In a potential leap forward for diabetes management, VX-880 may restore the function of pancreatic islet cells, including glucose-responsive insulin production, and thereby the body’s regulation of glucose levels. Administered via hepatic portal vein infusion, VX-880 requires long-term immunosuppressive therapy to protect the transplanted islet cells from immune rejection.

Cell therapy as a functional cure for diabetes represents a direction scientists have pursued ardently in recent years.

Vertex’s Clinical Trial Milestone

On June 24, 2024, Vertex Pharmaceuticals shared new data from a phase 1/2 clinical trial of stem cell therapy VX-880. Within 90 days following a single full-dose infusion of VX-880, all type 1 diabetes (T1D) patients exhibited successful islet cell transplantation and insulin production responsive to glucose. At their last follow-up, 11 out of 12 patients either reduced or entirely ceased using exogenous insulin.

VX-880 is an investigational stem cell-derived, fully differentiated islet cell therapy aimed at treating T1D patients with impaired hypoglycemic awareness and severe hypoglycemia. Notably, VX-880 has attained the Regenerative Medicine Advanced Therapy (RMAT) designation and Fast Track status granted by the FDA.

Understanding Diabetes

Diabetes is categorized as Type 1 (T1D), Type 2 (T2D), or gestational, among others, with T1D being an autoimmune disease. It leads to insulin deficiency due to the immune system mistakenly attacking the pancreatic β-cells, disrupting normal blood sugar regulation. T1D patients must endure lifelong insulin injections and blood sugar monitoring, which besides being painful, risk complications including hypoglycemia, seizures, coma, and even death.

According to data from The Lancet, there are currently 529 million people with diabetes globally, with projections of up to 1.3 billion by 2050.

Vertex announced the phase 1/2 trial as a sequential, multi-part study, originally enrolling 17 patients, 14 of whom have been treated so far, with this announcement detailing the data of 12 patients from parts B and C.

Initially, all patients lacked detectable fasting C-peptide, indicating endogenous insulin secretion, with a history of recurrent severe hypoglycemia in the year before screening, requiring an average of 39.3 units of insulin daily. Post-infusion of VX-880, by Day 90, all 12 patients demonstrated islet cell implantation and glucose-responsive insulin production.

At their most recent visit, all patients showed improved glycemic control, reaching HbA1c levels below 7% and time in range above 70%. Remarkably, 11 participants ceased or reduced their use of exogenous insulin. During follow-up (starting at Day 90), none reported episodes of severe hypoglycemia. Three patients followed up for at least one year also achieved this milestone, free from severe hypoglycemia and maintaining HbA1c below 7%.

Regarding safety, Vertex reported VX-880 is generally well-tolerated. Most adverse events (AEs) reported were mild to moderate, with no serious adverse events associated with the VX-880 treatment. Two patient fatalities occurred, deemed unrelated to VX-880, with its safety profile consistent with the immunosuppressive regimen used, infusion process, and long-term complications of diabetes.

Previously, on June 24, 2023, Vertex disclosed partial trial outcomes, where two T1D patients from parts A and B no longer required insulin injections, and a significant decrease in disease biomarkers was observed. These results align with previously reported positive outcomes, bolstering the transformative potential of the therapy. Based on these promising data, Vertex plans to expand the trial to include approximately 37 patients.

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In the expansive frontier of genetic medicine, Intellia Therapeutics strides forward, manifesting the first clinical data to demonstrate the potential for repeated dosing with an in vivo CRISPR/Cas9 gene-editing therapy. This groundbreaking revelation not only reinforces the concept of in vivo gene editing but also indicates its potential applicability in treating a gamut of diseases where multiple dosing could be requisite.

The Clinical Trailblazers

On June 25, 2024, Intellia, founded by Nobel Laureate Jennifer Doudna, disclosed the latest clinical data concerning their CRISPR/Cas9 gene-editing therapy, NTLA-2001. Three patients with Transthyretin (ATTR) Amyloidosis, previously administered the lowest dose in a Phase I dose-escalation study, saw a median reduction of 90% in serum Transthyretin (TTR) protein levels following a successive 55 mg NTLA-2001 treatment.

The Battle Against ATTR Amyloidosis

Hereditary Transthyretin (ATTRv) Amyloidosis, a rare yet fatal condition, emerges from genetic mutations leading to abnormal protein production, accumulating and inflicting damage on vital organs such as the heart and nervous system. While curative therapy remains elusive with, currently available medications only slowing the misfolded TTR accumulation, NTLA-2001 offers a ray of hope by inactivating the TTR gene, thereby reducing TTR protein levels in the serum.

Strategic Alliances for Innovation

Intellia announced a key collaboration with Regeneron Pharmaceuticals on June 1, 2020, driving forward the development and commercialization of NTLA-2001, with Regeneron shouldering 25% of the costs in exchange for an equal share in profits.

Clinical Data Insights

Initial results from the Phase I trial revealed a 52% median reduction in serum TTR at a 0.1 mg/kg dosing on day 28, which was below the desired threshold. However, upon completion of a two-year observational phase, all three patients transitioned to a 55 mg dose, reaching a median serum TTR decline of 95% compared to baseline.

Subsequent dosing maintained favorable tolerability profiles. Only one patient experienced a mild infusion-related reaction at the 55 mg dose, indicative of the consistent safety and pharmacokinetics between repeated and single dosing. Even the earliest treated patient demonstrates continued safety and tolerability over three years post-treatment.

Looking Forward

While repeated dosing plans for ATTR amyloidosis are not currently in place for NTLA-2001, these findings mark a significant milestone for Intellia. John Leonard, Ph.D., Intellia’s President and CEO, shared that part of their commitment to patients in the Phase I study was to offer an optimized therapeutic dose if the initial protein reduction was incomplete. The data substantiates the platform’s capability for redosing, opening pathways to treat an array of conditions requiring more than one dose to achieve optimal therapeutic impact.

Comparative Milestones in the Field

Also capturing the spotlight is Alnylam Pharmaceuticals, an RNAi therapeutics pioneer. According to Endpoints News, their latest Phase III clinical trial data for Vutrisiran, treating ATTR amyloidosis with cardiomyopathy, is highly anticipated in 2024. Alnylam’s trials indicate a significant reduction in all-cause mortality rates and success in all secondary endpoints, advancing patient physical function.

Currently, ATTR cardiomyopathy patients have limited options, with Pfizer’s Tafamidis—a TTR stabilizer—being the notable treatment on the market, which garnered impressive sales in the previous year.

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In the vanguard of clinical exploration, Lexeo Therapeutics has reported encouraging outcomes from two clinical trials. Their pioneering gene therapy, LX2006, geared toward addressing Friedreich’s Ataxia (FA) cardiomyopathy, has shown good tolerance and significant absence of severe adverse events related to the treatment. Moreover, meaningful improvements in cardiac biomarkers have been observed, though the full impact on patients’ quality of life is still under close evaluation.

On the 15th of July, 2024, the American biotechnology firm announced the latest strides made with LX2006 in a Phase 1/2 clinical trial and a Phase 1a trial initiated by Weill Cornell Medicine researchers. LX2006 demonstrated a sound safety profile, with no serious adverse incidents tied to the therapy. Additionally, clinical biomarkers indicating cardiac health exhibited progressive enhancement over time.

The hereditary, progressive, and degenerative multisystem disorder, Friedreich’s Ataxia, springs from mutations in the FXN gene, hampering the production of the essential frataxin protein. Frataxin plays a pivotal role in mitochondrial function within cells and the maintenance of cardiac function. Its deficiency affects the peripheral nerves and brain regions governing movement and balance, leading to neurologically based symptoms like impaired muscle coordination or ataxia, which worsens as the disease advances. Patients often develop various heart conditions, including myocardial hypertrophy or hypertrophic cardiomyopathy and arrhythmias, as the ailment progresses.

Previously, on February 28, 2024, the FDA approved Skyclarys, the first prescription medication for individuals over the age of 16 suffering from Friedreich’s Ataxia, marking a significant milestone in treatment. However, there remained an unmet need globally for medications targeting FA cardiomyopathy.

LX2006, as delineated by Lexeo’s announcements, is an AAV-based gene therapy candidate designed for intravenous administration to tackle cardiomyopathy associated with FA. By delivering a functional frataxin gene, it seeks to bolster frataxin protein expression and restore mitochondrial function in cardiac cells.

The dataset shared encompasses records from eight participants with a minimum six-month follow-up. Findings indicate an uptick in FXN protein expression levels amongst assessable patients. Initially, four subjects demonstrated elevated left ventricular mass indices (LVMIs), and of these, three exhibited a reduction of more than 10% in LVMI at 12 months—a promising predictor of decreased morbidity and mortality in heart disease. Researchers also reported a regression in sidewall thickening, an early sign of cardiac dysfunction, and a decrease in biomarkers for myocardial injury.

In April 2024, Lexeo publicized that the FDA had granted LX2006 Rare Pediatric Disease designation, Fast Track designation, and Orphan Drug designation for the treatment of FA cardiomyopathy.

Per reports from Fierce Biotech, Lexeo has endeavored to assess the drug’s impact on patient lifestyles via VO2 max. This metric quantifies the maximum volume of oxygen an individual can utilize during exercise, a measure of cardiorespiratory fitness. While VO2 peak levels were inconclusive for three of the eight participants, the remaining five demonstrated an average improvement of 1% at six months and 4% at twelve months. Lexeo commits to ongoing VO2 peak evaluations and is exploring further cardiorespiratory exercise tests that may yield greater utility for the patient cohort.

While supporting evidence for LX2006 presently derives from cardiac evaluations, Lexeo underscores precedence for drug approvals based on LVMI or transgene expression modifications. Animated by these results, Lexeo anticipates accelerating the therapy’s development, including dialogues with regulatory bodies about pivotal trial designs and potential expedited approval.

Fierce Biotech notes contrasts between Skyclarys’ demonstrated neurological efficacy and LX2006’s cardiac focus. Nonetheless, the evolving landscape over the coming years hints at growing competition. Peers such as Voyager Therapeutics and Neurocrine Biosciences are exploring FXN gene therapy, with Solid Biosciences and Lacerta Therapeutics pursuing gene therapies, and both Prime Medicine and Tune Therapeutics trailblazing in early-stage gene editing projects.

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