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The FDA rejected an application to approve MDMA, also known as ecstasy. Now the agency treatment for PTSD. Next up among the psychedelics vying for an FDA approval: psilocybin for treatment resistant depression.

Long Strange Trip Continues for Psychedelics in PTSD, TRD

This is the first study to investigate the effectiveness of this combination to treat vitiligo. 

Adding a Statin to Light Therapy Significantly Improves Vitiligo Treatment Outcomes

Express Scripts alleges in its suit that the FTC followed “prejudice and politics, not evidence or sound economics,” and that there is no support for the assertion that the power of PBMs has increased over time.


Express Scripts Sues FTC to Withdraw its PBM Report

Peter Wehrwein has been the lead editor of Managed Healthcare Executive since February 2020.

Boehringer Ingelheim said that it will submit a new drug application for nerandomilast based on the positive results.

IPF Drug Meets Primary End Point

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Friedreich's ataxia (FDRA) is a rare, hereditary autosomal recessive disorder that affects coordination, balance, and speech. These clinical manifestations result from a deficiency in the frataxin protein, which regulates cellular iron levels. Without frataxin, the mitochondrial function is impaired, and oxidative injury results. FDRA has no cure; therefore, researchers focus their efforts on new ways to manage and treat its symptoms.

Existing treatments for FDRA are limited and often fail to effectively address the root causes of the disease or manage its neurological symptoms. The neurological manifestations stemming from progressive neurodegeneration in the dorsal root ganglia due to oxidative stress affect both the central and peripheral nervous systems. Symptoms, such as a decline in motor coordination and muscle weakening, typically emerge 10-15 years after onset and can lead to loss of motor function.

A significant hurdle in treating neurological conditions such as FDRA is the inability of therapeutic agents to penetrate the blood-brain barrier (BBB). A promising solution involves using diazoxide (DZX)-loaded solid lipid nanoparticles (SLNs) formulated through microfluidic techniques, a method recently detailed in the 

Journal of Drug Delivery Science and Technology

, and colleagues. This innovative approach holds great promise for the future of FA treatment and its neurological manifestations.

Functionally impaired mitochondria are prevalent in FDRA and tend to produce abundant amounts of reactive oxygen species. Previous research has shown that DZX, a medication for high blood pressure, regulates mitochondrial respiration and modulates reactive oxygen species production to ensure neuronal survival. Recently, researchers from the University of Bari in Italy designed a way to use SLNs to deliver DZX across the BBB. This approach showed potential in protecting fibroblast cells derived from an FA patient from oxidative stress and in crossing the BBB in lab models.

SLNs comprise biocompatible lipids that can encapsulate and deliver therapeutic compounds to specific target sites in the body. By encapsulating (or wrapping around) drugs, these lipid vehicles protect drugs from being broken down by the body before they reach their target. The lipid shell is especially important for delicate molecules like mRNA used in vaccines. These lipid vessels can travel through the bloodstream and cross biological barriers like the cell membrane, allowing the drug to reach specific cells or tissues more effectively.

Once SLNs reach their target, they release the drug in a controlled manner. The delivery system ensures the drug is at the right place and time, enhancing its effectiveness and reducing side effects. Made from materials that are generally safe and well-tolerated by the body, they are a preferred choice for delivering a wide range of drugs, including those that are difficult to produce using traditional methods.

Additionally, SLNs can be tailored to carry different types of drugs, including hydrophilic (water-loving) and lipophilic (fat-loving) compounds. This versatility makes them suitable for various therapeutic applications.

The results showed that compared to plain DZX, the SLN-DZX vehicle demonstrated enhanced permeability and reduced oxidative stress in FDRA fibroblast cells, which were marked by reduced reactive oxygen species levels. SLN-DZX also exhibited improved endothelial permeability across the blood-brain barrier model over DZX alone, supporting the idea that lipid vehicles traverse the BBB more effectively.

A novel approach, SLN-DZX offers several advantages for treating FDRA. First, the encapsulation of diazoxide within SLNs can protect the drug from degradation and improve its bioavailability, allowing for better delivery to defective cells in the body. Additionally, the small size of the nanoparticles enables them to penetrate the blood-brain barrier, reaching the central nervous system that FA primarily affects.

Furthermore, the controlled release of diazoxide from the SLNs can result in sustained therapeutic effects, reducing the frequency of dosing and potential side effects associated with the drug. This targeted and efficient delivery system could significantly improve the quality of life for individuals living with FDRA.

The study presents compelling evidence that SLN-DZX formulations significantly enhance drug permeability through in vitro BBB models. Mitigating oxidative damage — one of the vital pathological processes in FDRA — could improve cell viability and patient outcomes. This suggests that the methodology can be adapted for other treatments requiring effective brain delivery, potentially revolutionizing how neurological diseases are approached.

Further studies and clinical trials are needed to fully evaluate the safety and efficacy of the novel SLN-DVX treatment strategy, but the potential benefits have been shown to be worth pursuing.

Existing treatments for FDRA are limited and often fail to effectively address the root causes of the disease or manage its neurological symptoms.

Clinical

Revolutionizing Friedreich's Ataxia Treatment: A Novel Approach to Drug Delivery 

Telomeres are short nucleotide sequences at the end of chromosomes that protect genetic information. They have been analogized to the tips of shoelaces, called aglets, that keep the laces from fraying.  Inflammation and increased levels of oxidative stress can affect telomere length, and several neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease and spinocerebellar ataxias have characteristic telomere shortening, often resulting from immune system insult and oxidative stress that follows. Shortened telomeres have been associated with age-related diseases such as cardiovascular diseases, neurodegenerative disorders and certain types of cancer

Leukocyte telomere length (LTL), specifically, might hold some answers to Friedreich's ataxia (FA) progression, according to Daniela Scarabino, Ph.D., from the Institute of Molecular Biology and Pathology at the National Research Council in Rome, Italy, and colleagues in a study published in 

Seeking to establish LTL as a potential biomarker for monitoring disease progression, the study explored the relationship between LTL and various clinical and genetic factors in a cohort of FA patients, including biallelic patients, heterozygous carriers, and healthy controls. The hallmark feature of FA, frataxin protein deficiency, leads to oxidative stress, mitochondrial dysfunction and inflammation, which affecttelomere length.

Telomere shortening is linked to cell division limits, aging, disease risk, cellular senescence and is a biomarker for health and disease progression. Monitoring telomere length can provide insights into disease susceptibility, severity, and progression.

LTL was quantified using real-time polymerase chain reaction in a cohort comprised of 61 biallelic FA patients, 29 heterozygous carriers, and 87 age-matched healthy controls. The researchers assessed the relationship between LTL, age at blood sampling, repeating frataxin gene sequences, disease duration and various clinical parameters, including the presence of cardiomyopathy and diabetes.

The findings revealed a notable age-dependent behavior in LTL among the studied groups. For individuals 35 and younger, FA patients exhibited longer LTL than controls, while the opposite was true for those over 36 and older. Additionally, heterozygous carriers maintained longer LTL across all ages.

The study found a positive correlation between specific repeating DNA sequences encoding frataxin and LTL and an inverse relationship with age at blood sampling. Importantly, shorter LTL was significantly associated with the presence of cardiomyopathy, providing a potential link between telomere shortening and certain clinical manifestations of FA.

The analysis suggested that LTL was not only altered in FA but may serve as a valuable biomarker for tracking disease progression. The relationship between telomere dynamics and FA is, however, complex. According to Scarabino, how an initial increase in LTL during early cellular replication can be followed by accelerated shortening due to oxidative stress and inflammation requires further investigation.

Researchers are studying how leukocyte telomere length may be associated with  the progression of Friedreich's ataxia.

Telomere Length May Be a Helpful Biomarker in Friedreich's Ataxia Patients

 Genentech’s Tecentriq Hybreza (atezolizumab and hyaluronidase-tqjs), the first PD-(L)1 inhibitor for subcutaneous (SC) administration. Tecentriq Hybreza can be injected subcutaneously over approximately seven minutes, compared with 30 minutes to 60 minutes for standard intravenous (IV) infusion of Tecentriq (atezolizumab). Genentech is a member of the Roche Group.

“This approval represents a significant option to improve the patient experience,” Ann Fish-Steagall, RN, senior vice president of Patient Services at the LUNGevity Foundation, said in a 

. “When patients have options, they feel empowered to be vital participants in their own care and choose their preferred treatment option.”

Tecentriq Hybreza combines Tecentriq with Halozyme Therapeutics’ Enhanze drug delivery technology. Tecentriq Hybreza will be available in a few weeks and be priced at parity with the IV Tecentriq 1200 mg vial.

Tecentriq is available to treat patients with early-stage non-small-cell lung cancer, small cell lung cancer and hepatocellular carcinoma. It is a monoclonal antibody designed to bind with PD-L1 that is expressed on tumor cells and tumor-infiltrating immune cells. This enables the reactivation of T cells.

The cost of Tecentriq 840 mg/14 mL intravenous is around $8,062, and the cost of Tecentriq 1200 mg/20 mL is 11,512.57, according to 

Genentech offers a $0 copay assistance program for eligible patients with commercial insurance with a limit of $25,000 a year. The 

 say that Genentech may cap the assistance if “Genentech determines that a third party has implemented a program that adjusts patient cost-sharing obligations based on the availability of support under the Program and/or excludes the assistance provided under the program from counting towards the patient’s deductible or out-of-pocket cost limitations.”

The approval of Tecentriq Hybreza was based on data from the phase 1b/3 IMscin001 study, which enrolled 371 patients and showed comparable levels of Tecentriq in the blood, when administered subcutaneously. The safety and efficacy profile were consistent with the IV formulation. 

The phase 2 IMscin002 study enrolled 179 patients and showed that 71% of patients preferred Tecentriq Hybreza over intravenous atezolizumab. The most common reasons were less time in the clinic, increased comfort during treatment and reduced emotional distress.

Tecentriq Hybreza will be available in a few weeks and be priced at parity with the IV Tecentriq 1200 mg vial.

Formulary Watch

FDA Approves Subcutaneous Tecentriq to Treat Multiple Cancers

The FDA has approved a subcutaneous form of Genentech’s Ocrevus to treat patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). Ocrevus Zunovo (ocrelizumab and hyaluronidase-ocsq) approved as a twice-a-year, approximately 10-minute subcutaneous injection to be administered by a healthcare practitioner.

Ocrevus Zunovo will be available in a few weeks and be priced at parity with the Ocrevus IV.

This is the second approval in two days for subcutaneous formulations Genentech’s previously approved products.

“People are living longer with chronic illnesses and with fewer disabilities because of the extensive progress that has been made in the development of medicines that can slow their progression,” Natalie Blake, executive director of the MS Foundation, said in a 

. “But still, not everyone has access to these medicines. It’s crucial to acknowledge each experience with MS is as unique as the individual navigating it, so providing choices to address each person’s needs is essential.”

Ocrevus was first approved as an intravenous injection. It is a humanized monoclonal antibody designed to target CD20-positive B cells, a specific type of immune cell thought to be a key contributor to myelin and nerve cell damage. The 

Genentech offers a copay program for $0 a treatment for eligible commercially insured patients with a limit of $20,000 per calendar year. 

Ocrevus Zunovo combines Ocrevus with Therapeutics’ Enhanze drug delivery technology. There is no word yet on Ocrevus Zunovo will be available or what the price will be.

The FDA approval of Ocrevus Zunovo is based on pivotal data from the phase 3 OCARINA II trial, which enrolled 236 patients and showed no clinically significant difference in the levels of Ocrevus in the blood when administered subcutaneously. The safety and efficacy profile are consistent to the IV formulation in people with RMS and PPMS.

Out of the exploratory outcomes measured, Ocrevus Zunovo was consistent with IV, demonstrating suppression of relapse activity (97%) and MRI lesions (97%) through 48 weeks. Additionally, more than 92% of trial participants reported being satisfied or very satisfied with the subcutaneous administration of Ocrevus Zunovo.

“Patients treated with subcutaneous Ocrevus experienced appropriate B-cell suppression and impressive near-complete suppression of new inflammatory disease activity,” Scott Newsome, D.O., lead author, Johns Hopkins University School of Medicine, said in a previous news release. These results demonstrate the potential of subcutaneous Ocrevus as a treatment option that can be matched to the individual needs of people with MS and healthcare professionals.”

Ocrevus Zunovo can be administrated by providers twice a year with a 10-minute subcutaneous injection. Ocrevus Zunovo will be available in a few weeks and be priced at parity with Ocrevus IV.

FDA Approves Subcutaneous Ocrevus for Multiple Sclerosis

In what might be a potential breakthrough for a significant unmet need, Lexeo Therapeutics announced last month that their gene therapy candidate, LX2006, had achieved positive interim 

 clinical data for treating Friedreich Ataxia (FA) cardiomyopathy. This marks a significant milestone in developing new therapies for this devastating condition.

Given the lack of approved treatments for FA cardiomyopathy, LX2006's potential could represent a breakthrough for patients suffering from a disease characterized by severe cardiac complications.

FA is an exceptionally rare, autosomal recessive disease caused by a mutation in the frataxin gene. The absence of an approved therapy that can slow down the progression of cardiomyopathy in FA, which is responsible for a significant portion of FA-related deaths, underscores the urgent need for new treatments.

FA cardiomyopathy is usually identified by an increase in left ventricular mass index (LVMI) that can lead to heart failure. ​ Elevated LVMI in adults with FA cardiomyopathy is a sign of left ventricular hypertrophy and is associated with mortality in various cardiovascular conditions, including FA cardiomyopathy. ​

Given as a one-time infusion, LX2006 is an adeno-associated virus gene therapy that delivers a functional frataxin gene to cardiac cells to promote the production of normal frataxin protein and restore mitochondrial function in heart muscle cells. Without a working copy of the frataxin gene, the heart is unable to sustain energy production, and it cannot work correctly.

The interim results shared from the SUNRISE-FA Phase 1/2 clinical trial and the Weill Cornell Medicine investigator-initiated 

 suggest that LX2006 is well-tolerated, with no serious adverse events reported. The evidence of clinically meaningful improvements across various cardiac biomarkers, particularly concerning left ventricular hypertrophy, is noteworthy. Since left ventricular hypertrophy is a hallmark of FA cardiomyopathy and correlates with mortality, these findings could pave the way for improved patient outcomes.

Data from eight participants with more than six months of follow-up demonstrated an average reduction in LVMI of 11.4% at 12 months and 18.3% at 18 months. Seventy-five percent of participants with elevated LVMI at the start of the study experienced a reduction in LVMI of over 10% at 12 months.Most participants showed sustained and consistent improvements in other necessary measures of cardiac health, such as left ventricular wall thickness and troponin I, at 12 months.

The restoration of frataxin protein expression observed in cardiac biopsies further underscores the therapeutic potential of LX2006. As the disease progresses with low levels of frataxin leading to heart failure, restoring this protein could be crucial for improving cardiac function and enhancing the overall quality of life for affected individuals.

The fact that LX2006 has received Rare Pediatric Disease designation, Fast Track designation, and Orphan Drug designation from the FDA indicates a strong regulatory interest and support for this treatment. These designations can facilitate a more expedited development and review process, potentially leading to accelerated approval.

Despite the promising data, it is essential to acknowledge the inherent risks and uncertainties associated with clinical trials and the development of new therapies. Lexeo's cautionary note regarding forward-looking statements underscores the unpredictable nature of drug development, where new challenges could arise that may affect trial outcomes or regulatory processes.

Although the initial results are promising, LX2006's ultimate success will depend on ongoing safety evaluations, long-term efficacy data, and the ability to navigate the regulatory landscape.

Lexeo Therapeutics' interim clinical data for LX2006 represents a potentially transformative advancement in treating Friedreich Ataxia cardiomyopathy. While the early results are encouraging, ongoing clinical evaluations and regulatory engagements will be vital in determining the future of this promising gene therapy. 

Lexeo Therapeutics' LX2006 Shows Promise in Treating Friedreich's Ataxia Cardiomyopathy

A number of drugmakers are racing to win the first FDA approval of a Bruton’s kinase (BTK) inhibitor to treat multiple sclerosis (MS). Roche showed it is in the thick of the competition with an announcement of positive results for its BTK candidate, fenebrutinib. In an open-label extension of the phase 2 FENopta study. According to the company's announcement,  96% of participants who received fenebrutinib had no relapses after one year and no change in Expanded Disability Status Scale (EDSS) score over 48 weeks. The overall annualized relapse rate was 0.04.

Furthermore, MRI scans showed that 99% of patients had no new T1 lesions, a measure of active inflammation, according to the Roche news release. T2 lesions, which indicate chronic disease burden, were reduced by three times during the 48-week open-label period compared to the end of the blinded trial. The safety profile was comparable to previously reported results, with the most common adverse effects being urinary tract infection, COVID-19 and pharyngitis.

The FENopta study randomized 109 adults ages 18 to 55 years with relapsing forms of MS to receive oral fenebrutinib or placebo twice daily for 12 weeks. After the three-month period, 99 participants chose to enroll in the open-label extension study, in which all participants will continue to receive daily fenebrutinib for up to three and a half years.

Roche is scheduled to present data from the extension study at the 

40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)

Roche's drug is one of a number competing to become the first Bruton's kinase inhibitors approved as a treatment for multiple sclerosis.

Doreen Pon, PharmD, BCOP, BCP

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