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Positive Results Announced in Largest Pivotal Phase 3 Trial of a First-in-Class Oral Antibiotic to Treat Uncomplicated Gonorrhea
The Global Antibiotic Research & Development Partnership (GARDP), in partnership with Innoviva, Inc. (Nasdaq: INVA), had announced a significant milestone. They revealed that zoliflodacin, a groundbreaking antibiotic, successfully achieved its primary goal in a groundbreaking global pivotal Phase 3 clinical trial. Researchers conducting the study observed that when compared to the current global standard treatment, which involves intramuscular (IM) injection of ceftriaxone and oral azithromycin, oral zoliflodacin exhibited a comparable microbiological cure rate at the urogenital site, demonstrating statistical non-inferiority. Moreover, the trial found that zoliflodacin was generally well-tolerated, with no instances of serious adverse events or fatalities reported.
In the Phase 3 trial, a total of 930 patients with uncomplicated gonorrhea, including women, adolescents, and individuals living with HIV, were recruited. This trial stands as the most extensive clinical study ever conducted for a novel gonorrhea treatment, with 16 trial locations situated in regions where gonorrhea is highly prevalent, spanning five countries: Belgium, the Netherlands, South Africa, Thailand, and the U.S. The study involved a comparison between a single, oral 3g dose of zoliflodacin and a globally recognized standard treatment regimen (comprising 500mg ceftriaxone via intramuscular injection plus 1g of oral azithromycin) for managing uncomplicated gonorrhea. Zoliflodacin met the prespecified statistical test for non-inferiority when compared to ceftriaxone and oral azithromycin. Noninferiority of zoliflodacin was demonstrated within the pre-specified margin of 12% and, furthermore, within the margin of 10% as specified in U.S. Food and Drug Administration guidance.
This is the first study to address a World Health Organization priority pathogen that has been sponsored and led by a non-profit organization. These positive preliminary findings offer hope for patients with this condition, particularly in the face of rising antibiotic resistance to current regimens. It also paves the way for a new research and development model in the global fight against antimicrobial resistance (AMR). If approved, zoliflodacin will be the first new antibiotic for treating gonorrhea in decades.
“This is a significant step forward in the treatment of gonorrhea, and also shows that GARDP’s public-private partnership model can play a crucial role in helping to fix the public health failure at the heart of the global AMR crisis,” said Dr. Manica Balasegaram, Executive Director of GARDP. “Despite the extremely high public health value, there has been a lack of investment to develop new drugs for gonorrhea. This zoliflodacin program demonstrates that it is possible to develop antibiotic treatments targeting multidrug-resistant bacteria that pose the greatest public health threat, and which may not otherwise get developed.”
“The success of this study could have a profound effect on how physicians approach gonorrhea infections, as an oral alternative to an injection could improve patient access and compliance, as well as help reduce the increasing spread of antibiotic-resistant strains of the disease,” said Pavel Raifeld, Chief Executive Officer, Innoviva, Inc. “Such a positive outcome represents an important milestone for Innoviva Specialty Therapeutics and reinforces our position as a premier infectious disease and critical care company.”
Gonorrhea represents a significant public health burden due to its prevalence and increasing antibiotic resistance. Neisseria gonorrhoeae, the bacteria responsible for gonorrhea, has been progressively developing resistance to various classes of antibiotics used for treatment. Consequently, ceftriaxone, administered as a single intramuscular injection, has emerged as the last remaining recommended treatment option for gonorrhea on a worldwide scale. As per information provided by the NORD, desmoid tumors account for just 0.03% of all tumors. The estimated occurrence rate within the general population ranges from 2 to 4 cases per one million people annually. These tumors tend to be more frequently observed in individuals aged between 10 and 40 years, although they can affect other age groups as well. Notably, desmoid tumors are known to be more common in women following childbirth, with a female-to-male gender ratio of 2 to 1. In children, the gender distribution is equal. Globally, there are over 82 million new gonorrhe cases each year, making it the third most prevalent sexually transmitted infection. This infection affects both men and women and can lead to severe and long-lasting health complications. Pharmaceutical companies, such as Innoviva, among others, are actively developing innovative treatments to combat this growing challenge.
FDA Awards Orphan Drug Designation to Rhenium Obisbemeda in Breast Cancer With Leptomeningeal Metastases
Plus Therapeutics announced that the U.S. Food and Drug Administration (FDA) has declared Orphan Drug Designation to rhenium (186Re) obisbemeda for its application in treating breast cancer patients who have leptomeningeal metastases. The Orphan Drug Designation is granted by the FDA to experimental drugs or biological products designed to prevent, diagnose, or treat rare diseases or conditions that affect fewer than 200,000 individuals in the United States. Companies that receive this designation enjoy several benefits, such as assistance in the drug development process, tax credits for clinical expenses, exemptions from specific FDA fees, and a marketing exclusivity period of 7 years post-approval.
Marc H. Hedrick, M.D., President, and Chief Executive Officer of Plus Therapeutics, emphasized the significance of obtaining the Orphan Drug Designation from the FDA, noting that it validates their radiotherapeutic candidate for breast cancer patients with leptomeningeal metastases who currently lack FDA-approved treatment options. Leptomeningeal metastases is a rapidly advancing and life-threatening complication associated with various cancers, including breast cancer, and its incidence is on the rise.
The Orphan Drug Designation, in combination with the previously granted Fast Track designation, underscores the pressing need for new treatment options for leptomeningeal metastases. Plus Therapeutics believes that rhenium (186Re) obisbemeda has the potential to address this unmet need and is eager to continue making progress with their ReSPECT-LM program.
Rhenium (186Re) obisbemeda is currently under assessment in the ReSPECT-LM Phase 1/2a dose escalation clinical trial. Cohort 4 of the ReSPECT-LM trial has recently finished enrollment, and the company anticipates moving on to Cohort 5 following the standard safety review. Updates on the ReSPECT-LM trial will be presented at the Society for Neuro-Oncology Annual Meeting scheduled for November 15-19, 2023. In addition to the Orphan Drug Designation, the FDA had previously granted Fast Track designation to rhenium (186Re) obisbemeda for the treatment of leptomeningeal metastases.
FDA Approves Merck’s KEYTRUDA Plus Gemcitabine and Cisplatin as Treatment for Patients With Locally Advanced Unresectable or Metastatic Biliary Tract Cancer
Merck has announced that the U.S. Food and Drug Administration (FDA) has granted approval for the use of KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with gemcitabine and cisplatin, for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). This approval is based on the results of the Phase 3 KEYNOTE-966 trial, where the combination of KEYTRUDA and chemotherapy exhibited a statistically significant improvement in the primary outcome of overall survival (OS), reducing the risk of death by 17% when compared to chemotherapy alone at the predetermined final analysis for OS. The median OS was 12.7 months for the KEYTRUDA plus chemotherapy group, as opposed to 10.9 months for the chemotherapy alone group. This marks the sixth approved use of KEYTRUDA in gastrointestinal cancers.
It is important to note that immune-mediated adverse reactions, which can be severe or even fatal, may affect various organs or tissues and multiple body systems simultaneously. These reactions can occur at any time during or after treatment with KEYTRUDA and encompass conditions such as pneumonitis, colitis, hepatitis, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. The list of significant immune-mediated adverse reactions provided may not cover all potential severe and fatal immune-mediated adverse reactions.
Early detection and appropriate management of these reactions are crucial to ensure the safe use of KEYTRUDA. Depending on the severity of the adverse reaction, KEYTRUDA may need to be temporarily withheld or permanently discontinued, and corticosteroids may be administered as needed. Additionally, it’s worth noting that KEYTRUDA has the potential to cause severe or life-threatening infusion-related reactions due to its mechanism of action, and it can also lead to fetal harm when administered to pregnant women.
New Asundexian Phase III Study to Include Patients with Atrial Fibrillation Ineligible for Oral Anticoagulant Treatment
Bayer broadens its Phase III OCEANIC clinical development program for the investigational drug asundexian (BAY2433334) by introducing a third clinical trial, known as OCEANIC-AFINA. This new study, OCEANIC-AFINA, falls under the Phase III category and focuses on exploring the potential of asundexian as a treatment for atrial fibrillation in patients aged 65 and above who face a high risk of stroke or systemic embolism. These patients are considered ineligible for oral anticoagulation (OAC) treatment due to an increased risk of bleeding. OCEANIC-AFINA acts as a complement to OCEANIC-AF, an ongoing Phase III study assessing the effectiveness and safety of asundexian in preventing stroke or systemic embolism in individuals with AF at risk of stroke. The combined results from OCEANIC-AFINA and OCEANIC-AF aim to furnish substantial evidence regarding the efficacy and safety of asundexian across a diverse spectrum of AF patients. This includes those highly susceptible to ischemic stroke or systemic embolism as well as major bleeding events.
Research indicates that 1 in 3 atrial fibrillation patients are either undertreated or not treated at all with oral anticoagulants, underscoring a significant gap for an efficient therapy that doesn’t exacerbate bleeding risks during treatment. The elderly with AF are at high bleeding risk and AF patients with end-stage kidney disease (ESKD) undergoing hemodialysis often receive doses lower than guideline recommendations. Moreover, those discontinuing OACs face heightened susceptibility to subsequent ischemic strokes. Intervening with asundexian, an FXIa inhibitor, could potentially address this unmet necessity by offering protection against thrombotic events without a concomitant escalation in bleeding risk.
“The preliminary clinical findings we’ve observed thus far suggest that asundexian could represent a novel avenue for antithrombotic therapy for a wider spectrum of patients,” remarked Dr. Christian Rommel, a member of Bayer AG’s Pharmaceutical Division Executive Committee and the Global Head of Research and Development. “Our goal is to assist individuals with atrial fibrillation, particularly those who were previously excluded from oral anticoagulant treatments. We aspire to provide them with a new therapeutic option to enhance their quality of life, mitigating concerns about potential elevated bleeding risks and enabling healthcare professionals to confidently recommend antithrombotic therapy for patient protection. Through OCEANIC-AFINA, we are examining asundexian in an underrepresented, vulnerable patient cohort.”
Asundexian is an experimental compound that has not received approval from any health regulatory body for use in any nation or for any specific medical condition. It is presently under investigation as a potential daily oral Factor XIa (FXIa) inhibitor aimed at preventing thromboembolic events. The compound’s primary objective is to diminish abnormal clot formation while preserving the body’s ability to form clots necessary for stopping bleeding.
Zibotentan/dapagliflozin Combination Demonstrated Significant Albuminuria Reduction in Patients with Chronic Kidney Disease and Proteinuria in ZENITH-CKD Phase IIb Trial
The combination of zibotentan with dapagliflozin exhibited significant and clinically relevant reductions in the urinary albumin-to-creatinine ratio (UACR), a key indicator for assessing albuminuria, after the 12-week treatment period in the Phase IIb ZENITH-CKD trial compared to the use of dapagliflozin alone. At the conclusion of the 12-week treatment, the UACR differences for the zibotentan/dapagliflozin combination versus dapagliflozin alone were statistically notable. For the high dose (1.5 mg zibotentan / 10 mg dapagliflozin; n=179), the UACR difference was –33.7% (90% CI –42.5 to –23.5; p<0.001), and for the low dose (0.25 mg / 10 mg; n=91), it was –27.0% (90% CI –38.4 to –13.6; p=0.002). Furthermore, the percentage mean change from baseline in UACR demonstrated a substantial reduction of –52.5% (90% CI –59.0 to –44.9) for the high-dose combination and –47.7% (90% CI –55.7 to –38.2) for the low-dose combination. These findings were presented at the American Society of Nephrology (ASN) Kidney Week 2023 and simultaneously published in The Lancet.
Previous research indicates that endothelin A (ETA) receptor antagonists have been linked with elevated instances of fluid retention. The findings from the ZENITH-CKD trial revealed that while high-dose zibotentan/dapagliflozin did not exhibit comparable fluid retention events to dapagliflozin alone, low-dose zibotentan/dapagliflozin demonstrated similar occurrences. Specifically, 18.4% (33 out of 179), 8.8% (8 out of 91), and 7.9% (14 out of 177) of patients experienced such events in the high-dose combination, low-dose combination, and dapagliflozin groups, respectively.
Hiddo Heerspink, from the Department of Clinical Pharmacy and Pharmacology at the University of Groningen, University Medical Center Groningen in the Netherlands, remarked: “Elevated albuminuria levels correlate with a heightened risk of gradual kidney function decline. Lowering these levels can mitigate the risk of advancing to kidney failure. The promising findings from the ZENITH-CKD trial today exhibit therapeutic promise for assisting patients persistently at risk due to lingering albuminuria. This approach capitalizes on the favorable characteristics of an ETA receptor antagonist combined with an SGLT2 inhibitor, offering potential benefits.”
As per DelveInsight, the total diagnosed prevalent cases of CKD in the 7MM comprised of approximately 16 million cases in 2022 and are projected to increase during the forecasted period (2023-2032). CKD has been identified as a female-dominant disease; in our analysis, the number of females suffering was higher than males. In 2022, 52% of cases of CKD were in females, while 48% of cases were in males in the 7MM.
This innovative investigational treatment combines zibotentan, a highly targeted ETA receptor antagonist recognized for enhancing kidney blood flow and reducing albuminuria and vascular stiffness, with dapagliflozin, a specific inhibitor of the sodium-glucose cotransporter 2 (SGLT2) known for its efficacy in slowing the progression of chronic kidney disease in patients at risk of advancement. Dapagliflozin functions by facilitating the removal of excess fluid from the extravascular space, potentially further reducing the risk of fluid retention. These findings pave the way for advancement to Phase III trials, scheduled to commence in the fourth quarter of 2023, marking a significant step forward in the treatment’s development.
Ayala Pharmaceuticals Announces AL102 Receives Orphan Drug Designation for Desmoid Tumors
On Nov. 06, 2023, Ayala Pharmaceuticals (OTCQX: ADXS) announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to AL102, a Gamma Secretase Inhibitor (GSI), specifically for the treatment of desmoid tumors (DT). AL102 is an investigational small molecule Gamma Secretase Inhibitor (GSI) that is designed to potently and selectively inhibit Notch 1, 2, 3, and 4 and is currently being evaluated in the Phase 2/3 RINGSIDE clinical studies in patients with progressing desmoid tumors. AL102 is designed to inhibit the expression of Notch gene targets by blocking the final cleavage step by the gamma-secretase required for Notch activation.
Earlier, in November 2017, Ayala secured an exclusive global license to advance and market AL102 from Bristol-Myers Squibb Company. AL102 received U.S. FDA Fast Track Designation for its application in desmoid tumor treatment.
“Receiving FDA orphan drug status for AL102 underscores the significant unmet need for novel treatment options for people living with desmoid tumors. We look forward to continuing to work closely with regulators, clinical investigators, patients and their families to advance this potentially important medicine and make it available to those who may benefit from it,” said Kenneth Berlin, President and CEO of Ayala.
Desmoid tumors, also known as aggressive fibromatosis, are exceedingly rare connective tissue tumors with a penchant for developing in various parts of the body. These tumors often emerge in the upper and lower extremities, the abdominal wall, head and neck regions, mesenteric root, chest wall, and other anatomical locations. Unlike many other forms of cancer, desmoid tumors do not metastasize, but they exhibit a notably invasive nature, infiltrating neurovascular structures and vital organs, which can lead to substantial health challenges.
These tumors affect a relatively small number of individuals, with an estimated annual incidence of around 1,700 patients in the United States. Typically, they manifest in patients between the ages of 15 and 60 years, predominantly striking individuals in their 30s and 40s, with a higher prevalence among females. Living with desmoid tumors can be profoundly challenging, as patients often grapple with chronic pain, functional impairments, a significant decline in their overall quality of life, and dysfunction of affected organs.
One of the most pressing issues in the realm of desmoid tumor management is the absence of FDA-approved systemic therapies for the treatment of unresectable, recurrent, or progressive desmoid tumors. This underscores the critical need for innovative and effective treatment options to improve the outlook for those grappling with this challenging condition.
To address the growing burden of desmoid tumors, pharmaceutical companies such as Ayala Pharmaceuticals, along with several others, are actively engaged in research and development. They are working to develop novel therapies and treatment approaches to improve the management and outcomes of patients with this rare condition. These efforts offer hope for individuals affected by desmoid tumors by potentially providing more effective and less invasive treatment options, ultimately reducing the burden associated with this disease.