Archive for month: June, 2024

Novartis today presented results from the 6-month, double-blind period of the Phase III APPEAR-C3G study of Fabhalta (iptacopan) at the late-breaking clinical trials session of the European Renal Association (ERA) Congress. Patients treated with Fabhalta in addition to supportive care achieved a 35.1% (p=0.0014) reduction in proteinuria (as measured by 24-hour urine protein to creatinine ratio [UPCR]) at 6 months when compared to placebo on top of supportive care. In many kidney diseases, proteinuria reduction is an increasingly recognized surrogate marker correlating with delaying progression to kidney failure.

Fabhalta is an oral Factor B inhibitor of the alternative complement pathway being investigated in adult patients with C3 glomerulopathy (C3G). Regulatory submissions, including to the FDA and EMA, for the adult C3G indication are planned for the second half of 2024.

“C3G is an overlooked and devastating illness that often strikes when people are young. The prognosis for patients with C3G is poor, and around half of the affected patients progress to kidney failure requiring dialysis or transplant within 10 years of being diagnosed,” said Marianne Silkjær Nielsen, Founder of CompCure, a Danish non-profit association committed to improving outcomes for individuals with C3G and immune complex membranoproliferative glomerulonephritis (IC-MPGN). “Currently there are no therapies approved for C3G, but research into potential new treatments developed specifically for this disease gives us hope that we can improve outcomes for patients and blunt its emotional, physical and social effects.”

Additional data on the secondary endpoint of estimated glomerular filtration rate (eGFR), a measure of kidney function, showed a numerical improvement of +2.2 mL/min/1.73 m2 (p=0.1945) over 6 months with Fabhalta compared to placebo. The study also showed Fabhalta has a favorable safety profile with no new safety signals.

“This is an exciting milestone for patients and the potential future management of C3G. The hallmark of C3G is overactivation of part of the immune system called the alternative complement pathway, which damages the kidneys and leads to severe loss of kidney function in many patients. Currently used treatments don’t address the underlying biology of C3G and often come with significant side effects that add to the burden of the illness,” said Professor David Kavanagh, Professor of Complement Therapeutics & Honorary Consultant Nephrologist at the Faculty of Medical Sciences at Newcastle University and APPEAR-C3G Steering Committee Member. “Fabhalta is the first potential treatment that targets the alternative complement pathway in C3G, and its impact on measures of kidney damage and kidney function in this study, in addition to its safety profile, is encouraging for patients and the clinical community.”

The APPEAR-C3G study continues with an additional 6-month, open-label period following the 6-month double-blind period, in which all patients receive Fabhalta, including those previously receiving placebo, These data will be presented at an upcoming medical meeting when available.

At ERA, Novartis is also presenting new data across its rare disease portfolio, including results for investigational atrasentan in IgA nephropathy (IgAN) from the 36-week interim analysis of the Phase III ALIGN study, additional data for Fabhalta in IgAN from the 9-month interim analysis of the Phase III APPLAUSE-IgAN study, long-term 33-month efficacy and safety data for Fabhalta in C3G from the Phase II extension study, 1-year Phase I/II data for investigational zigakibart in IgAN, and data from real-world studies in C3G and atypical hemolytic uremic syndrome (aHUS).

“Our ambition is to transform the care of patients living with rare kidney diseases by discovering, developing and delivering innovative treatment options,” said David Soergel, M.D., Global Head, Cardiovascular, Renal and Metabolism Development Unit, Novartis. “The APPEAR-C3G results add to the growing body of evidence demonstrating Fabhalta’s potential to target the underlying pathophysiological drivers and to provide clinically meaningful outcomes in a range of rare conditions.”

About APPEAR-C3G

APPEAR-C3G (NCT04817618) is a Phase III multicenter, randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy and safety of twice-daily oral Fabhalta (200 mg) in C3G patients. In addition to the results from adult patients with C3G, enrollment is ongoing in a separate cohort of adolescent patients with C3G2,3. The study comprises a 6-month double-blind period where adult patients were randomized 1:1 to receive Fabhalta or placebo on top of supportive care, followed by a 6-month open-label period where all patients receive Fabhalta (including those who were previously on placebo).

The primary endpoint for the double-blind period was proteinuria reduction from baseline at 6 months for Fabhalta compared to placebo as measured by 24-hour UPCR. The primary endpoint for the open-label period is proteinuria reduction from baseline at 12 months for both treatment arms and proteinuria reduction from 6 to 12 months for the placebo arm. Secondary endpoints for the double-blind period include change in eGFR, proportion of participants meeting composite renal endpoint criteria (≤15% reduction in eGFR and ≥50% reduction in UPCR), change in glomerular inflammation (as measured by disease total activity score in renal biopsy), change in patient reported fatigue (as measured by FACIT-Fatigue score), and safety and tolerability.

About Fabhalta® (iptacopan)

Fabhalta (iptacopan) is an oral, Factor B inhibitor of the alternative complement pathway. 

Discovered at Novartis, Fabhalta is currently in development for a range of rare diseases including IgAN, C3G, aHUS, IC-MPGN and lupus nephritis (LN), and, as such, the safety and efficacy profile have not been established in these indications. There is no guarantee that Fabhalta will become commercially available for these indications.

Fabhalta was approved by the FDA in December 2023 and the EMA in May 2024 for the treatment of adults with the rare blood disorder paroxysmal nocturnal hemoglobinuria (PNH).

About C3 glomerulopathy (C3G)

C3G is an ultra-rare, progressive kidney disease that initially presents in mostly children and young adults. Each year, approximately 1-2 people per million worldwide are newly diagnosed with C3G, a form of membranoproliferative glomerulonephritis (MPGN).

In C3G, overactivation of the alternative complement pathway – part of the immune system – causes deposits of C3 protein to build up in kidney glomeruli (a network of blood vessels that filter waste and remove extra fluids from the blood). This triggers inflammation and glomerular damage that results in proteinuria (protein in urine), hematuria (blood in urine) and reduced kidney function. Approximately 50% of C3G patients progress to kidney failure within 10 years of diagnosis, at which point they will require dialysis and/or kidney transplantation6,7, with over 55% of patients with C3G experiencing disease recurrence post-transplant.

Researchers from Fred Hutch Cancer Center have found that active surveillance for prostate cancer patients with a low risk of progression is an effective alternative to immediate surgery or radiation to manage the disease. They found that half of men with low-risk prostate cancer remained free from progression or treatment 10 years after diagnosis when followed in a protocol-directed active surveillance program. This finding highlights the viability of active surveillance as a management strategy for favorable-risk prostate cancer, alleviating concerns about delayed treatment leading to worse outcomes. The results of the study have been published in JAMA .

For patients with chronic migraine, nerve decompression surgery effectively reduces the number of headache days-the outcome measure preferred by neurologists-along with other measures including the frequency and intensity of migraine attacks, reports a study in the June issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS). The journal is published in the Lippincott portfolio by Wolters Kluwer.

“Neurologists evaluating migraine treatments tend to focus on reduction in headache days, while plastic surgeons performing headache surgery are more likely to use a measure incorporating other headache outcomes, such as the Migraine Headache Index,” comments ASPS Member Surgeon and Professor of Plastic Surgery, Surgery, Neurosurgery and Neurology Jeffrey E. Janis, MD, of The Ohio State University Wexner Medical Center, Columbus. “Our study adds new evidence that headache surgery improves both sets of measures, providing a more comprehensive assessment of the results of headache surgery.”

Which outcomes are improved by headache surgery?

Peripheral nerve decompression surgery-sometimes called trigger point deactivation or headache surgery – has become an established surgical treatment for chronic migraine and certain other neurological causes of headache, such as occipital and supraorbital neuralgia. Migraine surgery seeks to relieve nerve compression at trigger sites in the head and neck, which are thought to contribute to headaches.

When plastic surgeons evaluate the outcomes of headache surgery, they typically use the Migraine Headache Index (MHI), which incorporates the frequency, intensity, and duration of migraine attacks. In contrast, neurologists-“the traditional experts on nonsurgical migraine treatment”-focus on the change in monthly migraine days.

“This discrepancy is one reason why some headache specialists have been slow to recognize the growing body of evidence showing the effectiveness of headache surgery,” says Dr. Janis. Current guidelines recommend against evaluating headache intensity or duration, citing a lack of standardization.

‘Strong evidence in support of headache surgery efficacy’

To help bridge the gap between specialties, the researchers reviewed 19 studies of headache surgery that reported information on monthly migraine days. Performed between 2005 and 2020, the studies included a total of 1,603 patients. Five of the studies were randomized controlled trials, the highest level of research evidence.

Of eight studies assessing monthly migraine days before and after migraine surgery, six showed a significant reduction in days with migraine attacks. On weighted analysis, patients averaged 14.11 fewer migraine days per month, from before to after surgery. Based on 12 studies, total migraine attacks decreased by 8.65 days per month.

Other outcomes also improved after headache surgery, including an average reduction of 76.59 points (out of a maximum of 300 points) in total MHI score. This included improvements in migraine intensity, which decreased by an average of 3.84 points (on a 0-to-10 scale); and attack duration, which decreased by 11.80 hours per month. The studies reported no major complications of headache surgery.

The study “demonstrates the efficacy of headache surgery on the outcomes used in both the [plastic surgery] and neurology literature,” Dr. Janis and coauthors conclude. They acknowledge some limitations of their study – notably including the variability in the trigger sites addressed by headache surgery. Nevertheless, the findings “provide strong evidence in support of headache surgery efficacy.”

“We hope our study will help to foster common communication between plastic surgeons and neurologists in assessing the effects of headache surgery for patients with chronic headache pain,” Dr. Janis comments. “Future studies of headache surgery should routinely include data on monthly migraine days, in order to better compare the outcomes of surgical and medical treatments.”

Reference:

Ormseth BH, ElHawary H, Huayllani MT, Weber KD, Blake P, Janis JE. Comparing Migraine Headache Index versus Monthly Migraine Days after Headache Surgery: A Systematic Review and Meta-Analysis. Plast Reconstr Surg. 2024 Jun 1;153(6):1201e-1211e. doi: 10.1097/PRS.0000000000010800.

China: In a groundbreaking development, a recent bidirectional Mendelian randomization study has uncovered a compelling causal association between low vitamin D levels and polycystic ovary syndrome (PCOS) incidence. This finding sheds new light on the intricate interplay between hormonal imbalances and nutritional factors in the development of this common endocrine disorder affecting women of reproductive age.

The findings, published in the Journal of Ovarian Research revealed that genetically predicted lower serum vitamin D (VD) levels may cause a higher risk of developing PCOS, which may be mediated by increased production of testosterone.

PCOS is characterized by a combination of symptoms, including irregular menstrual cycles, excess androgen levels, and ovarian cysts. While its exact etiology remains elusive, previous research has implicated genetic predispositions and environmental influences. Among these factors, vitamin D deficiency has long been suspected to play a role, given its regulatory functions in reproductive health and immune system modulation.

Bingrui Gao, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China, and colleagues aimed to investigate the cause-effect relationship between serum VD and PCOS, and the role of testosterone in the related pathological mechanisms.

For this purpose, the research team assessed the causality between serum VD and PCOS by using genome-wide association studies (GWAS) data in a bidirectional two-sample Mendelian randomization (TS-MR) analysis.

Subsequently, they conducted an MR mediation analysis to examine the mediating action of testosterone in the causality between serum VD and PCOS. Ultimately, they integrated GWAS data with cis-expression quantitative loci (cis-eQTLs) data for gene annotation, and potentially related genes were used for functional enrichment analysis to evaluate the involvement of testosterone and the potential mechanisms.

Based on the study, the researchers reported the following findings:

• TS-MR analysis showed that individuals with lower serum VD levels were more likely to develop PCOS (OR = 0.750).

• MR mediation analysis uncovered an indirect causal effect of serum VD level on the risk of PCOS via testosterone (OR = 0.983).

• Functional enrichment analysis showed that several pathways may be involved in the VD-testosterone-PCOS axis, such as steroid hormone biosynthesis and autophagy process.

“Our studies confirmed the causality between lower serum vitamin D level and higher PCOS risk,” the researchers wrote. “Furthermore, testosterone may act as a mediator between serum VD and PCOS.”

“These findings emphasize the clinical importance of testing serum vitamin D level and timely VD supplementation as possible primary prevention and treatment of PCOS,” they concluded.

Reference:

Gao, Bingrui, et al. “Causal Association Between Low Vitamin D and Polycystic Ovary Syndrome: a Bidirectional Mendelian Randomization Study.” Journal of Ovarian Research, vol. 17, no. 1, 2024, p. 95.