Drug combo reverses arthritis in rats (alpha-KLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs)

People with osteoarthritis, or "wear and tear" arthritis, have limited treatment options: pain relievers or joint replacement surgery. Now, Salk researchers have discovered that a powerful combination of two experimental drugs reverses the cellular and molecular signs of osteoarthritis in rats as well as in isolated human cartilage cells. Their results were published in the journal Protein & Cell on January 16, 2020.

"What's really exciting is that this is potentially a therapy that can be translated to the clinic quite easily," says Juan Carlos Izpisua Belmonte, lead author and a professor in Salk's Gene Expression Laboratory. "We are excited to continue refining this promising combination therapy for human use."

Affecting 30 million adults, osteoarthritis is the most common joint disorder in the United States and its prevalence is expected to rise in the coming years due to the aging population and increasing rate of obesity. The disease is caused by gradual changes to the cartilage that cushions bones and joints. During aging and repetitive stress, molecules, and genes in the cells of this articular cartilage change, eventually leading to the breakdown of the cartilage and the overgrowth of the underlying bone, causing chronic pain and stiffness.

Previous research had pinpointed two molecules, alpha-KLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs to treat osteoarthritis. αKLOTHO acts on the mesh of molecules surrounding articular cartilage cells, keeping this extra-cellular matrix from degrading. TGFβR2 acts more directly on cartilage cells, stimulating their proliferation and preventing their breakdown.

While each drug alone had only moderately curbed osteoarthritis in animal models of the disease, Izpisua Belmonte and his colleagues wondered if the two drugs would act more effectively in concert.

"We thought that by mixing these two molecules that work in different ways, maybe we could make something better," says Paloma Martinez-Redondo, a Salk research associate and first author of the new study.

The researchers treated young, otherwise healthy rats with osteoarthritis with viral particles containing the DNA instructions for making αKLOTHO and TGFβR2.

Six weeks after the treatment, rats that had received control particles had more severe osteoarthritis in their knees, with the disease progressing from stage 2 to stage 4. However, rats that had received particles containing αKLOTHO and TGFβR2 DNA showed recovery of their cartilage: the cartilage was thicker, fewer cells were dying, and actively proliferating cells were present. These animals' disease improved from stage 2 to stage 1, a mild form of osteoarthritis, and no negative side effects were observed.

"From the very first time we tested this drug combination on just a few animals, we saw a huge improvement," says Martinez-Redondo. "We kept checking more animals and seeing the same encouraging results."

Further experiments revealed 136 genes that were more active and 18 genes that were less active in the cartilage cells of treated rats compared to control rats. Among those were genes involved in inflammation and immune responses, suggesting some pathways by which the combination treatment works.

To test the applicability of the drug combination to humans, the team treated isolated human articular cartilage cells with αKLOTHO and TGFβR2. Levels of molecules involved in cell proliferation, extra-cellular matrix formation and cartilage cell identity all increased.

"That's not the same as showing how these drugs affect the knee joint in humans, but we think it's a good sign that this could potentially work for patients," says Martinez-Redondo.

The research team plans to develop the treatment further, including investigating whether soluble molecules of the αKLOTHO and TGFβR2 proteins can be taken directly, rather than administered through viral particles. They also will study whether the combination of drugs can prevent the development of osteoarthritis before symptoms develop.

"We think that this could be a viable treatment for osteoarthritis in humans," says Pedro Guillen, director of the Clinica CEMTRO and co-corresponding author.

https://en.wikipedia.org/wiki/Klotho_(biology)

https://en.wikipedia.org/wiki/TGF_beta_receptor_2

Drug combo reverses arthritis in rats

New drug limits cancer spreading

A research team that recently invented a drug to stop blood vessels from forming a treatment-resistant barrier around some cancers has now discovered the drug can be used to prevent cancer from spreading.

"We originally developed the drug to overcome a problem in some cancers that grow a chaotic barrier of blood vessels in the tumor which prevents the body's immune cells and treatments like chemotherapy entering the tumor," said Professor Ruth Ganss Co-Head of the Cancer and Cell Biology Division at Perth's Harry Perkins Institute of Medical Research.

"The drug also sets-up lymph-node-like structures within the cancer to draw in a patient's immune system and greatly enhance a patient's own capacity to shrink the cancer.

"What we've since discovered is that by 'normalizing' blood vessels the drug also stops cancer spreading because it counteracts the cancer's influence on blood vessels in other parts of the body.

"Cancer spreads when cancer cells travel through the blood stream and settle and grow in other organs, like the lung or brain.

 "They are able to establish themselves in a distant body part because the primary tumor secretes substances that make blood vessels in other organs 'leaky,' or easier to penetrate.

"So when cancer cells travel in the blood stream they typically settle and grow where there are optimal conditions that have actually been created by the primary tumor.

"The primary tumor effectively 'talks' to the site where the metastasis is going to form so when the floating cancer cells arrive, they find a nice cozy environment in which to grow.

"While this behavior of cancer was already known, what we have discovered is that we can interfere with this process because of the way this new drug affects blood vessels.

"We've discovered it restores the leaky vessels which result in the cancer cells flowing past and not setting up shop.

"For a patient, this means that in future it will be possible to remove the primary tumor, then use the new drug to prevent cancer cells in the blood system from successfully attaching themselves to another organ and growing.

"But, if the cancer cells have already settled elsewhere and started growing then the drug can also be used to increase the number of immune cells brought into the new tumor to help it shrink."

"So we now have a drug that not only opens up the primary tumor for increased immunotherapy and greater treatment access, but it prevents metastatic spreading and if cancer has already spread, then the drug escalates the patient's immune response to new cancer.

"We now know we can interfere early and late in cancer's journey," Professor Ganss said.

Co-author of the publication, Dr. Bo He who undertook laboratory work on the drug said the research focused on metastatic cancer because most patients succumb to secondary cancers, not the primary.

"Using the drug that the team developed and published in 2017 in Nature Immunology we explored whether it could prevent metastases as well as improve patient immune response."

"We're quite excited that we have moved into a different phase of exploring how this drug could be used.

"So far we've successfully applied it to melanoma and lung cancer models in a metastatic setting," said Dr.

Watch the Video

https://scx2.b-cdn.net/gfx/video/2020/newdruglimit.mp4

https://www.perkins.org.au/news/new-drug-limits-cancer-spreading

Study first to show pharmacological chaperone therapy prevents Alzheimer's in mice

Like pieces of tape that crumple, stick together, and can be turned into a ball, proteins that begin to lose their shape become sticky and tend to clump together. When this happens, rather than being transported to recycling sites within cells, old or dysfunctional proteins instead become trapped within cellular compartments. Eventually, they accumulate to the point that they gum up cellular machinery, causing major problems.

Fortunately, cells are equipped with molecular machinery that detects defective proteins, sorts them out, and then either removes or stabilizes them, preventing them from accumulating and causing harm. In recent years, scientists have developed small drug molecules, known as pharmacological chaperones, that can help in this process.

Now, scientists at the Lewis Katz School of Medicine at Temple University show that pharmacological chaperones could fill a critical role in Alzheimer's disease therapy. In a new study published online January 21 in the journal Molecular Neurodegeneration, they describe a novel pharmacological chaperone capable of preventing Alzheimer's disease in animals prone to developing the condition.

The study is the first to show that a pharmacological chaperone drug can effectively disrupt the abnormal processes that damage neurons in the brain, fuel memory loss, and ultimately give rise to Alzheimer's disease.

"Our chaperone drug specifically restored levels of a sorting molecule known as VPS35, which helps move proteins out of endosomes, compartments inside cells where proteins are sorted for degradation," explained Domenico Praticò, MD, the Scott Richards North Star Charitable Foundation Chair for Alzheimer's Research, Professor in the Departments of Pharmacology and Microbiology, and Director of the Alzheimer's Center at Temple in the Lewis Katz School of Medicine. Dr. Praticò was a senior investigator on the new study.

The trafficking of proteins from endosomes to the cell membrane or to another cellular compartment known as the Golgi apparatus is fundamental for normal cell function. VPS35 is of particular importance to this trafficking system since it separates out dysfunctional and old proteins and sends them off for recycling.

In previous work, Dr. Praticò and colleagues found that VPS35 actively clears the brain of potentially harmful proteins such as amyloid-beta and tau. However, in Alzheimer's disease, VPS35 levels are reduced. This reduction is associated with the formation of tau tangles inside neurons, as well as the accumulation of amyloid-beta outside neurons. Eventually, these deposits of abnormal proteins interrupt neuron activity and contribute to neurodegenerative disorders, including Alzheimer's disease.

In the new study, the researchers investigated the effects of a pharmacological chaperone on protein sorting in mice engineered to develop Alzheimer's disease as they age. Mice were treated from a young age, before they began to show signs of disease. As the animals grew older, they were tested for effects on memory and learning.

Dr. Praticò's team found that, compared to untreated mice destined for Alzheimer's disease, the treated animals had much better memory and behaved just like normal, or wild-type, mice. When the researchers examined neurons from treated mice, they observed significant decreases in tau tangles, as well as decreases in amyloid-beta plaques—another type of protein aggregate that contributes to Alzheimer's disease. The researchers further noticed that VPS35 levels were restored and the junctions where neurons come together to exchange information, known as synapses, were fully functional following the pharmacological chaperone therapy.

"Relative to other therapies under development for Alzheimer's disease, pharmacological chaperones are inexpensive, and some of these drugs have already been approved for the treatment of other diseases," Dr. Praticò said. "Additionally, these drugs do not block an enzyme or a receptor but target a cellular mechanism, which means that there is much lower potential for side effects. All these factors add to the appeal of pursuing pharmacological chaperone drugs as novel Alzheimer's treatments."

Before moving to trials in human patients, however, Dr. Praticò plans to next investigate the effects of pharmacological chaperone therapy in older mice. "Because our most recent investigation was a preventative study, we want to know now whether this therapy could also work as a treatment for patients already diagnosed with Alzheimer's disease," he added.

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0350-4

https://en.wikipedia.org/wiki/Pharmacological_chaperone

https://en.wikipedia.org/wiki/VPS35

Study first to show pharmacological chaperone therapy prevents Alzheimer's in mice

Dasatinib Tops Imatinib for Ph+ Acute Lymphoblastic Leukemia

In continuation of my update on dasatinib and imatinib

Dasatinib is associated with improved survival for pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), according to a study published online Jan. 16 in JAMA Oncology.

Shuhong Shen, M.D., Ph.D., from the Shanghai Jiao Tong University School of Medicine, and colleagues conducted an open-label randomized trial at 20 hospitals in China involving patients aged 0 to 18 years with Philadelphia chromosome-positive ALL. Patients were randomly assigned to either daily dasatinib or imatinib (92 and 97 patients, respectively) in the context of intensive chemotherapy without prophylactic cranial irradiation.

The researchers found that the four-year event-free and overall survival rates were 71.0 and 88.4 percent, respectively, in the dasatinib group and 48.9 and 69.2 percent, respectively, in the imatinib group. The four-year cumulative risk for any relapse was 19.8 and 34.4 percent in the dasatinib and imatinib groups, respectively; the four-year cumulative risk for an isolated central nervous system relapse was 2.7 and 8.4 percent, respectively. There was no difference between the treatment groups in the frequency of severe toxic effects.

"The present study provides promising early outcome data supporting the use of a dasatinib-based regimen for Philadelphia chromosome-positive ALL," write the authors of an accompanying editorial. "It also highlights some key challenges that remain in the management of this disease."

Several authors disclosed financial ties to pharmaceutical companies, including Bristol-Myers Squibb, which manufactures dasatinib.

https://en.wikipedia.org/wiki/Dasatinib

Aspirin May No Longer Have Effect in Primary CVD Prevention

Aspirin may not be effective for primary prevention of cardiovascular disease and cancer mortality, according to research published online Nov. 21 in Family Practice.

Frank Moriarty, Ph.D., from the Royal College of Surgeons in Dublin, and Mark H. Ebell, M.D., from the University of Georgia in Athens, compared the benefits and harms of aspirin for primary prevention before (1978 to 2002) and after (2005 onward) widespread use of statins and screening for colorectal cancer.

The researchers found that for older versus newer studies, the relative risks for vascular outcomes were 0.89 (95 percent confidence interval [CI], 0.83 to 0.95) versus 0.93 (0.86 to 0.99) for major adverse cardiovascular events; 1.73 (1.11 to 2.72) versus 1.06 (0.66 to 1.70) for fatal hemorrhagic stroke; 0.86 (0.74 to 1.00) versus 0.86 (0.75 to 0.98) for any ischemic stroke; 0.84 (0.77 to 0.92) versus 0.88 (0.77 to 1.00) for any myocardial infarction; and 0.79 (0.71 to 0.88) versus 0.94 (0.83 to 1.08) for nonfatal myocardial infarction. In newer studies, there was no significant decrease observed for cancer mortality (relative risk, 1.11; 95 percent CI, 0.92 to 1.34). Significant increases were seen in major hemorrhage (older studies, relative risk, 1.48 [95 percent CI, 1.25 to 1.76] versus newer studies, relative risk, 1.37 [95 percent CI, 1.24 to 1.53]).

"In a modern era characterized by widespread statin use and population-wide cancer screening, aspirin no longer reduces the absolute risk of cancer death or myocardial infarction when given as primary prevention," the authors write.

https://academic.oup.com/fampra/advance-article/doi/10.1093/fampra/cmz080/5637484

Coffee Consumption Does Not Affect Insulin Sensitivity

In continuation of my updates on coffee

Consumption of four cups of coffee daily does not impact insulin sensitivity, according to a study published online Dec. 31 in the American Journal of Clinical Nutrition.

Derrick Johnston Alperet, from the National University of Singapore, and colleagues conducted a 24-week trial involving 126 overweight, non-insulin-sensitive adults aged 35 to 69 years. Participants were randomly assigned to receive either four cups of instant regular coffee or four cups of a placebo beverage per day (62 and 64 in each group, respectively). The amount of glucose metabolized per kilogram of body weight per minute (Mbw) was measured as the primary outcome.

The researchers observed no significant change in insulin sensitivity with coffee consumption versus placebo (percentage mean difference in Mbw, 4.0 percent; 95 percent confidence interval [CI], −8.3 to 18.0 percent; P = 0.53). In addition, there were no between-group differences during 24 weeks of the intervention in fasting plasma glucose or biological mediators of insulin resistance such as plasma adiponectin. Compared with participants in the placebo arm, those in the coffee arm experienced a loss of fat mass (−3.7 percent; 95 percent CI, −6.3 to −1.1 percent; P = 0.006) and a reduction in urinary creatinine concentrations (−21.2 percent; 95 percent CI, −31.4 to −9.5 percent; P = 0.001).

• "Coffee consumption was associated with a modest loss in body fat mass compared with the placebo beverage, and this potential impact on adiposity warrants confirmation in additional trials," the authors write.

https://academic.oup.com/ajcn/advance-article-abstract/doi/10.1093/ajcn/nqz306/5686860?redirectedFrom=fulltext

Tivozanib Bests Sorafenib in Metastatic Renal Cell Carcinoma

In continuation of my update on Tivozanib  and  Sorafenib

Among patients with metastatic renal cell carcinoma, progression-free survival was longer in those receiving tivozanib versus sorafenib as third- or fourth-line therapy, according to a study published online Dec. 3 in The Lancet Oncology.

Brian I. Rini, M.D., from the Cleveland Clinic Taussig Cancer Institute, and colleagues conducted an open-label randomized trial at 120 academic hospitals in 12 countries and enrolled patients older than 18 years with histologically or cytologically confirmed metastatic renal cell carcinoma and at least two previous systemic treatments, including at least one with a vascular endothelial growth factor receptor inhibitor. Patients were randomly assigned to either tivozanib 1.5 mg orally once daily in four-week cycles or sorafenib 400 mg orally twice daily on a continual basis (175 patients to each); patients were followed for a median of 19 months.

The researchers found that median progression-free survival was significantly longer with tivozanib than sorafenib (5.6 versus 3.9 months; hazard ratio, 0.73). Hypertension was the most common grade 3 or 4 treatment-related adverse event (20 and 14 percent of tivozanib- and sorafenib-treated patients, respectively). Serious treatment-related adverse events occurred in 11 percent of tivozanib and 10 percent of sorafenib patients. There were no reports of treatment-related deaths.

"These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including AVEO Oncology, which manufactures tivozanib and funded the study.

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext

One-Cycle BE500P Seems Safe for High-Risk Early Testicular Cancer

 

Bleomycin                                                                             etoposide

Cisplatin

In continuation of my update on etoposide and cisplatin

For high-risk stage 1 nonseminoma germ cell tumors of the testis (NSGCTT), one cycle of adjuvant bleomycin, etoposide (500 mg/m²), and cisplatin (BE500P) is safe, resulting in a two-year malignant recurrence (MR) rate of 1.3 percent, similar to that reported for two cycles of BE360P, according to a study published online Jan. 1 in European Urology.

Michael Cullen, M.D., from the University Hospitals Birmingham NHS Foundation Trust in the United Kingdom, and colleagues compared recurrence rates for one cycle of BE500P to recurrence rates for two cycles of BE360P among 246 patients with vascular invasion-positive stage 1 NSGCTT or combined seminoma + NSGCTT registered in a single-arm prospective study.

Patients were followed for a median of 49 months. Ten patients with increasing tumor markers were excluded at baseline. The researchers found that four patients had MR at six, seven, 13, and 27 months; all were treated with secondary chemotherapy, and at five years, three remained recurrence-free. The rate of two-year MR was 1.3 percent (95 percent confidence interval, 0.3 to 3.7 percent). Nonmalignant recurrences developed in three patients who had localized differentiated teratoma; after surgery, they were rendered disease-free. In 6.8 percent of patients, grade 3 to 4 febrile neutropenia occurred.

"Our study has found strong evidence to suggest that testicular cancer chemotherapy can be safely reduced from two cycles to just one -- making their treatment shorter, kinder, and cheaper," a coauthor said in a statement.

https://www.europeanurology.com/article/S0302-2838(19)30895-4/fulltext
https://en.wikipedia.org/wiki/Bleomycin
https://en.wikipedia.org/wiki/Etoposide
https://en.wikipedia.org/wiki/Cisplatin

Tea Drinking Linked to Reduced Risk for Atherosclerotic CVD

In continuation of my update on Tea

Habitual tea consumption is associated with a reduced risk for atherosclerotic cardiovascular disease (CVD) and all-cause mortality, according to a study published online Jan. 9 in the European Journal of Preventive Cardiology.

Xinyan Wang, from the Chinese Academy of Medical Sciences and Peking Union Medical College, and colleagues examined the association of tea consumption with the risk for atherosclerotic CVD and all-cause mortality among 100,902 general Chinese adults in 15 provinces in China. Standardized questionnaires were used to obtain information on tea consumption.

The researchers found that 3,683 atherosclerotic CVD events, 1,477 atherosclerotic CVD deaths, and 5,479 all-cause deaths were recorded during a median follow-up of 7.3 years. For habitual tea drinkers, the hazard ratios were 0.80, 0.78, and 0.85 for atherosclerotic CVD incidence, atherosclerotic CVD mortality, and all-cause mortality, respectively, compared with never or nonhabitual tea drinkers. At the index age of 50 years, habitual tea drinkers were free from atherosclerotic CVD for 1.41 more years and had a life expectancy of 1.26 years longer. Among participants who kept the habit during follow-up, the observed inverse associations were strengthened.

"Our findings give a further insight into the beneficial role of tea consumption, and have great public health implications for guiding primary prevention among general Chinese adults," the authors write.

FDA: Weight Control Drug Lorcaserin May Raise Cancer Risk

In continuation of my update on lorcaserin

The prescription weight control medicine lorcaserin (Belviq, Belviq XR) may increase the risk for cancer, according to the results of a clinical trial assessing the safety of the drug, the U.S. Food and Drug Administration says.

The agency said, "[W]e cannot conclude that lorcaserin contributes to the cancer risk" but "wanted to make the public aware of this potential risk. We are continuing to evaluate the clinical trial results and will communicate our final conclusions and recommendations when we have completed our review."

Health care providers should balance the benefits of taking lorcaserin against the potential risks when deciding whether to prescribe or continue patients on the medication, the FDA advised. It said that patients currently taking lorcaserin should talk to their health care professionals about the potential increased risk for cancer with use of the medication.

Lorcaserin is approved for use with a reduced-calorie diet and increased physical activity to help weight loss in adults who are obese or are overweight and have weight-related medical problems. Lorcaserin increases feelings of fullness so that people eat less. It is available as a tablet (Belviq) and an extended-release tablet (Belviq XR).

https://en.wikipedia.org/wiki/Lorcaserin

FDA Approves Valtoco (diazepam nasal spray) as a Seizure Rescue Treatment

Neurelis, Inc.,  announced that the U.S. Food and Drug Administration (FDA) has approved Valtoco (diazepam nasal spray) as an acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in people with epilepsy 6 years of age and older. The unique formulation of Valtoco incorporates Intravail® for consistent and reliable absorption.

“Cluster or acute repetitive seizures are challenging to treat and highly disruptive in the lives of people with epilepsy,” said Neurelis President and CEO Craig Chambliss. “Valtoco was developed to provide an effective combination of reliability, safety and tolerability in a ready-to-use nasal spray. This is a defining moment for Neurelis as Valtoco is our first FDA-approved product. We are excited that we can now offer this treatment option to patients and provide additional support to the epilepsy community.”

Chambliss added that Valtoco was also granted seven years of Orphan Drug Exclusivity by the FDA Office of Orphan Products Development.

Valtoco is a proprietary formulation of diazepam incorporating the Science of Intravail. Intravail transmucosal absorption enhancement technology enables the non-invasive delivery of a broad range of protein, peptide and small molecule drugs. In the United States, there are over 3.4 million people with epilepsy, with approximately 200,000 new patients diagnosed each year. Despite the availability of chronic, daily oral medications to control epilepsy, a significant number of these patients continue to experience seizures. Of these uncontrolled patients, as many as 170,000 are at risk for episodes of frequent seizure activity, also known as cluster or acute repetitive seizures, representing a significant unmet need in the epilepsy community.

“This is an important development in the epilepsy community,” said R. Edward Hogan, MD, Director of the Washington University and Barnes-Jewish Epilepsy Center in St. Louis. “Most seizures that require intervention are treated in an inconvenient manner. To be able to reliably treat seizure activity when and where it happens with a caregiver-administered option like Valtoco is a significant step forward. The availability of Valtoco may positively impact the lives of thousands of people with epilepsy who experience cluster or acute repetitive seizures and their care partners.”

In a long-term, open-label, repeat dose, clinical trial, the safety of Valtoco was evaluated: over 130 patients were enrolled and more than 2,000 seizures were treated. The clinical trial included patients aged 6 and above. “Until recently, approved treatment outside of medical care settings was only available as a rectally administered medication,” Dr. Hogan said. “The FDA approval of diazepam nasal spray is a significant advancement for the epilepsy community.”

Enrique Carrazana, MD, Chief Scientific Officer for Neurelis, notes that Valtoco was generally safe and well tolerated during clinical studies. The most common adverse reactions (at least 4%) were somnolence, headache, and nasal discomfort.

Jacqueline A. French, MD, professor in the Department of Neurology at NYU Langone Health’s Comprehensive Epilepsy Center and Chief Medical & Innovation Officer for the Epilepsy Foundation, commented, “One of the goals of rescue therapy is to treat seizure clusters, recognized as medical emergencies, before negative consequences may be experienced. These consequences may include injury and seizure progression to status epilepticus. Having a seizure rescue treatment that is generally safe, reliable and ready-to-use is very empowering. We encourage all epilepsy patients to work with their doctors to make sure they have a seizure rescue treatment plan in place.”

Indication

Valtoco (diazepam nasal spray) is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 6 years of age and older.

https://www.chemdiv.com/valtoco-is-approved-by-fda/

FDA Approves Numbrino (cocaine hydrochloride) Nasal Solution for Nasal Anesthesia

In continuation of my update on Cocaine

Lannett Company, Inc. (NYSE: LCI),  announced that the U.S. Food and Drug Administration (FDA) has approved the New Drug Application (NDA), submitted under the 505(b)(2) regulatory pathway, for Cocaine Hydrochloride (HCl) Nasal Solution 4% (40 mg/mL), the company's branded local anesthetic product.Lannett Company, Inc. (NYSE: LCI) today announced that the U.S. Food and Drug Administration (FDA) has approved the New Drug Application (NDA), submitted under the 505(b)(2) regulatory pathway, for Cocaine Hydrochloride (HCl) Nasal Solution 4% (40 mg/mL), the company's branded local anesthetic product.

"The FDA's approval of our Cocaine HCl product, the first NDA approval to include full clinical trials in the company's history, marks a major milestone in Lannett's 70+ years of operations," said Tim Crew, chief executive officer of Lannett. "We believe the product has the potential to be an excellent option for the labeled indication. We expect to launch the product shortly, under the brand name Numbrino®."

Numbrino® (cocaine hydrochloride) nasal solution is an ester local anesthetic indicated for the introduction of local anesthesia of the mucous membranes for diagnostic procedures and surgeries on or through the nasal cavities of adults. The 505(b)(2) NDA submission was supported by two Phase III, randomized, double-blind, placebo-controlled, multicenter studies in several hundred patients, as well as a Phase I pharmacokinetic study.

About Lannett Company, Inc.:

Lannett Company, founded in 1942, develops, manufactures, packages, markets and distributes generic pharmaceutical products for a wide range of medical indications. For more information, visit the company's website at www.lannett.com.

This news release contains certain statements of a forward-looking nature relating to future events or future business performance.  Any such statement, including, but not limited to, successfully commercializing Numbrino®, whether expressed or implied, is subject to market and other conditions, and subject to risks and uncertainties which can cause actual results to differ materially from those currently anticipated due to a number of factors which include, but are not limited to, the risk factors discussed in the Company's Form 10-K and other documents filed with the SEC from time to time, including the prospectus supplement related to the proposed offering to be filed with the SEC.  These forward-looking statements represent the Company's judgment as of the date of this news release.  The Company disclaims any intent or obligation to update these forward-looking statements.

https://en.wikipedia.org/wiki/Cocaine

FDA Approves Vyondys 53 (golodirsen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 53

In continuation of my update on oligonucleotide.

Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved Vyondys 53™ (golodirsen). Vyondys 53 is an antisense oligonucleotide from Sarepta’s phosphorodiamidate morpholino oligomer (PMO) platform, indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation amenable to exon 53 skipping. This indication is based on a statistically significant increase in dystrophin production in skeletal muscle observed in patients treated with Vyondys 53, which is reasonably likely to predict clinical benefit for those patients who are exon 53 amenable. Consistent with the accelerated approval pathway, the continued approval of Vyondys 53 may be contingent on confirmation of a clinical benefit in this post-marketing confirmatory trial.

Sarepta’s placebo-controlled, post-marketing confirmatory trial to support the Vyondys 53 accelerated approval – titled ESSENCE – is currently enrolling and expected to conclude by 2024.

Hypersensitivity reactions, including rash, pyrexia (fever), pruritis, urticaria (hives), dermatitis, and skin exfoliation have occurred in patients who were treated with Vyondys 53. Renal toxicity was observed in animal studies. Although not observed in the clinical studies with Vyondys 53, renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. The most common adverse reactions that occurred in at least 20% of Vyondys 53-treated patients and more frequently than in placebo-treated patients were headache (41%), pyrexia (41%), fall (29%), abdominal pain (27%), nasopharyngitis (27%), cough (27%), vomiting (27%), and nausea (20%).

Following a New Drug Application (NDA) submission to and review by the Division of Neurology Products (the Review Division) for Vyondys 53, which the Review Division recommended for approval, the Office of Drug Evaluation 1 issued a complete response letter (CRL) in August of 2019. Thereafter, Sarepta made a formal dispute resolution request as outlined in relevant FDA Guidance. With the support of the Review Division, the matters raised in the CRL were rapidly evaluated and resolved by Dr. Peter Stein, Director of the Office of New Drugs (OND). OND granted the Company’s appeal and Sarepta re-submitted its NDA to the Review Division, which worked expeditiously to review and approve Vyondys 53.

“Today is monumental for Sarepta and, more importantly, for the DMD community,” said Doug Ingram, president and chief executive officer, Sarepta. “Vyondys 53, our second approved exon-skipping RNA therapy for DMD, may treat up to 8% of the DMD community, representing those patients who have a confirmed exon 53 amenable mutation. Along with EXONDYS 51® (eteplirsen), we now offer treatment options for approximately 20% of those with DMD in the U.S.”

Ingram continued, “In the span of four months, we commenced and completed the formal dispute resolution process culminating in the grant of our appeal, resubmitted our NDA and obtained an approval – a great benefit to DMD patients awaiting treatment. This unprecedented timing could not have been achieved without the commitment of the Review Division under the leadership of Dr. Billy Dunn, and the Office of New Drugs, which expeditiously heard and granted our appeal. Along with the DMD community, we owe our gratitude to both the Review Division and the OND for their objective, evidence-based approach to this review, for their fairness, and for the sense of urgency with which they addressed and resolved the CRL and granted this approval.”

“With the approval of Vyondys 53, up to another 8% of Duchenne families will have a therapy to treat this devastating disease,” said Pat Furlong, founding president and chief executive officer, Parent Project Muscular Dystrophy (PPMD). “For 25 years, PPMD has been working with researchers, clinicians, industry, and the Duchenne community to find treatments for all people living with Duchenne. And while we need to ensure that these approved therapies are accessible for patients, today we celebrate this approval and thank Sarepta for their continued leadership in the fight to end Duchenne.”

Vyondys 53 is priced at parity to EXONDYS 51, the price of which has not increased since its launch in 2016. Patients and physicians can access more information at www.SareptAssist.com or by calling 1-888-727-3782.

About Vyondys 53

Vyondys 53 is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Vyondys 53 uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion, or “skipping,” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.

https://www.rxlist.com/vyondys-53-drug.htm

FDA Approves Arazlo (tazarotene) Lotion for the Topical Treatment of Acne Vulgaris

In continuation of my update on tazarotene

Bausch Health Companies Inc. (NYSE/TSX: BHC) and its dermatology business, Ortho Dermatologics, one of the largest prescription dermatology health care businesses,  announced the U.S. Food and Drug Administration (FDA)   approval of   the New Drug Application for Arazlo (tazarotene) Lotion, 0.045%, for the topical treatment of acne vulgaris in patients nine years of age and older.1 Arazlo is the first tazarotene acne treatment available in a lotion form, and has been shown to provide strong efficacy with favorable tolerability.

"Today's approval of Arazlo showcases our continued commitment to expanding our acne portfolio to help the approximately 50 million Americans who are impacted by this prevalent skin condition," said Bill Humphries, president, Ortho Dermatologics. "As our fourth FDA approval in just 14 months, Arazlo will provide dermatologists the efficacy expected of tazarotene in a new formulation that helps minimize the dryness and irritation historically associated with tazarotene use, which can cause many acne patients to discontinue treatment. We are purposely timing the launch of Arazlo to coincide with the start of acne season in the first half of 2020."

Retinoids like tazarotene are a core component of acne treatment. However, a common barrier to their use is that treatment with retinoids is often associated with skin irritation, such as dryness.2 In a head-to-head study, Arazlo demonstrated similar efficacy as Tazorac (tazarotene) Cream 0.1% with about half the adverse events.2  The most frequent adverse events reported with Arazlo (≥1%) were application site pain, dryness, exfoliation, erythema and pruritus.1

"Many of my patients with moderate to severe acne can benefit from the efficacy of tazarotene, but struggle to stay on treatment due to tolerability issues," said Emil Tanghetti, M.D., lead Arazlo study investigator and founder, Center for Dermatology and Laser Surgery, Sacramento, Calif. "Tazarotene has typically been reserved only for patients with severe acne, but offering it in a well-tolerated lotion formulation that includes hydrating agents can help more patients with most types of acne take advantage of its efficacy. I look forward to adding Arazlo to my practice armamentarium."

Arazlo Comprehensive Clinical Data

The FDA approval for Arazlo was based on data from two Phase 3 multicenter, randomized, double-blind, vehicle-controlled clinical trials in 1,614 patients with moderate to severe acne. In both Phase 3 studies, all primary efficacy endpoints were met with statistical significance (p<.001). Arazlo was also shown to be generally well-tolerated in the clinical study population.

In a Phase 2, head-to-head study, Arazlo and Tazorac (tazarotene) Cream 0.1% showed similar treatment success rates and similar reductions in both inflammatory and non-inflammatory lesions over 12 weeks. While there were no significant differences in patient satisfaction or quality of life between the two treatments and both were well-tolerated, there were numerically about double the number of treatment-related adverse events with Tazorac (5.6 percent with Tazorac versus 2.9 percent with Arazlo).

https://en.wikipedia.org/wiki/Levamlodipine

FDA Approves Turalio (pexidartinib) for the Treatment of Symptomatic Tenosynovial Giant Cell Tumors (TGCT) in Adults

In continuation of my update on pexidartinib

U.S. Food and Drug Administration granted approval to Turalio (pexidartinib) capsules for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not responsive to improvement with surgery.

“TGCT can cause debilitating symptoms for patients such as pain, stiffness and limitation of movement. The tumor can significantly affect a patient’s quality of life and cause severe disability,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Surgery is the primary treatment option, but some patients are not eligible for surgery, and tumors can recur, even after the procedure. Today’s approval is the first FDA-approved therapy to treat this rare disease.”

TGCT is a rare tumor that affects the synovium (thin layer of tissue that covers the surfaces of the joint spaces) and tendon sheaths (layer of membrane that covers tendons, which are fibrous tissue that connect muscle to bone). The tumor is rarely malignant but causes the synovium and tendon sheaths to thicken and overgrow, causing damage to surrounding tissue.

The approval of Turalio was based on the results of a multi-center international clinical trial of 120 patients, 59 of whom received placebo. The primary efficacy endpoint was the overall response rate (ORR) analyzed after 25 weeks of treatment. The clinical trial demonstrated a statistically significant improvement in ORR in patients who received Turalio, with an ORR of 38%, compared to no responses in patients who received placebo. The complete response rate was 15% and the partial response rate was 23%. A total of 22 out of 23 responders who had been followed for a minimum of six months following the initial response maintained their response for six or more months, and a total of 13 out of 13 responders who had been followed for a minimum of 12 months following the initial response maintained their response for 12 or more months.

The prescribing information for Turalio includes a Boxed Warning to advise health care professionals and patients about the risk of serious and potentially fatal liver injury. Health care professionals should monitor liver tests prior to beginning treatment and at specified intervals during treatment. If liver tests become abnormal, Turalio may need to be withheld, the dose reduced, or permanently discontinued, depending on the severity of the liver injury. Turalio is available only through the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program.

Common side effects for patients taking Turalio were increased lactate dehydrogenase (proteins that helps produce energy in the body), increased aspartate aminotransferase (enzymes that are mostly in the liver but also in muscles), loss of hair color, increased alanine aminotransferase (enzymes that are primarily in the liver and kidney) and increased cholesterol. Additional side effects included neutropenia (low level of white blood cells that help the immune system defend against disease and infection), increased alkaline phosphatase (enzymes that are mostly in the cells of bone and the liver), decreased lymphocytes (white blood cells that help the immune system defend against disease and infection), eye edema (swelling around the eyes), decreased hemoglobin (protein in red blood cells that carry oxygen), rash, dysgeusia (altered sense of taste) and decreased phosphate (electrolytes that help with energy).

The FDA advises health care professionals to tell females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Turalio. Women who are pregnant or breastfeeding should not take Turalio because it may cause harm to a developing fetus or newborn baby. Turalio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

The FDA granted this application Breakthrough Therapy designation and Priority Reviewdesignation. Turalio also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Turalio to Daiichi Sanky.

https://en.wikipedia.org/wiki/Pexidartinib