From Business Wire
Kadmon to Present Additional Data Demonstrating Tesevatinib Safety for the Treatment of Polycystic Kidney Disease at ASN Kidney Week 2016
Kadmon Holdings, Inc. (NYSE:KDMN) (“Kadmon” or the “Company”) today announced additional data from its ongoing Phase 2a clinical study demonstrating the safety of tesevatinib, the Company’s oral tyrosine kinase inhibitor, for the treatment of autosomal dominant polycystic kidney disease (ADPKD). The data will be presented in a poster session on Saturday, November 19 at the American Society of Nephrology (ASN) Kidney Week 2016 in Chicago, IL.
Recent findings from Kadmon’s ongoing Phase 2a study in patients with ADPKD have demonstrated that tesevatinib is well tolerated and have also identified tesevatinib 50 mg once daily (QD) as the optimal dose to treat ADPKD.
New data reported in the poster indicate that tesevatinib is a new member of a group of drugs known as MATE 1/2-K transporter inhibitors, such as cimetidine, which mildly increase levels of serum creatinine. Normally, an increase in serum creatinine can be used to indicate kidney damage, but in the case of MATE 1/2-K inhibitors, these serum creatinine increases occur without clinically meaningful alterations in renal function.
Specifically, new data demonstrated that serum creatinine levels in tesevatinib patients increased by 10% to 14% during the first 28 days of treatment and reversed upon treatment discontinuation. Importantly, levels of cystatin C, another measure of renal function, were relatively unchanged during the same period. In vitro studies demonstrated that tesevatinib potently inhibits MATE1/2-K transporters at tesevatinib concentrations achieved with the 50 mg QD dose. Therefore, MATE inhibition by tesevatinib may explain mild serum creatinine increases associated with tesevatinib treatment.
“Kadmon has identified a contradiction in PKD drug development: MATE transporters such as tesevatinib increase levels of creatinine, the standard measure of PKD drug efficacy, but without clinically relevant effects on kidney function,” said James Tonra, Ph.D., Senior Vice President, Nonclinical Development at Kadmon and first author of the poster. “These findings further characterize the safety of tesevatinib while highlighting the need for alternative methods to evaluate kidney function in PKD drug development.”
“We believe these findings support the continued development of tesevatinib for PKD,” said John Ryan, M.D., Ph.D., Executive Vice President and Chief Medical Officer at Kadmon. “Kadmon has had discussions with the FDA to develop innovative methods to demonstrate drug safety and efficacy in PKD, a major unmet medical need. These discussions will have important implications for clinical trial designs for tesevatinib as well as other therapies in development for renal diseases, especially MATE inhibitors.”
From WhaTech
Recent report on polycystic kidney disease - pipeline review, H2 2016 just published
Polycystic kidney disease (PKD) is a disorder in which clusters of cysts develop primarily within kidneys. Polycystic kidney disease symptoms may include high blood pressure, back or side pain, headache, blood in urine, frequent urination and kidney failure.
The predisposing factors include age and family history. Treatment includes antihypertensive drugs and diuretics.
Report Highlights
This report Pharmaceutical and Healthcare latest pipeline guide Polycystic Kidney Disease - Pipeline Review, H2 2016, provides comprehensive information on the therapeutics under development for Polycystic Kidney Disease (Genetic Disorders), complete with analysis by stage of development, drug target, mechanism of action (MoA), route of administration (RoA) and molecule type. The guide covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases.
The Polycystic Kidney Disease (Genetic Disorders) pipeline guide also reviews of key players involved in therapeutic development for Polycystic Kidney Disease and features dormant and discontinued projects. The guide covers therapeutics under Development by Companies /Universities /Institutes, the molecules developed by Companies in Pre-Registration, Phase III, Phase II, Phase I, Preclinical and Discovery stages are 1, 1, 2, 1, 11 and 2 respectively for Similarly, the Universities portfolio in Preclinical and Discovery stages comprises 2 and 2 molecules, respectively for Polycystic Kidney Disease.
Polycystic Kidney Disease (Genetic Disorders) pipeline guide helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. The guide is built using data and information sourced from a proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations and featured press releases from company/university sites and industry-specific third party sources.
Additionally, various dynamic tracking processes ensure that the most recent developments are captured on a real time basis.
From Nephrology News
Scientists have developed a method to coax human pluripotent stem cells to mature into cells that go on to form the functional units of the kidney and demonstrated how the method can be used to study human kidney diseases
A new method to create kidney organoids from patient cells may provide insights into how kidney diseases arise and how they should be treated. The research is presented at ASN Kidney Week 2016 November 15-20 in Chicago.
Previously, Ryuji Morizane, MD, PhD, from Brigham and Women’s Hospital, and his colleagues developed a method to coax human pluripotent stem cells (hPSCs) to mature into cells that go on to form the functional units of the kidney.
In their latest work, they show how their method can be used to study human kidney diseases. Researchers used hPSCs derived from patients with autosomal recessive polycystic kidney disease (ARPKD) to generate kidney organoids that possessed tubules with large cysts like those seen in patients with the disease.
“Establishment of a novel platform to model ARPKD using human kidney organoids will facilitate studies on mechanisms of cyst formation and contribute to the development of chemical screening systems to find potential therapeutic agents for polycystic kidney disease,” said Morizane. “Also, our organoid system enables in vitro studies of kidney pathophysiology, nephrotoxicity assays, and disease modeling, and ultimately will lead to development of bioengineered kidneys for regenerative medicine.”
Study: “Kidney organoids derived from human pluripotent stem cells contain multiple kidney compartments and model polycystic kidney disease” (Abstract 2139)
Previously, Ryuji Morizane, MD, PhD, from Brigham and Women’s Hospital, and his colleagues developed a method to coax human pluripotent stem cells (hPSCs) to mature into cells that go on to form the functional units of the kidney.
In their latest work, they show how their method can be used to study human kidney diseases. Researchers used hPSCs derived from patients with autosomal recessive polycystic kidney disease (ARPKD) to generate kidney organoids that possessed tubules with large cysts like those seen in patients with the disease.
“Establishment of a novel platform to model ARPKD using human kidney organoids will facilitate studies on mechanisms of cyst formation and contribute to the development of chemical screening systems to find potential therapeutic agents for polycystic kidney disease,” said Morizane. “Also, our organoid system enables in vitro studies of kidney pathophysiology, nephrotoxicity assays, and disease modeling, and ultimately will lead to development of bioengineered kidneys for regenerative medicine.”
Study: “Kidney organoids derived from human pluripotent stem cells contain multiple kidney compartments and model polycystic kidney disease” (Abstract 2139)
From Northwestern Medicine, BY SARAH PLUMRIDGE
A new study published in the journal Cell provides insight into potential mechanisms for the activation of a mutated gene in autosomal dominant polycystic kidney disease (ADPKD), a life-threatening genetic disorder that afflicts more than 600,000 Americans and more than 12 million people worldwide.
The gene, named polycystic kidney disease 2 (PKD2), codes for a protein that is a part of a large ion channel and sits on the membrane of cells. A team of scientists, including co-author Paul DeCaen, PhD, assistant professor of Pharmacology, used a type of microscopy called single-particle electron cryo-microscopy combined with nanodisc technology to determine the structure of the PKD2 ion channel.
The structure described in the paper establishes the molecular basis for the majority of disease-causing mutations in PKD2-related ADPKD. They show how the extracellular domain (outside of the cell) of PKD2 — a hotspot for mutations — contributes to channel assembly and may serve as a location for extracellular stimuli to bind to and affect the function of the channel’s gates, which monitor ion flow.
They further uncovered details of the channel’s current and regulation of the flow of ions, or the permeation pathway, using electrophysiology methods.
“Although we know the PKD2 dysfunction leads to ADPKD, we don’t know how to treat patients,” DeCaen said. “This work provides a structural template for drug design, which is an exciting possibility since none currently exist.”
Currently, there are no treatments for ADPKD; right now, treatment can only alleviate some symptoms of the disease. A better understanding of PKD2 structure and function could further the development of better treatments, according to the authors.
The study was supported by the National Institutes of Health NIDDK Pathway to Independence (PI) Award (K99/R00), Howard Hughes Medical Institute, and National Institutes of Health grant R01 DK110575-01A1.
From EMPR.com, Boston, MA
The investigative agent, pasireotide LAR (SOM230) was found to delay the progressive increase in liver volume and total kidney volume in patients with polycystic liver disease (PLD) and autosomal dominant polycystic kidney disease (ADPKD), in a study presented at The Liver Meeting® 2016.
Octreotide LAR, a somatostatin receptor analog, has been reported to reduce liver volume, improve quality of life in symptomatic PLD and slow glomerular filtration rate (GFR) decline in ADPKD. Maria V. Irazabal, MD, and colleagues from the Mayo Clinic, Rochester, MN, aimed to assess the safety and efficacy of pasireotide LAR in severe PLD and ADPKD. Pasireotide, a novel multi-receptor ligand somatostatin analog, possesses a "broader binding profile and higher affinity to known somatostatin receptors with potential for greater efficacy."
In the 1-year, double-blind randomized trial, 48 study patients were assigned 2:1 to receive pasireotide LAR 60mg or placebo every 28 days; patients were stratified by ADPKD and ADPLD.
"Primary endpoint was change in liver volume; secondary endpoints were change in kidney volume, estimated GFR [eGFR], and quality of life [QOL]," explained Dr. Irazabal. Forty patients completed liver volume measurements at 12 months.
The researchers reported a 3.3% decrease in annualized change in liver volume (4271 ± 2373mL to 4104 ± 2265mL) in the pasireotide LAR group vs. a 6.3% increase in liver volume (4047 ± 1298mL to 4294 ± 1314mL) in the placebo group (P=0.001).
Regarding kidney volume, researchers reported a 1.1% decrease in the pasireotide LAR group vs. a 3.9% increase in the placebo group (P=0.024).
"Changes in eGFR were not different between groups," noted Dr. Irazabal.
Pasireotide LAR the target dose, was reached in 87.5% of patients within the first year. Patients in the pasireotide LAR group, however, experienced a higher incidence of adverse events such as hyperglycemia (73% vs. 20%; P=0.003) and diabetes (30% vs. 0%; P=0.042) compared to the placebo group.
Overall, pasireotide LAR slowed the progressive growth in both liver and total kidney volume in patients with PLD and ADPKD. Bigger studies are warranted to determine the impact of somatostatin receptor analogs on eGFR decline, concluded study authors.
The tiny fruit fly can help humans investigate the genetic and neural bases of detecting painful or harmful cold stimuli and offer intriguing, potential implications for human health, according to a new study.
A team of researchers led by Dr. Daniel N. Cox, associate professor of neuroscience at Georgia State University, has discovered that fruit flies have cold-sensing neurons that when activated drive specific, aversive behaviors to damaging cold, which requires the function of evolutionarily conserved ion channels known as Transient Receptor Potential (TRP) channels.
In the journal Current Biology, the researchers establish the fruit fly, Drosophila melanogaster, as a powerful genetic and behavioral model for unraveling questions about the cellular and molecular bases of damaging cold perception, which have not been well understood.
The study explores the concept of nociception, the peripheral and central nervous systems' perception of painful or potentially tissue damaging stimuli, which is generated by activating sensory nerve cells called nociceptors. This evolutionarily conserved process is critically important for survival.
Nociception, coupled with pain sensation, alerts an organism to possible environmental dangers and allows it to execute behavioral responses to protect against incipient damage. Acute and chronic pain can manifest as altered nociception in neuropathic pain states.
The study found that one of the implicated TRP channel genes called Pkd2 has been causally linked to autosomal dominant polycystic kidney disease (PKD), the most common monogenic disease in humans. Pkd2 ion channels appear to function as cold sensors and misexpression of Pkd2 can confer cold sensitivity to normally insensitive neurons. While it is not yet known if PKD patients have cold nociception defects, these new findings suggest this merits further investigation as a potential non-invasive diagnostic.
These same cold-sensing neurons also function as mechanosensors for touch, revealing that they, as well as the TRP channels identified in this study, are multimodal and raising the question of how neurons and ion channels distinguish between harmless and harmful stimuli to drive specific behavioral responses. Using sophisticated optical assays of neural activation by touch versus cold stimuli, the researchers demonstrate that these sensory neurons have different activation thresholds, with touch having a low threshold and cold having a high threshold, that ultimately determine the appropriate behavioral response.
"This new model sets the stage for uncovering evolutionarily conserved molecular control of nociception," said Cox. "It also provides a powerful genetic platform for unraveling the neural circuitry and molecular mechanisms that integrate multimodal sensory input to produce specific behaviors in response to diverse environmental stimuli."
The research team included Kevin Armengol, Atit A. Patel, Nathaniel J. Himmel, Luis Sullivan, Dr. Srividya C. Iyer and Dr. Eswar P.R. Iyer of the Cox Lab at Georgia State's Neuroscience Institute and Center for Behavioral Neuroscience, and collaborators Heather N. Turner and Michael J. Galko from MD Anderson Cancer Center.
The next steps will be to dissect the neural circuitry, additional molecular players and synaptic mechanisms that modulate cold nociception and multimodal sensory processing.
Octreotide LAR, a somatostatin receptor analog, has been reported to reduce liver volume, improve quality of life in symptomatic PLD and slow glomerular filtration rate (GFR) decline in ADPKD. Maria V. Irazabal, MD, and colleagues from the Mayo Clinic, Rochester, MN, aimed to assess the safety and efficacy of pasireotide LAR in severe PLD and ADPKD. Pasireotide, a novel multi-receptor ligand somatostatin analog, possesses a "broader binding profile and higher affinity to known somatostatin receptors with potential for greater efficacy."
In the 1-year, double-blind randomized trial, 48 study patients were assigned 2:1 to receive pasireotide LAR 60mg or placebo every 28 days; patients were stratified by ADPKD and ADPLD.
"Primary endpoint was change in liver volume; secondary endpoints were change in kidney volume, estimated GFR [eGFR], and quality of life [QOL]," explained Dr. Irazabal. Forty patients completed liver volume measurements at 12 months.
The researchers reported a 3.3% decrease in annualized change in liver volume (4271 ± 2373mL to 4104 ± 2265mL) in the pasireotide LAR group vs. a 6.3% increase in liver volume (4047 ± 1298mL to 4294 ± 1314mL) in the placebo group (P=0.001).
Regarding kidney volume, researchers reported a 1.1% decrease in the pasireotide LAR group vs. a 3.9% increase in the placebo group (P=0.024).
"Changes in eGFR were not different between groups," noted Dr. Irazabal.
Pasireotide LAR the target dose, was reached in 87.5% of patients within the first year. Patients in the pasireotide LAR group, however, experienced a higher incidence of adverse events such as hyperglycemia (73% vs. 20%; P=0.003) and diabetes (30% vs. 0%; P=0.042) compared to the placebo group.
Overall, pasireotide LAR slowed the progressive growth in both liver and total kidney volume in patients with PLD and ADPKD. Bigger studies are warranted to determine the impact of somatostatin receptor analogs on eGFR decline, concluded study authors.
From News-Medical
A team of researchers led by Dr. Daniel N. Cox, associate professor of neuroscience at Georgia State University, has discovered that fruit flies have cold-sensing neurons that when activated drive specific, aversive behaviors to damaging cold, which requires the function of evolutionarily conserved ion channels known as Transient Receptor Potential (TRP) channels.
In the journal Current Biology, the researchers establish the fruit fly, Drosophila melanogaster, as a powerful genetic and behavioral model for unraveling questions about the cellular and molecular bases of damaging cold perception, which have not been well understood.
The study explores the concept of nociception, the peripheral and central nervous systems' perception of painful or potentially tissue damaging stimuli, which is generated by activating sensory nerve cells called nociceptors. This evolutionarily conserved process is critically important for survival.
Nociception, coupled with pain sensation, alerts an organism to possible environmental dangers and allows it to execute behavioral responses to protect against incipient damage. Acute and chronic pain can manifest as altered nociception in neuropathic pain states.
The study found that one of the implicated TRP channel genes called Pkd2 has been causally linked to autosomal dominant polycystic kidney disease (PKD), the most common monogenic disease in humans. Pkd2 ion channels appear to function as cold sensors and misexpression of Pkd2 can confer cold sensitivity to normally insensitive neurons. While it is not yet known if PKD patients have cold nociception defects, these new findings suggest this merits further investigation as a potential non-invasive diagnostic.
These same cold-sensing neurons also function as mechanosensors for touch, revealing that they, as well as the TRP channels identified in this study, are multimodal and raising the question of how neurons and ion channels distinguish between harmless and harmful stimuli to drive specific behavioral responses. Using sophisticated optical assays of neural activation by touch versus cold stimuli, the researchers demonstrate that these sensory neurons have different activation thresholds, with touch having a low threshold and cold having a high threshold, that ultimately determine the appropriate behavioral response.
"This new model sets the stage for uncovering evolutionarily conserved molecular control of nociception," said Cox. "It also provides a powerful genetic platform for unraveling the neural circuitry and molecular mechanisms that integrate multimodal sensory input to produce specific behaviors in response to diverse environmental stimuli."
The research team included Kevin Armengol, Atit A. Patel, Nathaniel J. Himmel, Luis Sullivan, Dr. Srividya C. Iyer and Dr. Eswar P.R. Iyer of the Cox Lab at Georgia State's Neuroscience Institute and Center for Behavioral Neuroscience, and collaborators Heather N. Turner and Michael J. Galko from MD Anderson Cancer Center.
The next steps will be to dissect the neural circuitry, additional molecular players and synaptic mechanisms that modulate cold nociception and multimodal sensory processing.
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