Friday, August 31, 2018
Jefferies sees prescription rebound for Optinose’s Xhance
. After meeting with Optinose management, Jefferies analyst David Steinberg says that despite the recent setback, he continues to believe that Xhance will become a large product. Post adjustments to Xhance launch tactics, management believes they have made the proper changes and expect prescriptions to reaccelerate as summer ends, Steinberg tells investors in a research note. He points out that the company highlighted positive physician and patient feedback on the performance of the drug. The analyst keeps a Buy rating on Optinose with a $31 price target.
https://thefly.com/landingPageNews.php?id=2784563
Thursday, August 30, 2018
Chardan: Tocagen’s Brain, Spinal Cord Tumor Candidate Has $877M Potential
Tocagen Inc TOCA 10.73%, which focuses on developing cancer-selective gene therapies based on a retroviral replicating vector platform, has earned a bullish review from Chardan.
The Analyst
Analyst Gbola Amusa initiated coverage of Tocagen with a Buy rating and $30 price target, suggesting more than 250 percent upside.
The Thesis
Tocagen’s lead asset Toca 511, a RRV that selectively infects cancer cells, and Toca FC, an orally administered, extended-release formulation of 5-flurorocytosine, are in a pivotal Phase 3 trial for high-grade gliomas, or HGG, which are tumors occurring in brain and spinal cord, Amusasaid in a Thursday note.
The initial Phase 1 study produced impressive and in some cases durable results in rHGG patients who otherwise die in eight to 11 months, the analyst said.
The Toca 511 and Toca FC Phase 3 trial is evaluating rHGG patients, Amusa said. Yet Tocagen is also testing the regiment in Phase 1 trials in newly diagnosed HGG and other advanced cancers.
Citing the robust data, the analyst estimates risk-adjusted 2030 sales of $877.6 million for Toca 511 and Toca FC in HGGs.
Chardan’s bullish rating is due to “the risk-reward proposition on its pivotal, Phase III, BTD/PRIMEdesignated therapy, Toca 511 & Toca FC, for high-grade gliomas.”
Interim data from the late-stage study is due in the first-half of 2019, Amusa said.
CRISPR halts Duchenne muscular dystrophy progression in dogs
Scientists for the first time have used CRISPR gene editing to halt the progression of Duchenne muscular dystrophy (DMD) in a large mammal, according to a study by UT Southwestern that provides a strong indication that a lifesaving treatment may be in the pipeline.
The research published in Science documents unprecedented improvement in the muscle fibers of dogs with DMD — the most common fatal genetic disease in children, caused by a mutation that inhibits the production of dystrophin, a protein critical for muscle function.
Researchers used a single-cut gene-editing technique to restore dystrophin in muscle and heart tissue by up to 92 percent of normal levels. Scientists have estimated a 15 percent threshold is needed to significantly help patients.
“Children with DMD often die either because their heart loses the strength to pump, or their diaphragm becomes too weak to breathe,” said Dr. Eric Olson, Director of UT Southwestern’s Hamon Center for Regenerative Science and Medicine. “This encouraging level of dystrophin expression would hopefully prevent that from happening.”
DMD, which affects one in 5,000 boys, leads to muscle and heart failure, and premature death by the early 30s. Patients are forced into wheelchairs as their muscles degenerate and eventually onto respirators as their diaphragms weaken. No effective treatment exists, though scientists have known for decades that a defect in the dystrophin gene causes the condition.
The Science study establishes the proof-of-concept for single-cut gene editing in dystrophic muscle and represents a major step toward a clinical trial. Already Dr. Olson’s team has corrected DMD mutations in mice and human cells by making single cuts at strategic points of the mutated DNA.
The latest research applied the same technique in four dogs that shared the type of mutation most commonly seen in DMD patients. Scientists used a harmless virus called adeno-associated virus (AAV) to deliver CRISPR gene-editing components to exon 51, one of the 79 exons that comprise the dystrophin gene.
CRISPR edited the exon, and within several weeks the missing protein was restored in muscle tissue throughout the body, including 92 percent correction in the heart and 58 percent in the diaphragm, the main muscle needed for breathing.
“Our strategy is different from other therapeutic approaches for DMD because it edits the mutation that causes the disease and restores normal expression of the repaired dystrophin,” said Dr. Leonela Amoasii, lead author of the study and Assistant Instructor of Molecular Biology in Dr. Olson’s lab. “But we have more to do before we can use this clinically.”
The lab will next conduct longer-term studies to measure whether the dystrophin levels remain stable and to ensure the gene edits do not have adverse side effects.
Dr. Olson hopes the next step beyond dogs is a clinical trial, which would be among several that UT Southwestern’s gene therapy center aims to launch in the coming years to address numerous deadly childhood diseases.
In the meantime, Dr. Olson’s recent work has spawned a biotechnology company, Exonics Therapeutics Inc., which is working to further optimize and bring this technology to the clinic. Exonics intends to extend the approach to additional DMD mutations, as well as other neuromuscular diseases. Exonics has licensed the technology from UT Southwestern.
Story Source:
Materials provided by UT Southwestern Medical Center. Note: Content may be edited for style and length.
Journal Reference:
- Leonela Amoasii, John C.W. Hildyard, Hui Li, Efrain Sanchez-Ortiz, Alex Mireault, Daniel Caballero, Rachel Harron, Thaleia-Rengina Stathopoulou, Claire Massey, John M. Shelton, Rhonda Bassel-Duby, Richard J. Piercy, Eric N. Olson. Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science, 2018; eaau1549 DOI: 10.1126/science.aau1549
Survey: Cancer Patients Will Pay Anything for Treatment
As costs for cancer therapy routinely reach into seven figures, and patients demand access to investigational medicines knowing they’ll have to pay out of pocket, results of a new survey will surprise no one.
When 300 cancer patients were asked what sacrifices they would make to obtain treatment, many said they would sell their homes and declare bankruptcy if necessary.
In fact, these patients were willing to make such sacrifices even though three-quarters of survey participants had stage IV disease.
These findings, according to researchers led by Fumiko Chino, MD, at Duke University in Durham, North Carolina, suggest that shared decision-making between patients and caregivers is “important to ensure patients fully understand the goals, risks, and benefits of therapy before they make such personal sacrifices.”
The results of the survey were published in the Journal of Oncology Practice.
“Financial toxicity” — the economic burden associated with cancer care — is understood to represent potential harm to cancer patients, and is being addressed by the American Society of Clinical Oncology (ASCO) through the ASCO Value Framework.
It’s “a reality that actually is happening every day,” said Lowell E. Schnipper, MD, FASCO, chief of the division of hematology/oncology and clinical director of the Beth Israel Deaconess Medical Center Cancer Center, and chair of the ASCO Value in Cancer Care Task Force.
Chino and her colleagues noted that little is known about how patients consider costs, and what kind of sacrifices they will make when making treatment decisions.
To help fill the gap, they conducted a longitudinal survey of insured cancer patients with solid tumors who had received chemotherapy or hormonal therapy at least 30 days before enrollment.
Three hundred patients completed a baseline survey, while 245 (82% retention) completed a follow-up survey 3 months later.
The median cancer-related out-of-pocket costs reported by patients who completed both surveys were $393 per month (range $0 to $26,586) at baseline and $328 per month (range $0 to $8,210) at follow-up.
At baseline, at least 65% of patients were willing to make some kind of sacrifice, such as spending less on basics and vacations, or borrowing money, in order to pay for their cancer care. Some 38% were willing to sell their homes and 49% declare personal bankruptcy.
Those percentages changed minimally upon follow-up, with the greatest change a 7% decline in patients willing to declare bankruptcy.
The extent to which patients appeared willing to make major personal and financial sacrifices in order to receive cancer care is “concerning,” wrote Chino and her colleagues, and suggests that patients may not clearly understand the benefits — often limited or nonexistent — they’ll gain as a result of these sacrifices.
Chino and colleagues were especially concerned since 76% of patients in the survey had stage IV cancer, and thus had very low probability that any treatment would help them substantially.
“There is a potential disconnect between the value that patients place on their cancer treatment and the benefit they stand to gain in terms of prolongation of life or relief of symptoms,” the researchers wrote, adding that their findings “highlight the importance of shared decision making and ensuring that treatment decisions reflect patient goals and preferences.”
Schnipper told MedPage Today that the results of this study, along with others, demonstrate that “doctors not only need to be aware of, but conversant with their patients about matters affecting them and their families because of out of pocket expenses.”
He pointed out that while these conversations are beginning to happen, “they’re not happening to an extent we would consider to be ideal.” He added that associations such as ASCO and the American College of Physicians are working to find innovative ways of incorporating this kind of discussion into conversations with patients.
Schnipper said he has heard suggestions that physicians should consider approaching a conversation about financial toxicity the same way they would approach a patient’s vital signs, such as blood pressure or respiratory rate.
“I don’t know if we are ready for that,” Schnipper said. “But, there is a group of physicians across specialties who understand the impact on our patients and feel as though we not only need to be the stewards of their health, but need to be able help them make discriminating decisions and protect their pocketbooks when it is appropriate.”
Chino had no relationships to disclose.
LAST UPDATED
FDA Warns of Common Diabetes Meds Link to Dangerous Genital Infection
Rare but serious genital infections, as well as one death, have been reported in some patients taking a certain class of type 2 diabetes medicine, the U.S. Food and Drug Administration says.
As a result, the FDA has ordered a new warning about this risk to be added to the prescribing information and patient medication guide of all sodium-glucose cotransporter-2 (SGLT2) inhibitors.
The bacterial infection of the genitals and area around the genitals is called necrotizing fasciitis of the perineum, also called Fournier’s gangrene. The bacteria typically enter the body through a cut or break in the skin.
Between March 2013 and May 2018, the FDA identified 12 cases of Fournier’s gangrene in patients taking an SGLT2 inhibitor. However, this number includes only reported cases and those found in the medical literature, so there may be more cases, the FDA said in a news release.
Fournier’s gangrene developed within several months after the 12 patients starting taking an SGLT2 inhibitor, and use of the drug was stopped in most cases. All 12 patients were hospitalized and required surgery. Some patients required multiple disfiguring surgeries, some developed complications, and one patient died, according to the FDA.
A review of more than 30 years of data identified only six cases of Fournier’s gangrene among patients taking other classes of diabetes drugs, the FDA said. All six of those cases occurred in men, but five of the 12 recently reported cases involved women.
In 2017, about 1.7 million U.S. patients filled prescriptions for an SGLT2 inhibitor at outpatient retail pharmacies, the FDA said.
SGLT2 inhibitors were first approved by the FDA in 2013, and include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin.
Brand names of FDA-approved SGLT2 inhibitors include Invokana, Invokamet, Invokamet XR, Farxiga, Xigduo XR, Qtern, Jardiance, Glyxambi, Synjardy, Synjardy XR, Steglatro, Segluromet and Steglujan.
Patients taking these drugs should seek medical attention immediately if they have any tenderness, redness or swelling of the genitals, or the area from the genitals back to the rectum, and have a fever above 100.4 F or a general feeling of being unwell, the FDA advised.
The agency said health care providers should assess patients for Fournier’s gangrene if they have such symptoms. If Fournier’s gangrene is suspected, start treatment immediately with broad-spectrum antibiotics and surgery if necessary, discontinue the SGLT2 inhibitor, closely monitor blood sugar levels, and provide appropriate alternative therapy for blood sugar control, the agency added.
More information
The National Organization for Rare Disorders has more on Fournier’s gangrene.
SOURCE: U.S. Food and Drug Administration, news release, Aug. 29, 2018
FDA widening probe into heart drugs linked to cancer risk
After learning an ingredient used to make a widely prescribed heart drug contained a substance linked to cancer, the Food and Drug Administration is now testing all drugs in that class for traces of the toxic material.
The probe into angiotensin II receptor blockers is part of a widening investigation into a mystery over an impurity known as NDMA, which was found last month in generic valsartan blood pressure pills made by Zhejiang Huahai Pharmaceutical. NDMA, which is considered a possible carcinogen by the Environmental Protection Agency, is an organic chemical once used to make rocket fuel and is an unintended by-product of certain chemical reactions.
The finding caused widespread concern and product recalls by several manufacturers as the FDA and regulators from other countries scrambled to determine how the substance found its way into the medicine. The FDA issued a statement saying it believes the problem occurred “through a specific sequence of steps in the manufacturing process,” but the agency is “still not 100 percent sure this is the root cause.”
Due to the uncertainty, the FDA is “testing all the products in the ARB class to determine if they contain NDMA,” according to the statement by FDA Commissioner Scott Gottlieb and Janet Woodcock, who heads the FDA’s Center for Drug Evaluation and Research. “These tests will continue until we identify all products that may contain NDMA in the ARB class, and they are no longer available in the U.S.”
“This is a serious matter that is being managed closely by the FDA’s leadership,” they wrote.
Numerous companies either manufacture or repackage these drugs, which are regularly used to combat high blood pressure and heart failure. As of now, they noted that more than half of all valsartan medicines that are on the market are being recalled.
The episode underscores ongoing concerns about the quality of the pharmaceutical supply chain emanating from countries such as China and India that are large ingredients manufacturers, but have a history of inconsistent — some say inadequate — government oversight. A 2016 report by the U.S. Government Accountability Office found the FDA was struggling to assess its overseas inspection efforts.
Mindful of such concerns, the FDA statement took pains to explain the steps taken by the agency to respond to the NDMA problem. These included alerts issued to patients and health care providers on the agency web site; analysis by FDA staff at its St. Louis laboratory; communicating with regulators in Canada, Europe, and Japan; and inspecting Zhejiang Huahai facilities in China.
At the same time, the FDA reiterated an earlier alert that attempted to put the risk into context.
The agency estimated that if 8,000 people took the highest valsartan dose of 320 mg in a pill containing NDMA daily for four years — which is the amount of time the FDA believes the affected pill had been on the U.S. market — there may be one additional case of cancer over their lifetimes beyond the average cancer rate among Americans.
“This estimate represented the highest possible level of NDMA exposure. It was a measure of the risk under the most extreme circumstances. Most patients who were exposed to the impurity through the use of valsartan received less exposure than this worst-case scenario,” Gottlieb and Woodcock wrote in a bid to reassure the public about the likelihood of the risk of developing cancer.
Meanwhile, they added that they plan to use what they learn from this scare to “inform assessments of product applications being submitted and currently reviewed by the FDA. We will disseminate that information to manufacturers of all drugs and to the scientific community and re-evaluate our existing guidance to manufacturers.”
Possible Tie to 1st-Line ADHD Med, Hallucinations, Psychotic Symptoms
Hallucinations and other psychotic symptoms may arise in children and adolescents treated with methylphenidate (multiple brands) for attention-deficit/hyperactivity disorder (ADHD), new research suggests.
The meta-analysis, which included 10 randomized controlled trials, 17 nonrandomized studies, and 18 patient reports, showed that 1% to 2.5% of participants experienced such troublesome symptoms. However, investigators emphasize that the quality of the data in the included studies is subpar and that there is a possibility of bias.
Therefore, the results do not provide definitive proof of an association between methylphenidate and increased risk for psychotic symptoms, they write.
Nonetheless, until more definitive findings become available, “physicians, patients, and their caregivers should be aware of this possible adverse event,” lead author Erica Ramstad, a pregraduate research student in the Department of Children and Youth Psychiatry, Psychiatric Research Unit, Region Zeland, Denmark, told Medscape Medical News.
“However, concerns about this rare possible adverse event should of course be balanced against the potential beneficial effects of methylphenidate on ADHD symptoms, general behavior, and quality of life,” Ramstad added.
The study was published online July 10 in the Scandinavian Journal of Child and Adolescent Psychiatry and Psychology.
First-Line Therapy
Methylphenidate and other psychostimulants are the recommended first-line therapy for ADHD in multiple guidelines.
Previous studies have reported psychotic symptoms in children and adolescents treated with this agent for ADHD. However, Ramstad and colleagues note that to the best of their knowledge, no previous systematic review of the literature has examined psychotic symptoms in this patient population.
“Because so many children and adolescents are prescribed methylphenidate, it is important that the risk of adverse events is better understood,” they write.
The investigators examined two previous Cochrane systematic reviews that assessed the safety and efficacy of methylphenidate in children and adolescents with ADHD.
One review assessed randomized clinical trials; the other, which is currently in press, included observational studies, randomized trials without a placebo or comparator group, and patient reports.
The researchers updated these systematic reviews with additional randomized clinical trials published through March 2017.
The study included 1103 participants from randomized clinical trials, another 76,237 participants from nonrandomized studies, and 12 reports or small series describing 18 additional patients.
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