Novel drug candidate prevents nerve cell damage in mouse model of Parkinson's disease

A team of scientists at the University of Nebraska Medical Center (UNMC) and Longevity Biotech, Inc., has demonstrated that neuroprotection could be attained in preclinical models by a novel drug candidate that changes immune responses.

The results, published today in the Journal of Neuroscience, describe the prevention of nerve cell damage in a mouse model of Parkinson's disease. Notably, the drug protected nerve cells that produce dopamine, which is the chemical responsible for agility and movement that is lost in human disease.

"The results are exciting as they provide a bridge between the immune system and nerve cell protection in Parkinson's disease," said Scott Shandler, Ph.D., co-founder and CEO of Longevity Biotech.

"The idea was birthed nearly a decade ago when specific types of circulating blood cells called lymphocytes were found to damage the types of nerve cells responsible for disease," said Howard Gendelman, M.D., the Margaret R. Larson Professor and chair of the UNMC Department of Pharmacology and Experimental Neuroscience. "The new Longevity Biotech drug (LBT-3627) was able to change the function of these cells from killing the nerve cells to protecting them. This is especially significant for the Nebraska team, as the mechanism parallels closely the human trials nearing completion for Parkinson's patients."

LBT-3627 is similar to the naturally occurring vasoactive intestinal peptide (VIP), a well-established anti-inflammatory peptide with beneficial effects across a variety of disorders. VIP is rapidly degraded by the body and is unable to distinguish between its two naturally intended receptors (VPAC1 vs. VPAC2). These limitations have stymied prior translational success using VIP.

Novel drug candidate prevents nerve cell damage in mouse model of Parkinson's disease

Cancer drug may protect kidneys from damage caused by chemotherapy agent cisplatin

In continuation of my update on cis platin...

A class of drugs used increasingly to help fight cancer may have the additional benefit of protecting the kidneys when packaged with the powerful chemotherapy agent cisplatin.

The nearly 40-year-old cisplatin can be a strong opponent against aggressive cancers, such as head and neck, ovarian and lung cancers.

But in more than 10 percent of patients, the drug, given intravenously for typically a handful of days, can also take a quick and potentially deadly toll on the kidneys, said Dr. Ganesan Ramesh, kidney pathologist at the Vascular Biology Center at the Medical College of Georgia at Augusta University and at the university's Cancer Center.

Ramesh and his colleagues have new laboratory evidence that histone deacetylase inhibitors, or HDAC inhibitors, can eliminate 80-90 percent of that kidney toxicity.

"Cisplatin is a very effective drug, and we don't want to stop using it," said Ramesh, corresponding author of the study in the journal Kidney International. "We want to reduce its toxicity to the normal tissue."

The super-busy kidneys filter the entire blood volume of the body every 20 minutes. A big part of their job is removing toxins for elimination in the urine and pushing back into the body valuables such as glucose and nutrients. The major problem with cisplatin is it can get stuck in the kidneys, where the platinum metal compounds the drug releases to kill a tumor can do serious harm. Inside the kidneys, the malingerer stimulates inflammation, DNA damage, free-radical production and cell death.

When MCG researchers gave HDAC inhibitors to mice receiving cisplatin, it dramatically suppressed the usual inflammation and cell death that follow cisplatin dosing alone.

Histones are the protein spools DNA wraps around, and histone deacetylase enables DNA to be wound tightly and regulates gene expression and protein function. One way HDAC inhibitors help fight cancer is by temporarily loosening DNA, increasing the expression of tumor-suppressing genes and making the tumor more vulnerable. Evidence that HDAC inhibitors also can protect kidneys following injury, led Ramesh to reason it was logical to pair these drugs with cisplatin.

Cancer drug may protect kidneys from damage caused by chemotherapy agent cisplatin

Ibrutinib ‘new standard’ for relapsed, refractory mantle cell lymphoma

In continuation of my update on Ibrutinib and Temsirolimus

Temsirolimus

Phase III trial findings suggest that patients with relapsed or refractory mantle cell lymphoma derive significantly greater benefits from ibrutinib than from temsirolimus therapy.

Ibrutinib

The results of this direct comparison of the two treatment options approved in the European Union for this patient population “clearly establish ibrutinib as a new standard for treatment” of relapsed or refractory mantle cell lymphoma, says Peter Martin (Weill Cornell Medical College, New York, USA) in a comment accompanying the report in The Lancet.

He adds: “Many clinicians expect that, within the next 2 years, ibrutinib will find its way into the front-line setting for treatment of mantle cell lymphoma in combination with standard chemotherapy”.

In the trial, a total of 280 patients with relapsed or refractory disease who had previously been treated with at least one rituximab-containing regimen were followed up for a median of 20 months.

Median progression-free survival (PFS) was 14.6 months for the 139 patients randomly assigned to receive open-label oral ibrutinib and 6.2 months for the 141 patients given intravenous temsirolimus, a significant difference with a hazard ratio for progression or death of 0.43. The corresponding 2-year PFS rates were 41% and 7%.

Significantly more patients given the Bruton’s tyrosine kinase inhibitor ibrutinib achieved an overall response compared with those given the mammalian target of rapamycin antagonist temsirolimus, with rates of 72% versus 40%. And complete responses were observed in 19% and 1% of patients, respectively.

Ibrutinib ‘new standard’ for relapsed, refractory mantle cell lymphoma

Capecitabine increases disease-free survival for HER2-negative breast cancer patients

Treatment with the chemotherapy agent capecitabine increased disease-free survival for women with HER2-negative breast cancer that was not eliminated by presurgery chemotherapy, according to results from the phase III CREATE-X clinical trial presented at the 2015 San Antonio Breast Cancer Symposium, held Dec. 8-12.

Treatment given to shrink or eliminate a tumor before surgery is called neoadjuvant therapy. In some patients with breast cancer treated with neoadjuvant chemotherapy, residual invasive cancer can be detected in breast tissue samples and lymph nodes removed during surgery. These patients tend to have worse long-term outcomes compared with women who respond completely to neoadjuvant therapy.

"It has been suggested that patients with residual invasive disease after neoadjuvant chemotherapy have chemoresistant breast cancer, but there have been no large-scale clinical trials to test whether adjuvant systemic chemotherapy is beneficial for these patients," said Masakazu Toi, MD, PhD, a professor at Kyoto University Hospital in Japan, and founder and senior director of the Japan Breast Cancer Research Group (JBCRG). "CREATE-X was designed to evaluate this clinical question by testing whether capecitabine could improve disease-free survival for patients with residual invasive disease after neoadjuvant chemotherapy.

Capecitabine increases disease-free survival for HER2-negative breast cancer patients

Study reveals why anti-hormone therapy tamoxifen works better in some women than others

In continuation of my update on tamoxifen

The anti-hormone therapy tamoxifen can reduce breast cancer recurrence by about half in women with hormone-sensitive breast cancer. But it works better in some women than others. Researchers are not sure why.

"We do know that some tumors are inherently resistant to tamoxifen because of tumor genetic changes," says Daniel L. Hertz, Pharm.D., Ph.D., an assistant professor in the University of Michigan College of Pharmacy and member of the U-M Comprehensive Cancer Center.

"These tumor have found pathways to overcome anti-estrogen treatment. But we also believe some patients may be less likely to benefit from tamoxifen or endocrine therapy because of their genetics," Hertz says.

One theory is that in some patients, tamoxifen is not activated to the more potent estrogen inhibitor endoxifen. Patients with low levels of endoxifen may have worse outcomes on tamoxifen.

A meta-analysis by the International Tamoxifen Pharmacogenetics Consortium points to genetic variants. Researchers found patients with certain variants on the gene CYP2D6 had worse survival. Later analyses of prospective clinical trials, however, did not find the same link.

Study reveals why anti-hormone therapy tamoxifen works better in some women than others

FDA approves Vistogard (uridine triacetate) for emergency treatment of chemotherapy overdose

The U.S. Food and Drug Administration today approved Vistogard (uridine triacetate) for the emergency treatment of adults and children  who receive an overdose of the cancer treatment fluorouracil or  capecitabine, or who develop certain severe or life-threatening 
toxicities within four days of receiving these cancer treatments.

 "Treating cancer requires not only selecting which drug may be most  effective and well tolerated, but ensuring the correct dose is given at  proper intervals. While rare, unintentional overdose can occur," said  Richard Pazdur, M.D., director of the Office of Hematology and Oncology  Products in the FDA's Center for Drug Evaluation and Research. "Today's  approval is a first-of-its-kind therapy that can potentially save lives following overdose or life-threatening toxicity from these chemotherapy agents."

 Fluorouracil (taken by infusion) and capecitabine (taken orally) are similar types of chemotherapy that have been used for decades to treat several types of cancer, including breast and gastrointestinal cancers. An overdose of fluorouracil or capecitabine is rare, but when it occurs,the effects are serious and can be fatal.

  

Vistogard, taken orally, blocks cell damage and cell death caused by fluorouracil chemotherapy. Patients should take Vistogard as soon as  possible after the overdose (whether or not they have symptoms) or early-onset (within four days) of severe or life-threatening toxicity. The patient's health care provider will determine when he or she should 
return to the prescribed chemotherapy after treatment with Vistogard.

  

The efficacy and safety of Vistogard were studied in 135 adult and pediatric cancer patients who were treated in two separate trials and had either received an overdose of flourouracil or capecitabine, or had early-onset, unusually severe or life-threatening toxicities within 96 
hours after receiving flourouracil (not due to an overdose). The studies' primary measure was survival at 30 days or until chemotherapy  could resume if prior to 30 days. Of those who were treated with  Vistogard for overdose, 97 percent were still alive at 30 days. Of those treated with Vistogard for early-onset severe or life-threatening toxicity, 89 percent were alive at 30 days. In both studies, 33 percent of patients resumed chemotherapy in less than 30 days.

FDA approves Vistogard (uridine triacetate) for emergency treatment of chemotherapy overdose

Role for carfilzomib in relapsed, refractory multiple myeloma treatment

In continuation of my update on carfilzomib

Carfilzomib significantly improves outcomes in previously treated patients with relapsed or refractory multiple myeloma, shows a head-to-head comparison with bortezomib.

In the ENDEAVOR phase III trial, published in The Lancet Oncology, median progression-free survival (PFS) was 18.7 months for the 464 patients randomly assigned to receive open-label carfilzomib plus dexamethasone. This was significantly longer than the 9.4 months for the 465 participants treated with bortezomib and dexamethasone, and equated to a 47% risk reduction in favour of carfilzomib.

Moreover, a significantly higher proportion of carfilzomib- than bortezomib-treated patients achieved an objective response, at 77% versus 63%, and the duration of response was also longer in the former group, at a respective 21.3 and 10.4 months.

The most common side effects of grade 3 or worse that occurred more frequently in the carfilzomib than the bortezomib treatment arm were anaemia and hypertension, with rates of 14% versus 10% and 9% versus 3%, respectively.

However, peripheral neuropathy of grade 3 was observed in 2% of carfilzomib-treated patients and there were no grade 4 events, compared with 8% of patients in the bortezomib arm who experienced events of grade 3 or 4.

Serious adverse events occurred in 48% of patients in the carfilzomib group and in 36% of those given bortezomib, but Meletios Dimopoulos (National and Kapodistrian University of Athens, Greece) and team note that the number of discontinuations and deaths attributable to adverse events were comparable between the groups.

They conclude that carfilzomib plus dexamethasone could be considered for multiple myeloma patients for whom bortezomib is indicated.

Role for carfilzomib in relapsed, refractory multiple myeloma treatment

Alecensa (alectinib) approved for treatment of people with advanced ALK-positive NSCLC

The U.S. Food and Drug Administration today approved Alecensa (alectinib) to treat people with advanced (metastatic) ALK-positive non-small cell lung cancer (NSCLC) whose disease has worsened after, or who could not tolerate treatment with, another therapy called Xalkori (crizotinib).

Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015, according to the National Cancer Institute. An ALK (anaplastic lymphoma kinase) gene mutation can occur in several different types of cancer cells, including lung cancer cells. ALK gene mutations are present in about 5 percent of patients with NSCLC. In metastatic cancer, the disease spreads to new parts of the body. In ALK-positive NSCLC metastatic patients, the brain is a common place for the disease to spread.

 Crizotinib

"Today's approval provides a new therapy for a group of patients who would have few treatment options once their disease no longer responds to treatment with Xalkori," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "In addition to the primary effect on tumors in the lung, Alecensa clinical trials provide evidence of an effect on tumors that had spread to the brain, which is an important effect for clinicians to understand."

Alecensa is an oral medication that blocks the activity of the ALK protein, which may prevent NSCLC cells from growing and spreading.

Alecensa (alectinib) approved for treatment of people with advanced ALK-positive NSCLC

Single dose of psilocybin decreases anxiety, depression in cancer patients

In continuation of my update on Psilocybin

A single dose of psilocybin, the major hallucinogenic component in magic mushrooms, induces long-lasting decreases in anxiety and depression in patients diagnosed with life-threatening cancer according to a new study presented today at the annual meeting of the American College of Neuropsychopharmacology.

Patients who receive a cancer diagnosis often develop debilitating symptoms of anxiety and depression. Reports from the 1960s and 1970s suggest that hallucinogenic drugs such as LSD may alleviate such symptoms in cancer patients, but the clinical value of hallucinogenic drugs for the treatment of mood disturbances in cancer patients remains unclear. In this new study, Roland Griffiths and colleagues from the Johns Hopkins University School of Medicine investigated the effects of psilocybin on symptoms of anxiety and depression in individuals diagnosed with life-threatening cancer. Five weeks after receiving a dose of psilocybin sufficiently high to induce changes in perception and mystical-type experiences, patients reported significantly lower levels of anxiety and depression compared with patients that received a low dose of the drug. The positive effects on mood persisted in the patients at 6 month follow-up.

The authors suggest that a single dose of psilocybin may be sufficient to produce enduring decreases in negative mood in patients with a life-threatening cancer.

Single dose of psilocybin decreases anxiety, depression in cancer patients

New heart failure drug may increase patients' risk of Alzheimer's disease, macular degeneration

In continuation of my update on sacubitril and Valsartan

Patients with mild heart failure stand to benefit from a new drug that can halt the progression of their disease and reduce their risk of cardiovascular-related death. But the drug -- a tablet that combines the agents valsartan and sacubitril, sold under the trade name Entresto by drugmaker Novartis -- may be too good to be true, according to Arthur M. Feldman, MD, PhD, Executive Dean of the Lewis Katz School of Medicine at Temple University (LKSOM), Chief Academic Officer of the Temple University Health System, and Laura H. Carnell Professor of Medicine at LKSOM.

In an article published online December 7th in the Journal of the American Medical Association, Dr. Feldman and colleagues at Thomas Jefferson University and the University of Florida warn that valsartan/sacubitril could theoretically increase patients' risk of Alzheimer's disease and macular degeneration, a blinding condition affecting the retina of the eye. The article raises these concerns about the drug, which was approved by the U.S. Food and Drug Administration in July 2015.

"Basic science data has caused us to speculate that off-target effects of valsartan/sacubitril may cause an exacerbation of Alzheimer's disease and could also exacerbate the course of macular degeneration," Dr. Feldman explained.

Dr. Feldman went on to note that "doctors are prescribing these drugs without knowledge of these theoretical risks."

Valsartan/sacubitril works by inhibiting an enzyme known as neprilysin, which normally plays a critical role in breaking down a wide array of peptides in cells. Among those substances are the so-called natriuretic peptides, which function in regulating scarring and cell growth in the heart when neprilysin is blocked. Because of those activities, valsartan/sacubitril can delay the progression of heart failure in some patients.

Neprilysin, however, also normally degrades amyloid beta, a peptide that can accumulate in the brain, where it contributes to Alzheimer's disease, as well as in the eye, where it is implicated in macular degeneration. The balance between the production and clearance of amyloid beta is crucial to the pathogenesis of Alzheimer's disease and is suspected to influence the development of macular degeneration. In animal models, blocking neprilysin disturbs that balance and exacerbates the development of Alzheimer's pathology.

New heart failure drug may increase patients' risk of Alzheimer's disease, macular degeneration

Marqibo now available to leukemia patients through myTomorrows' Internet-based platform

myTomorrows (Amsterdam, the Netherlands), announced today that it has started a collaboration with Spectrum Pharmaceuticals, Inc. (Henderson, USA; NasdaqGS: SPPI) to provide access to its liposome-encapsulated vincristine for treatment of Philadelphia chromosome negative acute lymphoblastic leukemia.

In August 2012, the US FDA approved the product for treatment of this rare type of leukemia. Through myTomorrows' Internet-based platform, the product is now also made available to patients and doctors in all other countries of the world, except China, Taiwan and Hong Kong, through an Early Access Program.

"We are pleased to make Marqibo® also available to leukemia patients outside of the United States, in countries where the treatment did not yet receive market approval," said Dr. Ronald Brus MD, founder and CEO of myTomorrows. "By taking care of the complex and time consuming process of receiving approval from regulatory authorities and healthcare insurers for individual patients, we aim to unburden these patients and their physicians by fulfilling their request as quickly as possible."

Joseph Turgeon, President and COO of Spectrum Pharmaceuticals said "We look forward to expand our collaboration with myTomorrows to also bring this product to doctors and patients through myTomorrows' global platform. It provides an additional option for acute lymphoblastic leukemia patients whose disease is unresponsive to available therapies and underscores Spectrum's efforts to combat this terrible disease."

Marqibo now available to leukemia patients through myTomorrows' Internet-based platform

Cancer drug can neutralize toxic RNA that causes myotonic dystrophy

A group of researchers has shown for the first time in cells and in a mouse model that a drug used to treat cancer can neutralize the toxic RNA that causes the prolonged muscle contractions and other symptoms of myotonic dystrophy type 1, the most common form of adult-onset muscular dystrophy. The researchers report their findings today Dec. 10, 2015 in the journal Cell Reports. (actinomycin-D)

"This finding opens a new avenue for a therapeutic strategy for this disease," said Andrew Berglund, Ph.D., a professor of biochemistry and molecular biology in the University of Florida College of Medicine. "This is the first evidence that specifically inhibiting transcription can be effective in knocking down the toxic material that causes the disease."

In myotonic dystrophy and other related neurological disorders, the symptoms stem from repeated individual nucleotides, or "building blocks," in the RNA in muscle tissue cells that can build up over time. These repeats, called CTG expansions in myotonic dystrophy type 1, become 'toxic' when transcribed from DNA. The expansions disrupt the RNA binding proteins responsible for splicing, the 'editing' needed so that the RNA can create appropriate proteins that allow muscles to function properly.

Cancer drug can neutralize toxic RNA that causes myotonic dystrophy

Tetra begins human Phase 1 safety trials of BPN14770

Tetra Discovery Partners ("Tetra") today announced that the company has initiated human Phase 1 safety trials of its lead compound BPN14770, which Tetra is developing as a potential treatment to both improve memory and slow the progression of Alzheimer's disease.

"There is a rapidly rising need for improved therapies for Alzheimer's disease. BPN14770 offers a novel approach that intervenes in important neural pathways related to learning and memory storage that underlie daily cognitive function in patients with Alzheimer's disease," said Mark Gurney, Ph.D., chairman and chief executive officer of Tetra. "Tetra Discovery has begun an initial human safety study with the compound in healthy volunteers, and expects to expand this to initial explorations of the compound benefit for cognition during 2016."

Tetra's Phase I clinical trials are designed to first evaluate BPN14770 in a single ascending dose study (SAD) to assess the safety, tolerability and pharmacokinetics in 48 healthy human volunteers. Endpoints for the study are safety, tolerability, and pharmacokinetics. Afterward, a multiple ascending dose (MAD) study will take place, enrolling young and elderly subjects to provide preliminary efficacy assessment of BPN14770 on long-term memory and other cognitive processes.

BPN14770 was developed through a cooperative research agreement with the National Institutes of Health (NIH) Blueprint Neurotherapeutics Network. "Tetra benefited greatly from the deep industry experience and commitment of NIH Blueprint consultants, CROs, and staff, the National Institute of Neurological Disorders & Stroke (NINDS) and the National Institute of Aging (NIA). The cooperative research program was milestone driven with a rigorous focus on meeting pharmaceutical industry metrics for CNS drug quality and safety. BPN14770 has shown efficacy in multiple animal models of learning and memory with an excellent safety margin for human clinical trials," commented Dr. Gurney.

Tetra begins human Phase 1 safety trials of BPN14770

New class of diabetes drugs differs in efficacy and safety profiles, shows new research

Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) differ in their efficacy and safety profiles, according to new research by the University of Leicester.

Compared to other once-weekly GLP-1RAs which are licensed and available, dulaglutide 1.5mg and once weekly exenatide showed the greatest reduction of HbA1c and fasting plasma glucose.

GLP-1RAs are a relatively new class of drugs that stimulate insulin and inhibit glucagon secretion, slow gastric emptying, and reduce food intake. While the first approved GLP-1RAs are administered as subcutaneous daily injections, more recently GLP-1RAs available via once-weekly administration have emerged, reducing the number of injections and side effects and potentially improving patient compliance.

In clinical studies, these drugs improve glucose control and reduce body weight, without an increased risk for hypoglycaemia. To date, however, no direct comparisons between once-weekly GLP-1RAs are available.

The research – carried out by the university’s Diabetes Research Centre, which is based at the Leicester Diabetes Centre – used an innovative method to evaluate the efficacy and adverse effects of once-weekly GLP-1RAs in adults with Type 2 diabetes.

Researcher Dr Francesco Zaccardi and colleagues conducted a network meta-analysis of randomised trials. In the absence of direct evidence, network meta-analysis is an increasingly used statistical methodology that allows the estimation of the comparative effectiveness of multiple treatments.

Dr Zaccardi concluded:

Compared to other available once-weekly GLP-1RAs, dulaglutide 1.5mg and once weekly exenatide showed a greater reduction of HbA1c and fasting plasma glucose. The risk of hypoglycaemia among once-weekly GLP-1RAs was comparable. Taspoglutide, one of the agents evaluated, has already been withdrawn from the market for high rates of nausea, and this has been confirmed in the meta-analysis.

New class of diabetes drugs differs in efficacy and safety profiles, shows new research

Palbociclib and paclitaxel combination shrinks tumors in patient with ER positive breast cancer

Combining the new breast cancer drug palbociclib with paclitaxel (Taxol) shrank tumors in nearly half of patient with estrogen-receptor (ER) positive breast cancer, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The results will be presented Saturday at the 2015 San Antonio Breast Cancer Symposium (Abstract P6-13-08). A second study (Abstract P4-13-04), to be presented Friday provides new clues to how breast cancer develops resistance to the palbociclib, a common occurrence among many patients who take the drug.

"Results of the first study found that palbociclib and paclitaxel can be safely combined on an alternating dosing schedule," said Angela DeMichele, MD, MSCE, the Alan and Jill Miller Associate Professor in Breast Cancer Excellence in Penn's Abramson Cancer Center, and senior author on the study. "The high response rate we saw suggests this combination may hold benefits for patients over paclitaxel alone. Based on these results, a larger clinical trial to determine the benefits is warranted."

A Complementary Therapy

Palbociclib targets the rapid division of tumor cells by inhibiting the activity of the enzymes CDK4 and CDK6, which help drive cell division and are upregulated in most cancers. The researchers suspected that palbociclib's unique mechanism of action may make it a good partner for other breast cancer drugs such as paclitaxel, which kills dividing cells at a certain point in the cell division process (also known as the "cell cycle"). Palbociclib effectively halts the cell cycle before that point, and thus in principle can synchronize cancer cells in a way that makes them more vulnerable to a closely following dose of paclitaxel.

Palbociclib and paclitaxel combination shrinks tumors in patient with ER positive breast cancer