FDA Issues Complete Response Letter for Apadaz New Drug Application

KemPharm, Inc.  a clinical-stage specialty pharmaceutical company engaged in the discovery and development of proprietary prodrugs,  announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for Apadaz™ (benzhydrocodone and acetaminophen), KemPharm’s investigational abuse-deterrent product candidate for the short-term management of acute pain.

 benzhydrocodone         acetaminophen

The FDA issues CRLs to indicate that the Agency considers the review cycle for an application is complete and that the application is not ready for approval in its present form. Included in the CRL is guidance that describes all specific deficiencies that the FDA has identified in the application. When possible, the FDA recommends actions that the applicant may take to place the application in condition for approval.

“After last week’s amendment request, a Complete Response Letter from the FDA was received for the Apadaz NDA,” said Travis C. Mickle, Ph.D., President and CEO of KemPharm. “We are currently evaluating the points raised in the CRL and intend to request an End of Review meeting with the Agency to determine the pathway forward for Apadaz.”

Allergan Announces FDA Acceptance of NDA Filing for Oxymetazoline HCI Cream 1.0%

Allergan plc  announced that the New Drug Application (NDA) filing for oxymetazoline HCl cream 1.0%, an investigational topical prescription product for the treatment of persistent facial erythema (redness) associated with rosacea in adults, has been accepted by the U.S. Food and Drug Administration (FDA) for standard review. Allergan expects the Prescription Drug User Fee Act (PDUFA) date to be in the first half of 2017.

"While rosacea is a common chronic skin condition that affects more than 16 million people in the U.S. alone1, there is a significant unmet need in effective, FDA-approved treatments for the condition," said David Nicholson, Chief R&D Officer, Allergan. "The NDA filing of oxymetazoline speaks to our strong commitment to ongoing innovation of our medical dermatology portfolio, and we look forward to bringing a new treatment option to patients with rosacea."

About Oxymetazoline

Oxymetazoline is a sympathomimetic agonist that is selective for the α1A-adrenoceptor over other α1-adrenoceptors and non-selective for the α2-adrenoceptors. As such, oxymetazoline is a potent vasoconstrictor of the cutaneous microvasculature. The NDA submission for oxymetazoline HCL cream 1.0% was based on data collected from two phase 3 pivotal clinical trials of a 29-day treatment duration and a 1-year open label clinical trial. These studies enrolled male and female patients ≥ 18 years of age with moderate to severe persistent facial erythema associated with rosacea.

AstraZeneca Receives Complete Response Letter from FDA for Sodium Zirconium Cyclosilicate (ZS-9) for Hyperkalemia

AstraZeneca today announced that the US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for sodium zirconium cyclosilicate (ZS-9), the investigational medicine being developed for the treatment of hyperkalemia (high potassium level in the blood serum) by ZS Pharma, a wholly-owned subsidiary of AstraZeneca.

The CRL refers to observations arising from a pre-approval manufacturing inspection. The FDA also acknowledged receipt of recently-submitted data which it has yet to review. The CRL does not require the generation of new clinical data. AstraZeneca and ZS Pharma are evaluating the      (see structure of  ZS-9 (sodium zirconium cyclosilicate) content of the CRL and will work closely with the FDA to determine the appropriate next steps for the NDA.AstraZeneca remains committed to the development of sodium zirconium cyclosilicate as a treatment option for patients with hyperkalemia. Interactions are ongoing with other health authorities in the European Union and Australia, where sodium zirconium cyclosilicate is currently under separate regulatory review.

About Sodium Zirconium Cyclosilicate (ZS-9) for Oral Suspension

Sodium zirconium cyclosilicate (ZS-9) is an insoluble, non-absorbed compound with a structure that was designed to preferentially trap potassium ions. The unique potassium selectivity of sodium zirconium cyclosilicate enables high in-vitro binding capacity for potassium ions even in the presence of other competing ions. Sodium zirconium cyclosilicate has been studied in three double-blind, placebo controlled trials and in one ongoing 12 month open label clinical trial in patients with hyperkalemia which represents over 1,600 patients treated. Sodium zirconium cyclosilicate is an investigational product that is not currently approved for any indication in any market.

About Hyperkalemia

Hyperkalemia (high potassium levels > 5.0 mEq/L in the blood serum) occurs in 23-47% of patients with advanced chronic kidney disease and/or chronic heart failure, and may lead to cardiac arrest and death (mortality of up to 30% in patients with severe hyperkalemia if not treated rapidly). Treatment with common heart medicines (RAAS inhibitors) can also be responsible for increases in hyperkalemia. Current therapeutic options are limited, leaving high unmet medical need.

Lexicon Announces FDA Priority Review of NDA for Telotristat Etiprate for the Treatment of Carcinoid Syndrome

Lexicon Pharmaceuticals, Inc.  announced that the U.S. Food and Drug Administration has accepted for filing the New Drug Application for telotristat etiprate, an oral drug for the treatment of carcinoid syndrome. The FDA has granted a Priority Review of the NDA filing and set a Prescription Drug User Fee Act (“PDUFA”) target action date of November 30, 2016.

“The granting of priority review by the FDA underscores the need for improving the lives of the patients and caregivers who live with carcinoid syndrome on a daily basis,” said Lexicon President and Chief Executive Officer, Lonnel Coats. “If approved, telotristat etiprate would be the only approved therapy for patients who are no longer able to control their carcinoid syndrome with the current standard of care alone.”

Carcinoid syndrome is a rare disease affecting thousands of cancer patients with metastatic neuroendocrine tumors (mNETs) that have spread to the liver and other organs from the gastrointestinal tract. The condition is characterized by frequent and debilitating diarrhea that often prevents patients from leading active, predictable lives, as well as facial flushing, abdominal pain, fatigue and, over time, heart valve damage.

About Telotristat Etiprate

Discovered using Lexicon’s unique approach to gene science, telotristat etiprate is the first investigational drug in clinical studies to target tryptophan hydroxylase, an enzyme that triggers the excess serotonin production within mNET cells that leads to carcinoid syndrome. While existing treatments for carcinoid syndrome work to reduce the release of serotonin outside tumor cells, telotristat etiprate works at the source to reduce serotonin production within the tumor cells. By specifically inhibiting serotonin production, telotristat etiprate seeks to control this important driver of carcinoid syndrome and, in turn, provide patients with more control over their disease.

Telotristat etiprate has received Fast Track and Orphan Drug designation from the U.S. Food and Drug Administration.

Lexicon retains rights to market telotristat etiprate in the U.S. and Japan, and is building the in-house commercial infrastructure to serve the U.S. market. Lexicon has a license and collaboration agreement with Ipsen to commercialize telotristat etiprate in Europe and other countries outside the U.S. and Japan.

Radius Announces FDA Acceptance for Filing of NDA for for the Treatment of Postmenopausal Women with Osteoporosis

Radius Health, Inc. ), a science-driven biopharmaceutical company that is committed to developing innovative therapeutics in the areas of osteoporosis, oncology and endocrine diseases, announced that its New Drug Application (NDA) for abaloparatide—SC has been accepted for filing by the U.S. Food and Drug Administration (FDA). The acceptance of the NDA reflects the FDA's determination that the application is sufficiently complete to permit a substantive review.

"The FDA's acceptance for filing of our abaloparatide-SC NDA is a major milestone for Radius and we look forward to continuing to work with the FDA as they review our application," said Robert E. Ward, President and CEO of Radius Health. "Given the high unmet medical need in osteoporosis, we believe that abaloparatide-SC, if approved, has the potential to become a promising new treatment option for the approximately 10 million postmenopausal women with osteoporosis, many of whom remain untreated."

The NDA is supported by data from the entire abaloparatide-SC development program, including the results from the 18-month Phase 3 ACTIVE trial in 2,463 postmenopausal women with osteoporosis and the first six months of the ACTIVExtend trial in 1,139 of the ACTIVE participants. Positive results for abaloparatide-SC treatment groups from the ACTIVE and ACTIVExtend trials have met the primary and secondary endpoints essential for submission of the NDA, including the primary endpoint of reduction of vertebral fractures as well as key endpoints of reduction of nonvertebral, clinical, and major osteoporotic fractures. In these and the other trials submitted in the NDA, abaloparatide-SC administered at a dose of 80 mcg daily was generally safe and well tolerated in postmenopausal women with osteoporosis.

As previously reported, Radius submitted a Centralised Marketing Authorisation Application (MAA) for abaloparatide-SC in the European Union on November 17, 2015, which was validated by the European Medicines Agency (EMA) in December 2015, and is currently undergoing active regulatory assessment by the Committee for Medicinal Products for Human Use of the EMA (CHMP). The EMA has granted Radius an additional 3-month extension to the procedural timetable for response in the ongoing MAA assessment. As a result of this extension to the procedural timetable, the Company now anticipates that the CHMP may adopt an Opinion regarding the MAA in late 2016 or in 2017.

Abaloparatide-SC is an investigational treatment for postmenopausal women with osteoporosis and its safety and efficacy have not been established.

Teva Announces FDA Approval of ProAir RespiClick (albuterol sulfate) Inhalation Powder for Pediatric Asthma Patients Ages 4 to 11

Teva Pharmaceutical Industries Ltd.,  announced  that the U.S. Food and Drug Administration (FDA) has approved ProAir RespiClick (albuterol sulfate) Inhalation Powder for the treatment or prevention of bronchospasm in children 4 to 11 years of age with reversible obstructive airway disease and for the prevention of exercise-induced bronchospasm (EIB).

ProAir RespiClick was approved by the FDA for use in patients 12 years of age and older in March 2015 and remains the only breath-activated, multi-dose, dry powder, short-acting beta-agonist (SABA) inhaler available in the U.S.

Flexion Therapeutics Receives Positive Guidance from FDA on NDA Submission for Zilretta for Osteoarthritis of the Knee

Flexion Therapeutics, Inc. announces that yesterday it received written responses from the U.S. Food & Drug Administration (FDA) to questions the company had submitted in advance of a pre-NDA meeting regarding Flexion's lead product candidate, Zilretta (also known as FX006). The FDA clearly indicates in its responses that the safety and efficacy data from the registration program for Zilretta are "acceptable to support filing of an NDA submission." Based on this positive FDA feedback, the in-person pre-NDA meeting has become unnecessary and the FDA responses will serve as the official meeting minutes.

Michael Clayman, M.D., President and Chief Executive Officer of Flexion, stated, "The endorsement from the FDA for the Zilretta NDA submission represents a major milestone in the development of this drug candidate and brings us one step closer to making it available to the many millions of knee osteoarthritis (OA) patients who lack good pain-relief options. We intend to submit the NDA in the fourth quarter of this year."

Allergan Receives FDA Approval of Teflaro (ceftaroline fosamil) for Pediatric Patients

Allergan plc, a leading global pharmaceutical company,  announced the U.S. Food and Drug Administration (FDA) has approved the company's supplemental New Drug Application (sNDA) for Teflaro (ceftaroline fosamil), granting new indications for pediatric patients 2 months of age to less than 18 years of age with acute bacterial skin and skin structure infections (ABSSSI), including infections caused by methicillin-resistant Staphylococcus aureus (MRSA), and community-acquired bacterial pneumonia (CABP) caused by Streptococcus pneumoniae and other designated susceptible bacteria.

"The impact of ABSSSI and CABP among children is significant, as these infections often require hospitalization and are met with limited pediatric treatment options, particularly as resistance increases among the pathogens that cause these infections," said David Nicholson, Chief R&D Officer, Allergan. "These new indications are yet another testament to our ongoing research and development in anti-infectives to address the evolving challenges of serious infections. Importantly, it allows us to educate physicians on the data they need to prescribe Teflaro to appropriate pediatric patients in need of an option that is safe and effective against some of the most difficult-to-treat pathogens in ABSSSI and CABP."

ABSSSI and CABP are common causes of healthcare visits and hospitalizations among children. Studies show more than 70,000 hospitalizations for ABSSSI occur among children per year – a rate that has more than doubled over the past 13 years.1 A study conducted by the Centers for Disease Control and Prevention (CDC) also found children younger than 5 years of age accounted for 70 percent of children hospitalized for community-acquired pneumonia.

These new indications were approved based on results from clinical studies evaluating TEFLARO in pediatric patients (2 months to less than 18 years of age), including one active-controlled study in ABSSSI and two active-controlled studies in CABP. In the ABSSSI active-controlled study, the efficacy and safety of Teflaro was compared with vancomycin or cefazolin (each with optional aztreonam). In the CABP studies, Teflaro was compared with ceftriaxone. Use of Teflaro in pediatric patients 2 months to less than 18 years of age is supported by evidence from adequate and well-controlled studies of Teflaro in adults, as well as additional pharmacokinetic and safety data from pediatric trials.

The primary objective of the pediatric ABSSSI and CABP studies was to evaluate the safety and tolerability of Teflaro. These studies were not powered for comparative inferential efficacy analysis, and no efficacy endpoints were identified as primary.

To evaluate the treatment effect of Teflaro in the ABSSSI pediatric trial, an analysis was conducted in 159 patients with ABSSSI in the Modified Intent-to-Treat (MITT) population. This analysis evaluated responder rates based on achieving both cessation of lesion spread and absence of fever on Study Day 3. Patients treated with Teflaro showed a higher response at Study Day 3 versus the comparator group, with clinical response achieved in 80.4 percent (86/107) of patients treated with Teflaro and 75 percent (39/52) of patients in the comparator group, with a treatment difference of 5.4 percent (95 percent Confidence Interval [CI] -7.8, 20.3). Clinical cure rates at the test of cure (TOC) visit (8 to 15 days after the end of therapy) for the ABSSSI pediatric trial were 94.4 percent (101/107) for patients treated with Teflaro and 86.5 percent (45/52) for the comparator, with a treatment difference of 7.9 (95 percent CI -1.2, 20.2).

To evaluate the treatment effect of Teflaro in the CABP trial submitted for this pediatric filing, an analysis was conducted in 143 patients with CABP in the MITT population. This analysis evaluated responder rates at Study Day 4 based on achieving improvement in at least two out of seven symptoms (cough, dyspnea, chest pain, sputum production, chills, feeling of warmth/feverish and exercise intolerance or lethargy), and worsening in none of these symptoms. The clinical response at Study Day 4 was 69.2 percent (74/107) for patients treated with Teflaro and 66.7 percent (24/36) for the comparator, with a treatment difference of 2.5 percent (95 percent CI -13.9, 20.9). Clinical cure rates at TOC were 87.9 percent (94/107) for patients treated with TEFLARO and 88.9 percent (32/36) for the comparator, with a treatment difference of -1.0 (95 percent CI -11.5, 14.1).

Results from the clinical studies in pediatric patients showed that Teflaro demonstrated a safety profile that was compatible with treatment of ABSSSI and CABP at the clinical dosages studied. The safety findings were similar to those seen in the adult studies, and no safety concerns were identified beyond those already known to be cephalosporin class effects.

Teflaro is the first and only cephalosporin indicated in adults and pediatric patients 2 months of age and older for the treatment of ABSSSI and CABP due to designated susceptible pathogens that can be administered by intravenous (IV) infusion in five minutes to one hour.

Allergan Announces FDA Approval of Byvalson (nebivolol and valsartan) for Hypertension

In continuation of my update on nebivolol and valsartan

Allergan plc (NYSE: AGN), a leading global pharmaceutical company,  announced the approval of Byvalson (nebivolol and valsartan) 5 mg/ 80 mg tablets, by the U.S. Food and Drug Administration (FDA) for the treatment of hypertension to lower blood pressure. Byvalson is the first and only fixed-dose combination (FDC) of a beta blocker (BB) and angiotensin II receptor blocker (ARB) available in the U.S.

 nebivolol  Valsartan

"Achieving blood pressure control is critical to reducing the risk of serious and life-threatening cardiovascular events. There remains a need for new therapies, as observed by the nearly half of patients in the U.S. who remain uncontrolled," said David Nicholson, Chief R&D Officer at Allergan. "We are pleased with the FDA approval of Byvalson, which will provide physicians a new fixed dose combination therapy treatment option for patients affected by hypertension."

Hypertension represents a significant public health problem with high prevalence in the U.S. Hypertension often has no warning signs or symptoms and has been associated with serious cardiovascular (CV) risks, such as stroke, heart failure, and myocardial infarction. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the beta-blocker class to which nebivolol principally belongs and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with Byvalson.

"The majority of patients with hypertension require two or more medications to achieve their blood pressure goals," said William B White, MD Professor of Medicine and Chief of the Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center at UConn Health in Farmington and immediate past president of the American Society of Hypertension. "Nebivolol and valsartan are used widely in the management of hypertension and are effective drugs. The new fixed-dose combination Byvalson, that includes these 2 therapies, offers reduction of blood pressure through multiple mechanisms of action."

The FDA approval of Byvalson was based on a Phase 3, double-blind, placebo-controlled, dose-escalating, 8-week efficacy and safety study, published in The Lancet, which randomized approximately 4,100 patients with Stage 1 or 2 hypertension. In this pivotal efficacy and safety study, treatment with the FDC of nebivolol and valsartan for 4 weeks demonstrated statistically significant reductions from baseline in diastolic and systolic blood pressure versus either nebivolol alone or valsartan alone. The overall rate of adverse events was similar across treatment groups and placebo during this 4 week period.

Metabolite of oral DMF drug for multiple sclerosis appears to slow onset of Parkinson's disease

In continuation of my update on dimethylfumarate 

The metabolite of a drug that is helping patients battle multiple sclerosis appears to significantly slow the onset of Parkinson's disease, researchers say.

The oral drug, dimethylfumarate, or DMF, and its metabolite, monomethylfumarate, or MMF, both increase activity of Nrf2, a protein that helps protect the body from oxidative stress and inflammation, hallmarks of both diseases, said Dr. Bobby Thomas, neuroscientist in the Department of Pharmacology and Toxicology at the Medical College of Georgia at Augusta University.

 dimethylfumarate  monomethylfumarate, 

But the new study provides the first evidence that the metabolite, which is essentially the active portion of the parent drug, more directly targets Nrf2, potentially reducing known side effects of the parent drug that include flushing, diarrhea, nausea, vomiting, abdominal pain and the brain infection encephalopathy, said Thomas, corresponding author of the study in The Journal of Neuroscience.

Particularly, the gastrointestinal side effects can exacerbate some problems patients with Parkinson's already experience, said Dr. John Morgan, neurologist, neuroscientist and Parkinson's disease specialist in the MCG Department of Neurology. In addition to destroying neurons in the brain that produce dopamine, a neurotransmitter that enables movement and learning, Parkinson's causes nerve cell death in the gastrointestinal tract and related problems such as severe constipation.

"Nrf2 is a natural protective mechanism we have for oxidative stress," Thomas said. The fact that multiple sclerosis and Parkinson's have in common evidence of declining activity of the Nrf2 pathway has generated interest in the drug for Parkinson's and other neurodegenerative diseases.

DMF was approved for multiple sclerosis three years ago by the Food and Drug Administration. While its metabolite MMF is not quite as potent as the parent drug in increasing Nrf2 activity, the new study indicates that its action is sufficient to dramatically slow the loss of dopamine-producing neurons as well as the parent drug, in an animal model of Parkinson's.

In their model, mice given the neurotoxin MPTP experience a dramatic loss of dopamine-producing neurons, losing about half within a handful of days, and rapidly develop Parkinson's-like symptoms. Patients, on the other hand, slowly develop symptoms over many years. By the time they seek medical care, patients may have lost 30-50 percent of their dopaminergic neurons, said Morgan, a study coauthor. "Presentation is after the disease is kind of out of the gate."

To accommodate the very compressed timeline in their model and the fact that several daily doses are needed before the drug starts to work, the researchers first gave the mice either the drug or metabolite the day before they started the toxin.

Dopamine-producing neurons are located in a darker-pigmented central portion of the brain called the substantia nigra. Even in the absence of disease, making dopamine is a stressful job for these neurons that makes them generally more fragile and actually results in oxidative stress even in a healthy scenario, Morgan said. To make a difficult situation worse, increased oxidative stress can make dopamine toxic to neurons, he said.

To increase Nrf2 activity, the parent drug DMF also appears to first make bad matters worse. DMF increases oxidative stress by depleting the natural antioxidant, glutathione, and reduces the power of cell powerhouses, called mitochondria, by limiting their ability to use oxygen and glucose to make energy leading to reduced viability of dopamine-producing cells, Thomas said.

The metabolite MMF appears to more directly activate Nrf2, and actually increases glutathione and improves mitochondrial function, brain cell studies showed. While the parent drug ultimately produces a higher Nrf2 activation, the researchers found the MMF effect was sufficient to stop the dramatic neuron loss in the animal model.

Both DMF and MMF slowed neuron loss to a more normal level, and the neurons that survived continued to make dopamine. Inflammation and oxidative stress levels also were significantly reduced, the researchers said.

As a next step, they are working toward a clinical trial of MMF in patients with early Parkinson's disease. Although the metabolite could be easily formulated for humans, it has not yet been done, Thomas notes.

"If we can catch them early enough, maybe we can slow the disease," Morgan said. "If it can help give five to eight more years of improved quality of life that would be great for our patients."

Clinical studies of the drug in Parkinson's are being planned in the United Kingdom and additional analogues of its metabolite, which could be used clinically and which the researchers think ultimately will be the best option for patients, are under development.

Oxidative stress is a byproduct of the body's use of oxygen. Free radicals, generated by oxygen use, are unstable molecules that can interfere with usual cell function and are believed to contribute to a wide range of conditions from normal aging to Alzheimer's disease. Simply giving antioxidants, such as vitamin E, which work more like scavengers to scarf up free radicals, has not worked in combating neurodegenerative disease, Thomas said. He's optimistic that directly targeting Nrf2 will be effective in at least slowing the disease, but there remains a need for clinically safe Nrf2 activators.

Activity of the Nrf2 pathway tends to slowly decline with age. Exercise upregulates Nrf2, and Morgan regularly encourages his patients to be as active as possible. A small group of patients with Parkinson's in Europe has a concentrated activation of Nrf2 that at least delays their disease onset. Parkinson's tends to be diagnosed in the mid-to-late 50s and early 60s and is more common in men.

One concern with chronically elevating anti-oxidant and anti-inflammatory molecules with drugs like DMF and MMF is creating some of the same problems that immunosuppressive drugs given to organ transplant patients create. Chronic suppression of the immune response makes patients more susceptible to invaders like cancers and infections.

Ref : http://www.jneurosci.org/content/36/23/6332.short?sid=e7a934c5-6996-4fff-bfa9-f2c600507e1f

Metabolite of oral DMF drug for multiple sclerosis appears to slow onset of Parkinson's disease

Researchers identify promising new compound for targeting triple-negative breast cancer

Researchers at the University of Michigan have identified a promising new compound for targeting one of the most aggressive types of breast cancer.

The compound, currently called UM-164, goes after a kinase known to play a role in the growth and spread of triple-negative breast cancer. UM-164 blocks the kinase c-Src and inhibits another pathway, p38, involved in this subtype. The researchers also found that the compound had very few side effects in mice.

"Triple-negative breast cancer is in dire need of new drugs. The treatments that have dramatically improved breast cancer outcomes don't apply to patients with this type of disease," says senior study author Sofia Merajver, M.D., Ph.D., scientific director of the breast oncology program at the University of Michigan Comprehensive Cancer Center.

Triple-negative breast cancer is more aggressive than other types of breast cancer. Patients are much more likely to see their cancer recur and spread. Currently there are no approved targeted therapies for triple-negative breast cancer, which represents about 20 percent of breast cancer diagnoses.

Triple-negative breast cancer is so-called because it is negative for two hormone receptors and the HER2 protein - the three markers that current treatments have successfully targeted. That leaves chemotherapy as the only treatment option for this type of cancer.

"We are gaining a better understanding of the biology of triple-negative breast cancer, which is essential to developing targeted therapies," says study first author Rabia A. Gilani, Ph.D., a post-doctoral research fellow at U-M.

Scientists have been interested in c-Src because of its role in breast cancer progression and metastasis. But drugs designed to target c-Src have proven mostly ineffective.

The U-M team took a different approach. While other c-Src inhibitors merely try to block the kinase, UM-164 binds to it and forces the kinase to turn off. Results of their study are published in Clinical Cancer Research.

"The reason our compound works is that we have a novel mechanism for binding the kinase. It has a response similar to removing the protein entirely from the cell, as opposed to only inhibiting the activity," says senior study author Matthew B. Soellner, Ph.D., assistant professor of medicinal chemistry at the University of Michigan.

In addition to blocking c-Src, the researchers found that UM-164 inhibited p38, another kinase pathway implicated in triple-negative breast cancer. By testing an existing c-Src inhibitor individually and then combining it with an existing p38 inhibitor, they found the combination was more effective. This work was done in cells.

"They're much better together than they are individually," Soellner says. "And with our compound, the outcomes were even stronger than with the existing drugs. We weren't trying to target p38, but it turns out to be a promising target in this disease."

The researchers also found that they could administer the drug to mice at a dose that was effective against the cancer but that caused few side effects. Much more laboratory testing is needed to understand the safety profile of UM-164 before any clinical trials could be considered. The researchers plan to do additional safety testing in specialized mouse models based on tissue from patients.

Ref: http://clincancerres.aacrjournals.org/content/early/2016/05/06/1078-0432.CCR-15-2158.abstract#aff-2

Researchers identify promising new compound for targeting triple-negative breast cancer

Drug candidate delivered by plant-virus-based carrier shows promise for triple-negative breast cancer

In continuation of my update on phenanthriplatin

In a pair of firsts, researchers at Case Western Reserve University and Massachusetts Institute of Technology have shown that the drug candidate phenanthriplatin can be more effective than an approved drug in vivo, and that a plant-virus-based carrier successfully delivers a drug in vivo. 

phenanthriplatin

Triple-negative breast cancer tumors of mice treated with the phenanthriplatin -carrying nanoparticles were four times smaller than those treated either with cisplatin, a common and related chemotherapy drug, or free phenanthriplatin injected intravenously into circulation.

The scientists believe the work, reported in the journal ACS Nano, is a promising step toward clinical trials.

"We may have found the perfect carrier for this particular drug candidate," said Nicole Steinmetz, an assistant professor of biomedical engineering at Case Western Reserve, who has spent 10 years studying the use of plant viruses for medical purposes.

She teamed with Stephen J. Lippard, Arthur Amos Noyes Professor of chemistry at MIT, and an expert in biological interactions involving platinum-based chemotherapies.

Platinum-based drugs are used to treat more than half of cancer patients receiving chemotherapy. Two of the most commonly used drugs are cisplatin and carboplatin. They form bifunctional cross-links with DNA in cancer cells, which block the DNA from transcribing genes and result in cell death, Lippard explained.

Despite widespread use, cisplatin has been shown to cure only testicular cancer, and many cancers have or develop immunity to the drug.

Lippard's lab altered cisplatin by replacing a chloride ion with phenanthridine and found that the new molecule also binds to DNA. Instead of forming cross-links, however, phenanthriplatin binds to a single site but still blocks transcription.

In fact, his lab found that phenanthriplatin is up to 40 times more potent than traditional platins when tested directly against cancer cells of lung, breast, bone and other tissues. The molecule also appears to avoid defense mechanisms that convey resistance.

But when injected into mouse models of cancer, the drug candidate performed no better than standard platins.

Lippard realized phenanthriplatin wasn't reaching its target. He had a drug delivery problem.

He found a potential solution while visiting Case Western Reserve's campus and heard Steinmetz explain her work investigating tobacco mosaic virus (TMV) for drug delivery more than a year ago.

"I envisioned that TMV would be the perfect vehicle," Lippard said. "So we had a beer and formed a collaboration."

The long, thin tobacco mosaic virus nanoparticles are naturals for delivering the drug candidate into tumors, said Steinmetz, who was appointed by the Case Western Reserve School of Medicine.

The virus particles, which won't infect humans, are hollow. A central tube about 4 nanometers in diameter runs the length of the shell and the lining carries a negative charge.

Phenanthriplatin is about 1 nanometer across and, when treated with silver nitrate, has a strong positive charge. It readily enters and binds to the central lining.

The elongated shape of the nanoparticle causes it to tumble along the margins of blood vessels, remain unnoticed by immune cells and pass through the leaky vasculature of tumors and accumulate inside. Little healthy tissue is exposed to the toxic drug.

Inside tumors, the nanoparticles gather inside the lysosomal compartments of cancer cells, where they are, in essence, digested. The pH is much lower than in the circulating blood, Steinmetz explained. The shell deteriorates and releases phenanthriplatin.

The shell is broken down into proteins and cleared through metabolic or natural cellular processes within a day while the drug candidate starts blocking transcription, leading to greater amounts of cell death through apoptosis than cross-linking platins.

The researchers say delivery of the phenanthriplatin into the tumor led to its improved performance over cisplatin or free phenanthriplatin.

Lippard and Steinmetz continue to collaborate, investigating use of this system to deliver other drugs or drug candidates, use in other types of cancers, the addition of agents on the exterior of the shell to increase accumulation inside tumors and more.

One-third of osteoporotic women taking oral bisphosphonates have elevated risk for bone fracture

Chemical structure of pyrophosphate (A, above) and bisphosphonates (B, below). P = phosphorus, O = oxygen, H = hydrogen, C = carbon, R = side chain. In bisphosphonates, the central oxygen atom is replaced with a carbon atom. All bisphosphonates share a common phosphorus-carbon-phosphorus motif with two side chains (R1 and R2 in the figure). The R2 side chain determines the chemical properties of the drug, and distinguishes individual types of bisphosphonates. This chemical structure affords a high affinity for calcium hydroxyapatite, allowing for rapid and specific skeletal targeting.

More than 53 million Americans age 50 and older, primarily women, have osteoporosis or are at high risk for the condition due to low bone density. A recent study of oral bisphosphonates, the most commonly prescribed osteoporosis treatment, found that approximately a third of women prescribed these drugs continue to be at elevated risk for bone fracture, an outcome that may have several origins.

Oral bisphosphonates are a pillar of preventive treatment for patients with osteoporosis and have been shown to be effective in reducing the risk of disabling bone fractures. It is known from clinical trials that no medication completely eliminates the risk of fracture. Additionally, medication effectiveness may be different in clinical practice compared to well-controlled research trials.

Research from the Regenstrief Institute-Merck (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.) collaboration suggests that many women still have indicators consistent with higher risk of fracture while taking these medications. The cross-sectional population health study was based on a retrospective database analysis of 7,435 women age 50 and older taking bisphosphonates for at least two years during the 2000-2012 time period. The analysis was published in the peer-reviewed journal Bone.

"While we found that a substantial proportion of patients who took oral bisphosphonates remain at risk for hip, spine, and other major fractures, this class of drug does improve bone density in the majority of patients and should remain a mainstay of osteoporosis management," said Erik Imel, M.D., the Indiana University School of Medicine endocrinologist and Regenstrief Institute-affiliated scientist who led the study.

"We limited our study to patients who were considered to be compliant with taking their medication, based on drug dispensing days covered, with the presumption being that those who filled prescriptions took the medication properly. We would expect even less benefit if patients fail to take their medication properly. To increase treatment effectiveness, patients and their doctors should be vigilant that the drug is taken reliably and properly. However, osteoporosis drugs are not enough. Physicians and their patients are well advised to discuss additional important modifications to decrease fall risk and fracture risk. These include exercise, smoking cessation, use of assistive devices such as canes or walkers, modifying the home to avoid obstacles that might lead to falls, and taking appropriate amounts of vitamin D and calcium."

Conducted under the auspices of a Regenstrief Institute-Merck collaboration, the retrospective cohort study utilized anonymized data from the Indiana Network for Patient Care, a health information exchange founded by the Regenstrief Institute. The study authors note that the data they used reflects real-life medical practice and patient behavior from a wide range of physicians and patient backgrounds. Adherence to bisphosphonate therapy was determined by prescription fulfillment records. Clinical data included information on bone density and fractures.

"We know that taking bisphosphonates decrease fracture risk compared to those not taking these drugs," Dr. Imel said. "But what about those women who weren't getting the anticipated benefit and are not improving bone density or even are losing bone density? What predicted that? The purpose of this study was to focus attention on those not doing well, in order to begin to decrease the odds of future fractures in this large group of vulnerable patients.

"Not everyone responds the same way to oral bisphosphonates or any drug. Various factors could convey continued risk of fracture in spite of bisphosphonate therapy, including other medical problems and risk factors for falling. Since we know that such a high percentage of women continue to have elevated fracture risk we -- doctors and patients -- need to focus on these factors," Dr. Imel said. "For example, we found that women who had other medical conditions in addition to low bone density--a frequent occurrence in this older population--had higher fracture risk. Taking some medications in combination with bisphosphonates seemed to increase fracture risk. However, having more medical conditions and taking more drugs are most likely markers of heightened risk rather than causative factors."

Neurologic problems, often linked to heightened risk of falls, as well as inflammatory and other chronic joint conditions including arthritis were found to be associated with higher odds of having a fracture among those taking bisphosphonates.

"I always tell my osteoporosis patients, 'Don't fall,'" said Dr. Imel. "They usually chuckle, and then we talk about things they can do to decrease the risk of falling, including proper footwear and assistive devices. Many patients are reluctant to use a cane or a walker. I try to get them to understand the importance of using any tool that decreases the chance of falling."

Maintenance lenalidomide treatment improves overall survival in multiple myeloma patients

In continuation of my update on lenalidomide 

 lenalidomide 

While several clinical trials have demonstrated that maintenance therapy with lenalidomide reduces the risk of disease progression in patients with multiple myeloma, there have been no definitive results regarding overall survival. While some previous studies found that maintenance lenalidomide after autologous hematopoietic stem cell transplant improved overall survival for newly diagnosed multiple myeloma patients, others showed no benefit to this approach. Philip McCarthy, MD, Director of Blood & Marrow Transplant at Roswell Park Cancer Institute (RPCI), will present the findings of an international team of researchers at the American Society of Clinical Oncology (ASCO) 52nd Annual Meeting in Chicago.

The new study is a meta-analysis of three randomized controlled trials conducted by the Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B) (CALGB) with support from the NCI, Intergroupe Francophone du Myélome (IFM), and the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA). It involved more than 1,200 participants. For this analysis, 605 patients with newly diagnosed multiple myeloma and treated with continuous lenalidomide (brand name Revlimid) following autologous stem cell transplant were compared to 604 patients who were treated with placebo or no maintenance. At seven years, 62% of those treated with maintenance lenalidomide had survived, compared to 50% of those in the control group. The benefit in overall survival was consistent across subgroups.

"Lenalidomide maintenance following autologous stem cell transplant can now be considered a standard of care for people with multiple myeloma," says Dr. McCarthy, senior author on the meta-analysis and Principal Investigator of the U.S. study, CALGB (Alliance) 100104. "The improvements over the last decade in terms of both survival and quality of life for patients with this disease are striking, and very encouraging."

Targeted therapy rucaparib shows promise in treating pancreatic cancer patients with BRCA mutation

The targeted therapy rucaparib, which has demonstrated robust clinical activity in ovarian cancer patients with a BRCA mutation, also showed promise in previously treated pancreatic cancer patients with the mutation, according to results from a phase II clinical study presented by Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania, at the American Society of Clinical Oncology (ASCO) Annual Meeting. (Abstract # 4110).

rucaparib

Overall, a clinical benefit was observed in 32 percent of patients (6 of 19) treated with rucaparib. Of the 19 pancreatic patients, one had a complete response and two had partial responses, while four patients had stable disease. The objective response rate, the primary endpoint for the study, was 16 percent (3 of 19).

"These results are encouraging and further demonstrate the clinical significance of the BRCA cancer genes outside of breast and ovarian, and not just in women," Domchek said. "Importantly, it points us to a potential new treatment avenue for pancreatic cancer, an aggressive disease that's often caught in the later stages. Though smaller in number, some patients with advanced disease and carrying a BRCA mutation may benefit from the same targeted therapy being used today in the clinic to successfully treat some ovarian cancer patients."

Given the poor prognosis and limited treatment options in pancreatic cancer, new therapies to combat the disease are desperately needed: Earlier this year, the American Cancer Society reported that it is estimated that in 2016, nearly 42,000 people will die from the disease, surpassing the number of deaths from breast cancer by more than 1,000.

Recent studies have shown that rucaparib, a PARP inhibitor, effectively treats patients with platinum-sensitive, relapsed, high-grade ovarian cancer harboring a BRCA mutation. In a study presented at ASCO in 2015, researchers showed that treatment resulted in a 69 percent RECIST response rate in these patients. In April 2015, it received a U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation. The FDA's designation, created in 2012, is intended to expedite the development and review of new medicines - both drugs and biologic agents - that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The success in ovarian patients prompted a clinical study in pancreatic patients with the same mutation--about nine percent of pancreatic patients are BRCA1/BRCA2 positive.

The team enrolled participants with measurable, relapsed disease who received one to three prior rounds of chemotherapy for locally advanced or metastatic cancer. The trial included 11 male and eight female patients, with a median age of 57. Twenty-one percent of the patients tested positive for the BRCA1 mutation, while 79 percent tested positive for BRCA2.

The disease control rate (defined as partial response or stable disease for more than 12 weeks) for all patients was 32 percent (6 of the 19 patients) and 50 percent (three of six patients) in patients who received one prior line of chemotherapy. Four patients had stable disease, nine patients had progressive disease, and three were not evaluable for response. One patient was on the drug for 72 weeks and is continuing to receive the drug. The drug had an acceptable safety profile. Common treatment-emergent side effects included nausea (63 percent) and anemia (47 percent).

All patients who responded received only one prior line of chemotherapy therapy, suggesting that the drug may be an option earlier in the treatment course.

Targeted therapy rucaparib shows promise in treating pancreatic cancer patients with BRCA mutation