April, 24, 2024

Anktiva: A Novel Bladder Cancer Treatment

By Lindsay Cohen 

Bladder cancer is considered the 10th most common cancer diagnosed globally, with a predicted 83,190 cases and 16,840 deaths for 2024 in the United States.1 In 2010, an estimated 80% of bladder cancer cases at diagnosis were non-muscular-invasive bladder cancer (NMIBC), which is characteristic of cancer remaining in the inner layer of the bladder wall.2 The first-line standard of care for NMIBC is the intravesical installation of bacillus Calmette-Guérin (BCG). This therapy is bacteria that creates an immune response in the bladder near the cancer cells that causes clearance of cancer in the area for most patients. However, BCG is ineffective in around 30 to 40% of patients; 50% may also experience recurrence among those who initially respond.3,4

On April 22nd, the FDA approved Anktiva (nogapendekin alfa inbakicept-pmln) as a first-in class IL-15 agonist, and designated Anktiva as an FDA breakthrough therapy to treat NMIBC. This innovative immunotherapy utilizes the body's natural killer cells (NK), CD8+ killer T-cells, and CD4+ T helper cells to attack tumor cells.5,6 

Anktiva's approval was based on the QUILT-3.032 clinical trial, which was an open-label, single-arm, multicenter study. This phase 2/3 trial evaluated 77 patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors. Patients received Anktiva in combination with BCG for up to 37 months. Key findings from the study demonstrated that Anktiva achieved a complete response rate (CRR) of 62% (95% CI, 51-73). The median duration of response (DOR) extended beyond 47 months in some patients, while 58% of responding patients maintained their response for at least 12 months, with 40% reaching at least 24 months with a maintained response. The most common side effects patients experienced while taking Anktiva were elevated creatine levels, dysuria, hematuria, urinary frequency, and infections. Serious adverse events occurred in 16% of patients, with one fatal cardiac arrest recorded.7

Before the entry of Anktiva, the therapeutic options for BCG-unresponsive NMIBC were limited, relying on intravesical chemotherapy such as Mitomycin C or Gemcitabine that had limited efficacy and high rates of recurrence, Checkpoint inhibitors such as pembrolizumab that were only effective for a subset of patients, or radical cystectomy which involved the removal of the bladder surgically and resulted in significant quality of life reductions due to the invasiveness and associated complications.3

Anktiva has attained clinically meaningful complete response rates as defined by the International Bladder Cancer Group (IBCG), equating to a complete response of at least 50% at six months and 30% at 12 months, with a 25% CR rate recommended at 18 months. This CR is for carcinoma in situ or a recurrence-free rate for papillary tumors. Meeting and exceeding IBCR benchmarks, Anktiva, with its CR of over 47+ months, establishes durable, complete responses and fills a critical gap where previous therapies have fallen short. The place in therapy for Anktiva would not be a first-line agent but rather a combination therapy to be used with BCG after a patient no longer responds to BCG alone. This combination therapy is approved for usage for up to 37 months.5

The approval of Anktiva represents a significant advancement in treating BCG-unresponsive NMIBC, offering new hope to patients facing this challenging condition. By integrating Anktiva into the treatment landscape, healthcare providers can offer an effective, less invasive alternative to radical cystectomy, improving both survival and quality of life for many bladder cancer patients.1,3,4

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April, 17, 2024

Seeing Breast Cancer in a New Light 

By Lindsay Cohen 

According to the 2024 American Cancer Society statistics, breast cancer accounts for 30% of all new cancer cases for women, making it the number one cancer women experience, and ranks as the second most common cancer women die from in the United States. The alarming rise in breast cancer cases, particularly among younger adults, underscores the urgent need for innovative diagnostic and treatment methods.1,2,3

Today, the FDA approved Lumisight (pegulicianine), an optical imaging agent designed to enhance the detection of cancerous breast tissue during surgery. This groundbreaking advancement is part of the Lumicell Direct Visualization System (DVS), a fluorescence-guided surgery tool that allows surgeons to visualize malignant tissues with increased precision. This drug-device combination product, referred to by researchers as pFGS, aims to reduce the likelihood that residual cancerous tissue is left behind, improving surgical outcomes. This is crucial as the surgeons have shared that the strongest predictor of local recurrence occurs with incomplete tumor removal and leads to secondary surgeries being required.4

Approval for Lumisight was based on data from the INSITE Trial, a prospective, randomized, and multicenter study. This study included 406 patients, of which 392 were randomly assigned to receive pFGS or standard surgery. Randomization was completed at a 10:1 ratio, with 357 patients receiving pFGS and 35 in the control group. The population included patients with invasive (316) and in situ (76) cancers. Results revealed that in the treatment group, 27 of 357 patients had successful removal of residual tumors after standard lumpectomy. This included 22 cases where standard margin evaluations had previously deemed there was no longer cancer present in the surgical site. The pFGS intervention also helped avoid second surgeries in 9 of 62 patients identified with positive margins, where positive margins are known to be areas where cancer cells still exist at the edges of the surgically removed tissue. The trial reported a specificity of 85.2% (95% CI, 83.7%-86.6%) and a sensitivity of 49.3% (95% CI, 37.0%-61.6%), indicating pFGS's accuracy in identifying non-cancerous and cancerous tissues, respectively. Pegulicianine administration was halted in six patients due to adverse events, with two experiencing grade 3 serious adverse events (hypersensitivity and anaphylactic reactions). However, the collective safety profile of Lumisight was positive, with most adverse events being mild and resolving without long-term effects. Overall, these results underline the importance of surgeons having access to enhanced precision with pFGS compared to standard methods.4

Additionally, from a cosmetic perspective, using pFGS resulted in an increase in the volume of breast tissue removed, with an average of 10 cm³, but still was lower than the 30% increase in tissue removal that occurs with traditional comprehensive margin shaving. This balance may maintain cosmetic outcomes while ensuring thorough cancer removal.4

Considering the findings, it is evident that Lumisight used in pFGS is a promising development for both patients and providers. It exemplifies the potential of combining advanced imaging technologies with surgical expertise to enhance cancer treatment. As more data becomes available and further studies are conducted, Lumisight is expected to become an integral part of breast cancer surgery, improving outcomes and offering hope to countless patients. For healthcare providers, staying informed about such advancements is crucial. Lumisight not only introduces a new tool in the fight against breast cancer but also underscores the importance of ongoing research and innovation in improving patient care. By incorporating these technologies into clinical practice, providers can continue delivering the best possible patient outcomes.4


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April, 10, 2024

Zevtera: A New Advanced Generation Cephalosporin 

By Lindsay Cohen 

Antimicrobial resistance (AMR) is an ever-growing public health concern resulting from the misuse and overuse of antibiotics. The FDA indicates that AMR complications result in 35,000 deaths annually in the United States alone. The battle to get ahead of bacterial resistance has been a struggle. Still, the risk of being unable to treat bacterial infections has powered scientists to search for new compounds to use as antibiotic agents. On April 3rd, the FDA approved a new drug, Zevtera (ceftobiprole medocaril sodium for injection), to add to the arsenal of antibiotic therapeutics for the treatment of adults with:1,2

 

Zevtera is an advanced fifth-generation cephalosporin antibiotic that offers broad-spectrum activity against Gram-positive and Gram-negative bacteria to combat resistant strains, such as MRSA. Similar to other beta-lactam antibiotics, Zevtera's mechanism of action targets penicillin-binding proteins (PBPs) that are critical for bacterial cell wall synthesis. Targeting PBPs helps disrupt cell wall maintenance, leading to bacterial cell death.3

 

Evidence backing the approval of Zevtera was based on phase 3 randomized, double-blinded control trials and indicated an 88.4% eradication of microbial presence when given to SAB patients, with a clinical cure rate of 81.1%. Zevtera also produced an 87.6% microbial eradication rate for ABSSSI patients, with a clinical cure rate of 85.3%. The microbial eradication rate for CABP patients treated with Zevtera was 84.2%, with a clinical cure rate of 76.4.%. Safety analyses have also shown that adverse effects of Zevtera are comparable to other cephalosporins in occurrence and severity, commonly surfacing as Gastrointestinal issues and less commonly as blood disorders or hypersensitivity.4,5,6

 

The approval of Zevtera is a significant advancement in light of the widespread antimicrobial resistance in the community. The broad-spectrum coverage, efficacy against resistant strains, and favorable safety profile will make Zevtera a strong option for treating severe non-responsive infections.

 

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April, 03, 2024

Forming New Bonds: Unlocking Alcohol-Alcohol Cross-Coupling

By Lindsay Cohen 

Chen et al., 2024, Science 383, 1350 - 1357

The endeavor to streamline synthetic pathways and expand the chemical space has been a central focus of organic chemistry. Recent research spearheaded by MacMillan and his team at Princeton University, alongside Alcázar from Janssen Research and Development, has brought diverse drug development closer to this goal. Their groundbreaking work on alcohol-alcohol cross-coupling, as detailed in the paper "Alcohol-alcohol cross-coupling enabled by SH2 radical sorting," introduces a novel method for creating C(sp3)-C(sp3) bonds from two alcohol subunits. This innovative approach could significantly impact various fields, from medicinal chemistry to materials science.1,2,3

This research utilizes nickel radical sorting to mediate the cross-coupling of two alcohol fragments. The team could activate alcohols by employing N-heterocyclic carbene (NHC) salts, forming transient alkyl radicals that can couple to produce new carbon-carbon bonds. This method leverages the ability of transition metals to stabilize and differentiate alkyl radicals based on their steric properties, allowing for selective and efficient bond formation.1,2,3

One of the major advantages of this approach is its operational simplicity. The reactions can be performed in a single flask, open to air, without requiring stringent exclusion of moisture or oxygen. This makes the process highly accessible and practical for large-scale applications.1,2,3

The team conducted a series of optimization experiments to fine-tune the reaction conditions. They found that they could achieve high yields in the methylation of secondary alcohols with methanol. In the presence of Ni(acac)2, the yield of the cross-coupled product increased significantly (from 16% to 70%), and the ratio of cross-coupled product to secondary homodimer improved from 2:1 to 17.5:1. This stark improvement underscores the efficacy of the nickel catalyst in promoting selective radical-radical coupling.1,2,3

Further evaluation of the reaction scope revealed its versatility across various alcohol substrates. Primary, secondary, and tertiary alcohols, as well as complex heterocycles, were successfully coupled with methanol, yielding products in good to excellent yields. For example, the cross-coupling of primary alcohols with methanol resulted in an impressive suppression of homodimer formation, highlighting the method's efficiency.1,2,3

The ability to create diverse C(sp3)-C(sp3) bonds from readily available alcohols opens new avenues for synthetic chemistry. This method can significantly reduce the time and resources needed to access complex molecules, which is particularly valuable in drug development and materials science.1,2,3

By offering a robust and user-friendly protocol, this alcohol-alcohol cross-coupling technique could become a standard tool in synthetic chemistry labs. Future research may focus on expanding the range of applicable substrates and exploring the mechanistic intricacies of the reaction to further enhance its efficiency and selectivity.1,2,3

The innovative work on alcohol-alcohol cross-coupling by MacMillan et al. represents a significant advancement in synthetic organic chemistry. By simplifying the process of forming C(sp3)-C(sp3) bonds, this research paves the way for more efficient and diverse chemical syntheses, with broad implications for various scientific and industrial fields.1,2,3


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March, 28, 2024

Exploring the Lung-Brain Connection Through Pseudomonas Aeruginosa

By Lindsay Cohen 

  Biofilm exopolysaccharide alter sensory-neuron-mediated sickness during lung infection

  Granton et al., 2024, Cell 187, 1–15


Pseudomonas aeruginosa, a bacterium implicated in respiratory infections, can exist in two forms: as a biofilm producer encased within an exopolysaccharide (EPS) matrix, or in a more vulnerable, non-biofilm state.1,2 

The Cumming School of Medicine at the University of Calgary has researched the interplay between bacterial biofilms, the immune system, and neural pathways in lung infections. Utilizing genetically modified mice and various Pseudomonas aeruginosa strains, their recent study probed the presence and absence of inflammation and sickness in response to infection.1

Surprisingly, the research unveiled that infections with EPS-producing, biofilm-forming bacteria induce milder initial symptoms or sickness but lead to more extensive cellular damage  or inflammation over time. This finding diverges from the conventional belief that symptoms directly correlate with the degree of cellular damage and patient outcomes. EPS biofilms afford the bacteria protective concealment, enabling a more insidious disease course without the usual illness markers.1,2 

A remarkable aspect of this study is the exploration of the lung-brain axis within infection and immunity. Non-EPS bacteria activate vagal nociceptors, initiating neurochemical cascades that activate corticotropin-releasing hormone (CRH) neurons within the hypothalamus's paraventricular nucleus (PVN). This activation is crucial to what's known as sickness behavior, including symptoms like fatigue, malaise, and anorexia. Conversely, EPS-bearing bacteria cunningly evade this neural alert system, highlighting how biofilms can bypass host defenses.1,3,4

At the molecular level, this study illuminates the evasion tactics of EPS+ biofilms. Key to this process is their stealthy avoidance of the Transient Receptor Potential Vanilloid 1 (TRPV1+) nociceptors. Although traditionally associated with pain, these sensory neurons also play a pivotal role in pathogen recognition, deploying toll-like receptor 4 (TLR4) to detect lipopolysaccharide (LPS) on non-biofilm bacteria. EPS-encased bacteria, however, elude detection, leading to delayed symptoms and a more complex infection trajectory.1

This research contradicts older ideas that pneumonia symptoms arise primarily from localized inflammation spreading to the brain through the circulatory system. Instead, it introduces the idea that these symptoms stem from the direct activation of the nervous system by TLR4 recognition of lung-resident pathogens. This signifies a major shift in our understanding of lung infection pathophysiology and suggests new treatment avenues that target the nervous system in addition to antimicrobial therapies.1

The urgency for innovative treatment approaches is necessary in the contemporary medical landscape where antibiotic efficacy wanes against biofilm-protected bacteria. Therapies designed to dismantle biofilm structures or prevent their formation could significantly enhance treatment outcomes for pneumonia and chronic lung diseases known for biofilm-related infections.1

Insights from this study expand the understanding of the pathophysiological framework of pulmonary infections, suggesting a shift in treatment paradigms. The pathogenic factors, immune defense mechanisms, and neurobiological pathways, underscore the need for comprehensive, multifaceted treatment strategies. As we navigate the complexities of host-pathogen interactions, the knowledge from this research may help drug developers undermine the defensive mechanisms of pathogens nestled within biofilm strongholds.1,3,4


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March, 20, 2024

Non-Alcoholic Steatohepatitis: First FDA-Approved Treatment 

By Lindsay Cohen 

The liver is one of the body’s vital organs and is responsible for critical functions including blood filtration to remove substances like alcohol and drugs, as well as helping the digestive system break down fats and eliminate waste through bile secretion.1

However, as individuals age, the risk of developing complex conditions such as obesity, diabetes, high cholesterol, and elevated blood pressure increases, leading to heightened inflammation and a greater likelihood of developing Non-Alcoholic Steatohepatitis (NASH). NASH, an advanced form of Non-Alcoholic Fatty Liver Disease (NAFLD), represents a concerning stage where fat accumulation in the liver evolves into liver fibrosis and dysfunction.1

For years, the medical community lacked an FDA-approved pharmacological intervention for NASH, focusing instead on lifestyle modifications such as diet and exercise. Despite these recommendations, a significant care gap persisted, urging continuous research for effective treatments. On March 14th, a groundbreaking development occurred with the FDA's accelerated approval of Rezdiffra (resmetirom), a groundbreaking treatment powered by thyroid hormone receptor-beta (THR-beta) agonism, specifically formulated for adults with NASH exhibiting moderate to advanced liver fibrosis. Rezdiffra, poised for distribution in April through selected specialty pharmacies, represents a significant leap forward, targeting liver fat reduction via partial activation of the thyroid hormone receptor, alongside recommended dietary, and exercise regimens.2,3

This accelerated approval was rooted in the promising results of trial NCTO3900429, which utilized surrogate endpoints of liver scarring and inflammation measurements at the 12-month mark. Rezdiffra's approval, contingent on the outcomes of a comprehensive 54-month study to confirm its sustained benefits, underscores the FDA's confidence in its early efficacy indications. These include reduced NASH progression, halted fibrosis, or improved liver scarring in patients dosed with 80 or 100 milligrams of Rezdiffra.2

 

While celebrating Rezdiffra's introduction as a transformative NASH treatment, it's also crucial to acknowledge its associated precautions, warnings, and the spectrum of common side effects such as diarrhea, nausea, abdominal pain, and dizziness. The medication's safety profile calls for vigilance against drug-induced hepatotoxicity and gallbladder-related adverse effects, explicitly advising against its use in patients with decompensated cirrhosis. Moreover, potential interactions with other medications, particularly statins for cholesterol management, necessitate careful patient monitoring.2

 

Rezdiffra's discovery and approval are monumental achievements for the treatment and management of NASH. As we venture into this new era of NASH treatment, Rezdiffra’s current insights and future clinical revalidation will deepen our understanding of this complex liver disease and hopefully spark the development of additional therapeutic options.


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March, 11, 2024

A New Horizon for Managing Pediatric Cholesterol 

By Lindsay Cohen 

In the fight against cardiovascular disease, managing high cholesterol, especially among the younger population, is critical. Familial hypercholesterolemia (FH), a genetic disorder leading to early high cholesterol levels, exemplifies the urgent need for effective treatments beyond traditional options like statins. Although statins have been beneficial for many, their efficacy is not universal, leaving a significant care gap for non-responders or those intolerant to such treatments.1,2,3

Praluent (alirocumab), a groundbreaking PCSK9 inhibitor, emerged in 2015 and significantly enhanced the liver's capacity to clear low-density lipoprotein cholesterol (LDL-C) from the bloodstream. This novel approach provided an essential alternative for adults with high LDL-C levels, particularly for those with heterozygous familial hypercholesterolemia (HeFH) or statin intolerance, marking a pivotal advancement in hypercholesterolemia management. This novel approach provided clinicians with a new medicinal tool to help patients still not responding to cholesterol treatment.1,2,3

The recent FDA approval for Praluent's use in pediatric patients 8 and older with HeFH to reduce LDL-C broadens its impact to a younger demographic grappling with this genetic condition. This indication was supported by the outcomes of trials DFI14223 and EFC14643, which addressed the post marketing requirement established in 2015 and provided necessary information regarding the efficacy and safety of using Praluent in this pediatric population.4,5,6

Traditionally, the management of elevated cholesterol levels in children centered around lifestyle modifications and pharmacotherapy with statins for those with familial hypercholesterolemia and other cardiovascular risk factors. Despite these efforts, there remained a population of children with genetic conditions like FH who continued to face elevated cholesterol levels, underscoring the need for innovative treatment avenues.1,2,3

Praluent's inclusion as an adjunct treatment represents a significant leap forward in pediatric care, providing a viable option for children and adolescents with HeFH, for whom traditional interventions proved inadequate. This approval fills a vital gap in managing familial hypercholesterolemia among younger populations. It underscores the importance of addressing cardiovascular risks early in life, potentially altering heart health trajectories for future generations.

It's clear that while lifestyle modifications and statins remain foundational, Praluent expanded label offers a promising advancement for pediatric patients at the highest risk. This development holds the potential for better outcomes and a healthier future for affected children, emphasizing the ongoing evolution in the management of hypercholesterolemia.

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