seven to eight hours a day to help prevent inflammation and disease, especially for those with underlying medical conditions.”

Does 90 Minutes of Sleep Make a Difference?

Swirski and his team conducted the investigation by evaluating the immune cells of 14 healthy adults who regularly achieved 8 hours of sleep each night and assessed their sleep for a duration of 6 weeks. Investigators continued to analyze their immune cells for the following 6 weeks while participating individuals reduced their sleep duration by 90 minutes each week.

Upon comparison, the team discovered significant changes in the samples of immune cells collected from the periods of full sleep and restricted sleep. At the conclusion of the 12th week, an increased number of immune cells were present in blood samples, due to the lack of sleep.

“This study begins to identify the biological mechanisms that link sleep and immunological health over the long-term,” Swirski stated. “It shows that in humans and mice, disrupted sleep has a profound influence on the programming of immune cells and rate of their production, causing them to lose their protective effects and actually make infections worse—and these changes are long-lasting.”

Investigators also observed an altered DNA structure was present in each participating individual, suggesting that recovering lost sleep time is not able to completely reverse the impact that inadequate sleep has.

“Our findings suggest that sleep recovery is not able to fully reverse the effects of poor-quality sleep,” Cameron McAlpine, PhD, Assistant Professor of Medicine at Icahn Mount Sinai, and co-lead investigator, stated. “We can detect a molecular imprint of insufficient sleep in immune stem cells, even after weeks of recovery sleep. This molecular imprint can cause the cells to respond in inappropriate ways leading to inflammation and disease.”

“It was surprising to find that not all clusters of stem cells responded to insufficient sleep in the same way,” he continued. “There were some stem cell clusters that proliferated and grew in number, while other clusters became smaller. This reduction in overall diversity and aging of the immune stem cell population is an important contributor to inflammatory diseases and cardiovascular disease.”

Sleep exerts lasting effects on hematopoietic stem cell function and diversity

New evidence from a Mount Sinai study suggested that consistent lack of sleep has negative effects on immune stem cells and increases the risk of inflammatory disorders and heart disease.