Below is in response to the inquiry: A 6-year-old patient with neurofibromatosis type 1 has inoperable plexiform neurofibromas causing significant morbidity. It covers a significant portion of their body with BSA 1.60 m^2. I've come across Gomekli (mirdametinib) as a treatment option. Would Gomekli be an appropriate systemic option for managing their condition? What should be done if they have adverse reactions?

Gomekli (mirdametinib) would be an appropriate systemic treatment option for this 6-year-old child with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas (PN). Mirdametinib is FDA-approved for adults and children 2 years of age and older whose PN are not amenable to complete resection. Because this patient’s BSA is 1.60 m², they qualify for the full recommended pediatric dose of 4 mg twice daily on days 1 to 21 of a 28 day cycle.

Clinical evidence from the ReNeu Phase IIb trial supports its use in this population. In children aged 2 to 17 years (n=56), 52 percent achieved a confirmed 20 percent or greater reduction in PN volume, with a median best reduction of 42 percent and durable responses beyond 12 to 24 months (Moertel et al., 2024). Morbidities such as pain, functional limitation, and disfigurement often improved on therapy, which aligns with this patient’s presentation. Before treatment, baseline echocardiogram and a comprehensive ophthalmologic exam are required because of risks of left ventricular dysfunction and ocular toxicity.

If adverse reactions develop, management is based on severity. For intolerable Grade 2 or Grade 3 reactions including rash, diarrhea, or abdominal pain, Gomekli should be withheld until toxicity improves to Grade 1 or baseline, then resumed at a reduced dose of 3 mg twice daily for this BSA category. More serious toxicities require stronger actions. Retinal vein occlusion requires permanent discontinuation, symptomatic retinal pigment epithelium detachment requires treatment interruption, and an LVEF decline of 20 percent or greater from baseline also requires permanent discontinuation.

Overall, sufficient evidence supports the use of Gomekli as a systemic option for this patient, with clear guidance available for monitoring and managing adverse reactions.

Reference:

1. Gomekli®. (n.d.). GOMEKLI® (mirdametinib). GOMEKLI DTC. https://www.gomekli.com/?utm_medium=ppc&utm_source=google&utm_term=gomekli&utm_id=PS250908150301&gad_source=1

2. Moertel CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma. J Clin Oncol. 2025;43(6):716-729. doi:10.1200/JCO.24.01034

Below is in response to the inquiry: I have prescribed my patient Humira as they have severe Rheumatoid arthritis and have already failed conventional DMARDs: methotrexate, plaquenil, and sulfasalazine. The patient's TB blood test came back positive, although the patient does not have any symptoms and their chest Xray is clear. The patient was started on Isoniazid, and has already been on it for 2 weeks. The patient wants to begin initiating Humira as she is having a bad joint flare, can she be on Isoniazid and Humira at the same time?

This patient is likely to have latent Tb infection (LTBI) based on the positive blood test and negative chest X-ray with no signs or symptoms. According to Humira’s package insert, anti-Tb therapy should be initiated, as treatment of LTBI prior to therapy with Tumor Necrosis Factor (TNF)  blocking agents has shown to reduce the risk of Tb reactivation during therapy.1

According to Iannone et al, most guidelines recommend waiting at least 1 to 2 months after starting treatment of LBTI before starting treatment with biologics.2 This evidence comes from the observation that initiation of anti-TNF-α therapy after 1 month of Tb treatment significantly reduced the risk of Tb activation in Rheumatoid Arthritis patients with positive LBTI. However, it is preferable to wait 1 additional month to avoid side effects of anti-TNF-α with isoniazid, which occur mainly within the first 2 months.

Therefore, it is not recommended to begin Humira therapy at this moment, as it has only been two weeks since the patient started isoniazid treatment. At this time, the patient should continue to be monitored for signs and symptoms of infection, and wait until at least 2 months after isoniazid treatment before starting Humira.

Reference: 

1. Humira. Package insert. Abbvie Inc; February 2024.

2. Iannone F, Cantini F, Lapadula G. Diagnosis of latent tuberculosis and prevention of reactivation in rheumatic patients receiving biologic therapy: international recommendations. Journal of Rheumatology Supplement. 2014;91(0):41-46. doi:10.3899/jrheum.140101

Below is in response to the inquiry: My patient has been on Cimzia for about 2 years for plaque psoriasis, with their most common flare being underneath their eyes. They also failed Humira and Enbrel. They use Lotemax as a steroid for their eyes but are not comfortable using this long term, as it seems to calm the irritation but does not shrink the plaques. They also take vitamin D and get 20 minutes of direct sunlight a day to help. The last medication they tried and failed was a compounded Colchicine cream to put around the eyes that did not help. What therapy would you recommend for this patient to try next as well as any newer therapies that could be tried?

Plaque psoriasis is a chronic, inflammatory, immune-mediated disease affecting both adults and children that clinically presents with well-demarcated, red plaques with silvery scales.1  Psoriasis involves cutaneous T cells, dendritic cells, and keratinocytes with subsequent release of inflammatory cytokines. This means that psoriasis can affect virtually any part of the skin, therefore finding the right treatment regimen for patients is critical in preserving their quality of life. For patients who fail TNF-alpha blockers such as Humira or Cimzia, it is important to consider different biologic agents that mediate alternative targets in the disease pathological pathway.

Guselkumab, approved on July 13th, 2017, is a fully human IgG1 lambda monoclonal antibody that could be used as monotherapy for moderate to severe psoriasis.2 Guselkumab works by binding to the p19 subunit of IL-23 in dendritic cells and keratinocytes, which inhibits proliferation of IL-23, a pro-inflammatory cytokine. In comparison to its clinical competitor adalimumab, at the 16 week mark of a 48 week phase III trial (VOYAGE 2), a higher percentage of patients taking guselkumab achieved greater than 90% improvement in the Psoriasis Area and Severity Index (PASI) than patients on adalimumab or placebo (70.0% vs 46.8% vs 2.4%). Additionally, of non-responders to adalimumab that switched to guselkumab, 66.1% achieved an improvement of PASI over 90% at week 48. 

In comparison to secukinumab, an IL-17 inhibitor, patients in a phase III ECLIPSE trial showed that 84% in the guselkumab group achieved a PASI of 90% at week 48 compared to 70% in the secukinumab group.3 Despite having a slower initial response than secukinumab, there were more patients with improvements in their psoriasis condition taking guselkumab. 

Pre-treatment assessment and monitoring for biologics should be considered for guselkumab. Potential adverse effects include increased risk of infection, injection site reactions, and hypersensitivity. Regardless, the data presented above shows promising results that guselkumab can be an effective option for TNF-alpha blocker treatment resistant psoriasis such as that being experienced by this patient.

Reference: 

1. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics
   Menter, Alan et al. Journal of the American Academy of Dermatology, Volume 80, Issue 4, 1029 - 1072

2. Blauvelt, A., Chiricozzi, A., Ehst, B. D., & Lebwohl, M. G. (2023). Safety of IL-23 p19 Inhibitors for the Treatment of Patients With Moderate-to-Severe Plaque Psoriasis: A Narrative Review. Advances in Therapy., 40(8), 3410–3433. https://doi.org/10.1007/s12325-023-02568-0

3. Reich, K., Armstrong, A. W., Langley, R. G., Flavin, S., Randazzo, B., Li, S., Hsu, M.-C., Branigan, P., & Blauvelt, A. (2019). Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (ECLIPSE): results from a phase 3, randomised controlled trial. The Lancet., 394(10201), 831–839. https://doi.org/10.1016/S0140-6736(19)31773-8 

Hello Doctor,

Below is in response to the inquiry: A 43 year old male solid organ kidney post-transplant patient who is on Prograf 8mg PO every 12 hours, came into the clinic 8 months post transplant with extreme drowsiness, confusion, nausea, and elevated renal and liver function markers such as creatinine, blood urea nitrogen, and liver enzymes.The patient is on Vitamin B12 (past 8 months) and Folic Acid (past 8 months) which was prescribed as a supplement post renal transplant by our team. The patient also indicated that Paxlovid Standard Dose Pack 300mg :100mg (past 4 days) was initiated by an outside provider of the hospital, her PCP. The patient weight is 80kg with a GFR of 80mL/min. Can you tell me what is going on with this patient and if I can continue all his medications or if any adjustments need to be made based on his symptoms, lab values, and drug therapy he is on?

Patients who are Immunocompromised, such as those receiving solid organ transplant, are ideal candidates for treatment with antiviral medications. In this case, Paxlovid, was recommended to be taken by an outside provider of the hospital, her PCP. Paxlovid is an antiviral medication that contains nirmatrevir and ritonavir as ingredients used in the treatment of COVID-19. However, Ritonavir is considered a CYP3A4 inhibitor which can impact the effectiveness of the patient’s Prograf (tacrolimus) due to its metabolism being guided by CYP3A4. Paxlovid and tacrolimus can interact with one another leading to a potential significant increase in body tacrolimus levels.

Based on the patients’ current symptoms along with elevated liver enzymes, serum creatinine, and blood urea nitrogen levels, the patient can be experiencing problems related to elevated levels of tacrolimus. In a case report done in August of 2022, a kidney transplant patient took Paxlovid while resuming their normal immunosuppressant maintenance therapy including Tacrolimus, mycophenolate, and prednisone. However, while taking the Paxlovid, the patient experienced symptoms such as nausea and vomiting by day 2 and his tacrolimus levels were elevated, leading to the Paxlovid to be discontinued by day 3. Acutely high tacrolimus levels can lead to elevated creatinine levels and an acute kidney injury.

In this patient’s presentation the patient looks to be experiencing toxicity due to the increase in tacrolimus levels due to the Paxlovids impact. It is recommended that due to the severity of the symptoms and the increase in serum creatinine and liver enzymes, the Paxlovid should be discontinued to prevent worsening of the patients symptoms due to toxicity and injury to the kidney and or liver. For this patient with a GFR of 80 mL/min, the Paxlovid dose required no dose adjustment. If possible, the tacrolimus should have been held for 2-3 days while taking Paxlovid. The dose of prograf should also have been reduced to prevent acute increases in the levels while the patient took Paxlovid. Since the patient is experiencing symptoms of toxicity, the prograf and Paxlovid should be discontinued until the patient's symptoms are resolved and the levels of the tacrolimus and serum creatinine should be monitored until they return within normal limits. Once the tacrolimus levels are within normal therapeutic limits, the prograf therapy should be restarted.

Reference: 

Prikis, M., & Cameron, A. (2022). Paxlovid (nirmatelvir/ritonavir) and Tacrolimus Drug-drug interaction in a kidney transplant patient with Sars-2-cov infection: A case report. Transplantation Proceedings, 54(6), 1557–1560. https://doi.org/10.1016/j.transproceed.2022.04.015

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

References:

1. Key Statistics for Bladder Cancer." American Cancer Society. Accessed April 24, 2024. https://www.cancer.org/cancer/types/bladder-cancer/about/key-statistics.html.

2. Maliski SL, Connor SE, Litwin MS. "Access to Urologic Cancer Care for African American Men." Canadian Urological Association Journal. 2010;4(2):77-82. doi:10.5489/cuaj.777.

3. American Urological Association. "Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline." American Urological Association. Accessed April 24, 2024. https://www.auanet.org/guidelines-and-quality/guidelines/bladder-cancer-non-muscle-invasive-guideline.

4. Kodera A, Mohammed M, Lim P, Abdalla O, Elhadi M. The Management of Bacillus Calmette-Guérin (BCG) Failure in High-Risk Non-muscle Invasive Bladder Cancer: A Review Article. Cureus. 2023;15(6):e40962. Published 2023 Jun 26. doi:10.7759/cureus.40962

5. Anktiva Package Insert. ImmunityBio, Inc. Revised: April 2024. Reference ID: 5368461.

6. Kamat AM, Sylvester RJ, Böhle A, et al. Definitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group. J Clin Oncol. 2016;34(16):1935-1944. doi:10.1200/JCO.2015.64.4070 

7. Clinical Studies - QUILT-3.032. Anktiva Package Insert. ImmunityBio, Inc. Reference ID: 5368461.

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

References:

1. American Cancer Society. Facts & Figures 2024. Available at: https://www.cancer.org/research/acs-research-news/facts-and-figures-2024.html. Accessed April 17, 2024. 

2. Breastcancer.org. Breast Cancer Facts and Statistics. Available at: https://www.breastcancer.org/facts-statistics. Accessed April 17, 2024. 

3. American Cancer Society. How Common Is Breast Cancer? Available at: https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html. Accessed April 17, 2024

4. Smith BL, Hunt KK, Carr D, et al. Intraoperative Fluorescence Guidance for Breast Cancer Lumpectomy Surgery. NEJM Evid. 2023;2(7). doi:10.1056/EVIDoa2200333 

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

• Staphylococcus aureus bloodstream infections (bacteremia) (SAB), including those with right-sided infective endocarditis

• Acute bacterial skin and skin structure infections (ABSSSI)

• Adult and pediatric patients three months to less than 18 years old with community-acquired bacterial pneumonia (CABP)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.

References:

1. Antimicrobial Resistance Information from FDA. U.S. Food and Drug Administration. https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/antimicrobial-resistance-information-fda. Accessed April 10, 2024

2. FDA New Drug Application Approval Process for Zevtera. U.S. Food and Drug Administration. https://www.fda.gov/drugs/new-drug-application-nda. Accessed April 10, 2024.

3. Munita JM, Arias CA. Mechanism of Action of Ceftobiprole. Antibiotics (Basel). 2023;11(5):320-328.

4. Bassetti M, Russo A, Bouza E, et al. Clinical Study of Ceftobiprole for Staphylococcus aureus Bloodstream Infections. J Clin Med. 2023;12(8):234-240.

5. O'Riordan W, Green S, Overcash JS, et al. Clinical Trials on Ceftobiprole for ABSSSI. N Engl J Med. 2023;388(15):1456-1465.

6. Bradley JS, Byington CL, Shah SS, et al. Efficacy of Ceftobiprole in Treating CABP. Pediatr Infect Dis J. 2024;43(2):112-118.

References:

1. Chen R, Intermaggio NE, Xie J, Rossi-Ashton JA, Gould CA, Martin RT, Alcázar J, MacMillan DWC. Alcohol-alcohol cross-coupling enabled by SH2 radical sorting. Science. 2024;383(1350):1350-1357. doi:10.1126/science.adl5890

2. Blakemore DC, et al. Organic Chemistry. Nat Chem. 2018;10:383-394.

3. Walters WP, et al. J Med Chem. 2011;54:6405-6416.

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

References:

1. Granton E, Brown L, Defaye M, et al. Biofilm exopolysaccharides alter sensory-neuron-mediated sickness during lung infection. Cell. Published online March 13, 2024. Accessed March 28,2024. doi:10.1016/j.cell.2024.03.001

2. Centers for Disease Control and Prevention. Pseudomonas Infections. CDC website. Accessed March 28, 2024. [https://www.cdc.gov/hai/organisms/pseudomonas.html]

3. Kawli T, He F, Tan MW. It takes nerves to fight infections: insights on neuro-immune interactions from C. elegans. Dis Model Mech. 2010;3(11-12):721-731. doi:10.1242/dmm.00387

4. Hakansson AP, Orihuela CJ, Bogaert D. Bacterial-Host Interactions: Physiology and Pathophysiology of Respiratory Infection. Physiol Rev. 2018;98(2):781-811. Accessed March 28,2024. doi:10.1152/physrev.00040.2016

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.

References:

1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Nonalcoholic Fatty Liver Disease (NAFLD) & NASH. NIDDK. Last reviewed April 2021.  Accessed March 20,2024 https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash

2. Food and Drug Administration (FDA). REZDIFFRA (resmetirom) Tablets for use. ​​ Madrigal Pharmaceuticals, Inc., 2024. Last revised March 2024. Accessed March 20,2024. ​ 217785s000lbl.pdf (fda.gov)

3. Optum Rx. Rezdiffra (resmetirom) - New drug approval. Accessed March 20,2024. drugapproval_Rezdiffra_2024-0315.pdf (optumrx.com)

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.

References

1. Creo AL, et al. High cholesterol in children: How is it treated? Mayo Clinic. Oct. 08, 2022. Accessed March 11, 2024. https://www.mayoclinic.org

2. National Center for Biotechnology Information. Pediatric Dyslipidemia. StatPearls. Accessed March 11, 2024.https://www.ncbi.nlm.nih.gov

3. Pediatric Endocrine Society. Hypercholesterolemia: A Guide for Families. June 17, 2020. Accessed March 11, 2024. https://pedsendo.org

4. U.S. Food and Drug Administration. Accessed March 11, 2024. Approval letter for BLA 125559/S-039. March 10, 2024.

5. Efficacy and Safety of Alirocumab in Pediatric Patients with Heterozygous Familial Hypercholesterolemia (DFI14223) [Internet]. ClinicalTrials.gov Identifier: NCT03510884; 2022 Feb 15 [cited 2024 Mar 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT03510884

6. Santos RD, Wiegman A, Caprio S, et al. Alirocumab in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial. JAMA Pediatr. 2024;178(3):283-293. doi:10.1001/jamapediatrics.2023.6477