In briefing documents released ahead of that meeting, FDA staff picked apart BioMarin's case for the DMD therapy, pointing to problems in each of the company's three supporting clinical trials and raising concerns about drisapersen's toxicity.
In a Phase III trial, the drug failed to significantly extend how far patients with the muscle-wasting disease could walk in 6 minutes, but BioMarin, looking at a subpopulation of volunteers, contends that drisapersen made enough of a difference to warrant approval. The FDA reached a much harsher conclusion in Friday's review, noting that "while there may be some evidence suggestive of efficacy of drisapersen, the evidence is inconsistent and in some cases contradictory, and does not reach the level of substantial evidence."
On the safety side, the FDA bristled at drisapersen's ties to potentially fatal blood-platelet deficiency, renal injury and severe injection-site reactions. "The safety issues can have life-threatening outcomes," agency staff wrote, concluding that "even in the context of an invariably disabling and fatal disease such as DMD, the safety profile of drisapersen is concerning."
BioMarin's shares fell as much as 9% on Friday morning as the review seemed to dim drisapersen's odds of securing a positive recommendation at Tuesday's panel meeting and, eventually, FDA approval.
But the drug's tepid reception doesn't guarantee FDA rejection. Prepanel documents tend to take a tough tack on in-development drugs that is not always shared by agency advisers. And next week's meeting will also allot two hours for comments from DMD patients and their families, a group that has long lobbied for drisapersen's approval.
Inhibiting the Janus kinase family of enzymes with a topical formulation of approved drugs played a direct role in promoting abundant hair growth, according to a team of investigators at Columbia University.
Angela Christiano headed up the research team showing that JAK inhibitors could restore hair growth in different forms of hair loss, both in mouse and human hair follicles, when applied directly to the skin.
The two JAK inhibitors that showed promise are already approved by U.S. Food and Drug Administration; ruxolitinib is used currently for the treatment of blood diseases, and tofacitinib for rheumatoid arthritis.
Last year, Christiano's team showed that JAK inhibitors could switch off the signal that mounts a host immune response against its own hair follicles that causes eventual hair loss, restoring normal hair growth.
Initially this finding was through an oral administration of the JAK inhibitor. But when they tried a topical administration they saw an improvement in hair growth, suggesting a dual effect of an autoimmune block and a direct interaction of the drug with the hair follicles.
The researchers pinned the actions of the drugs to a reactivation of dormant follicles and since hair cells are known to cycle between a resting and growing phase, restoring all to the latter may improve overall hair growth. After 5 days of treatment, mice with either JAK inhibitor saw new hair growth within 10 days.
"There are very few compounds that can push hair follicles into their growth cycle so quickly," said Dr. Christiano. "Some topical agents induce tufts of hair here and there after a few weeks, but very few have such a potent and rapid-acting effect."
As yet, the team has conducted their experiments in normal mice and human follicles and what remains to be seen is whether these hair growth-inducing drugs can benefit hair follicles arrested by androgenetic alopecia--the main cause of male and female pattern baldness.
"What we've found is promising, though we haven't yet shown it is effective for male pattern baldness," said Dr. Christiano. "More work needs to be done to test formulations of JAK inhibitors specially made for the scalp to determine whether they can induce hair growth in humans."
Intercept's much-hyped NASH drug misses the mark in Phase II
Intercept Pharmaceuticals' (ICPT) new drug for the pervasive liver disease NASH came up short in a Phase II trial in Japan, seeding some worries about an ongoing late-stage study designed to support future FDA approval.
Sumitomo Dainippon Pharma, Intercept's partner in Japan, tested three doses of the drug against placebo in a 200-patient trial, surveying whether the treatment, obeticholic acid, could register a two-point improvement on a common measure of liver disease without worsening scarring. Across the board, Intercept's drug failed to get a statistically significant number of patients to that goal, with only the highest doses, 20 mg and 40 mg, clocking a p value under 0.05. The drug also failed to reach statistical significance on secondary endpoints including liver fat, inflammation, ballooning and resolution of NASH symptoms, Intercept said.
Intercept's share price fell about 14% on the results Tuesday morning on concerns that the drug, abbreviated OCA, may struggle to replicate its earlier Phase II success as its 2,000-patient Phase III trial gets underway.
Last month, Intercept began enrollment in a global study testing 10 mg and 25 mg of OCA versus placebo with primary endpoints of improving NASH symptoms, reducing liver scarring, and preventing death and end-stage liver disease. Final data won't be ready until 2021, but Intercept has scheduled an interim analysis in 2017 that will evaluate how well OCA is doing at resolving NASH and reducing scars in about 1,400 patients and plans to submit those results to the FDA for a shot at early approval.
Omecamtiv mecarbil is a novel cardiac myosin activator. Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into the mechanical force resulting in cardiac contraction. Cardiac myosin activators are thought to accelerate the rate-limiting step of the myosin enzymatic cycle and shift the enzymatic cycle in favor of the force-producing state. Preclinical research has shown that cardiac myosin activators increase contractility in the absence of changes in intracellular calcium in cardiac myocytes.1,2,11
Omecamtiv mecarbil is being developed by Amgen in collaboration with Cytokinetics. Amgen holds an exclusive, worldwide license to omecamtiv mecarbil and related compounds, subject to Cytokinetics’ specified development and commercialization rights. Additionally, Les Laboratoires Servier obtained an exclusive option to commercialize omecamtiv mecarbil in Europe.
Eli Lilly and Company (LLY)’s stock fell more than 10 percent in pre-market trading this morning after the company announced it was discontinuing development of its late stage cardiovascular drug evacetrapib due to insufficient efficacy.
Indiana-based Eli Lilly said it was accepting the recommendation of an independent data monitoring committee to terminate the Phase III Accelerate trial studying the efficacy of evacetrapib for the treatment of high-risk atherosclerotic cardiovascular disease. The independent committee said there was a “low probability the study would achieve its primary endpoint based on results to date,” Eli Lilly said in a statement. In July, this same committee recommended the company continue the Phase III trial based on data from an interim futility analysis.
The discontinuation of the clinical trial is expected to cost the company a $90 million pre-tax charge. Eli Lilly said it will include the charge in its 2015 economic guidance when it releases its third-quarter statements on Oct. 27.
Evacetrapib was being studied for its impact on cholesterol in a Phase III clinical trial with 12,095 patients with high-risk atherosclerotic cardiovascular disease in 37 countries. Evacetrapib was being developed as a selective inhibitor of cholesteryl ester transfer protein. In earlier clinical trials, the drug had shown effects on high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and cholesterol efflux.
The loss is a financial blow to Eli Lilly as the drug was expected to generate $632.7 million in annual sales in 2020, according to an average of seven analysts’ predictions compiled by Bloomberg.
The failure of Evacetrapib is also serving as a warning to other drugmakers working on anti-cholesterol developers. In a Monday morning note, Joel Beatty, an investment analysts with Citi Group, said that Lilly’s decision could negatively impact Esperion Therapeutics' development of ETC-1002. Beatty speculated Lilly’s decision could increase the likelihood the FDA will require outcomes trial results for LDL-lowering drugs before approval, In his note, Beatty said evacetrapib’s effectiveness at lowering LDL is at about the same rate as Esperion’s experimental drug.
Advaxis believes the patient died due to the progression of cervical cancer, but FDA is asking for additional information to confirm the company's experimental therapy, axalimogene filolisbac, played no role. Until the FDA's concerns are resolved, four clinical trials involving Advaxis' axalimogene filolisbac are on clinical hold.
Shares of Advaxis fell 25% to $10.31 in after-hours trading on news of the clinical trials halt. The bad news couldn't come at a worse time as investors are already in a sour mood over a prolonged and painful retrenchment in biotech stocks.
The safety report involved a single event in one patient with end-stage cervical cancer who last received axalimogene filolisbac in early 2013 in a company-sponsored trial. In late July 2015 the patient was hospitalized for symptoms related to her cancer. During her stay, routine blood cultures detected Listeria monocytogenes (Lm). Further analysis determined that it was the highly attenuated strain of Lm used in axalimogene filolisbac, which was incapable of causing infection and was very sensitive to antibiotics. The patient received intravenous antibiotics and was discharged. A few weeks later, the patient returned to the hospital with respiratory distress caused by her metastatic cancer and died later that day. The investigator determined that the cause of death was due to the progression of her cervical cancer.
and we still have an hour to go today, who will hold through the weekend, robo computer not.
Short Form. The presence of fatty liver was determined using ultrasonography.
Of the people studied, nearly 40,000 had NAFLD. Importantly, the researchers found that both prolonged sitting time and decreased physical activity level were independently associated with increasing prevalence of NAFLD. Remarkably, these associations were also observed in patients with a body mass index (BMI) of less than 23.
Most likely South Koreans.
Our Chairs Are Killing Us,' Say Researchers
Amsterdam, The Netherlands, September 15, 2015 -- Prolonged sitting time as well as reduced physical activity contribute to the prevalence of non-alcoholic fatty liver disease (NAFLD) in a study of middle-aged Koreans. These findings support the importance of both reducing time spent sitting and increasing physical activity, say researchers. Their results are published in the Journal of Hepatology.
Physical activity is known to reduce the incidence and mortality of various chronic diseases. However, more than one half of the average person's waking day involves sedentary activities associated with prolonged sitting such as watching TV and using the computer and other devices.
Recently, attention has focused on the damaging effects of sedentary behavior regardless of additional physical activity. A growing number of epidemiologic studies have suggested an association between sedentary behavior and chronic diseases including obesity, diabetes, insulin resistance, metabolic syndrome, cardiovascular disease, cancer, and even death that is distinct from those related to a lack of physical activity. This association was still observed among patients participating in high levels of moderate to vigorous physical activity, indicating that regular high levels of physical activity do not fully protect against the risks associated with prolonged periods of sedentary behaviors. However, the association between physical activity and NAFLD has been largely unexplored.
In the current study researchers examined the association of sitting time and physical activity level with NAFLD in Korean men and women to explore whether any observed associations were related to the amount of body fat. They studied records of nearly 140,000 Koreans who underwent a health examination between March 2011 and December 2013. Physical activity level and sitting time were assessed using the Korean version of the international Physical Activity Questionnaire
oday’s drug discovery around G protein-coupled receptors (GPCRs) is quite different from decades ago, when GPCRs weren’t even known to be the target of the newest drugs on the market. Are today’s knowledge-based drug discovery approaches better and faster though? Join your scientific colleagues for this day and a half meeting to debate these questions and more. Learn how the latest functional screening strategies and cutting-edge GPCR crystal structures are/can be applied to drug discovery and development. Also hear case studies around drug candidates developed against specific GPCRs and keep abreast of their progress in the clinic and pharmacological challenges.
8:40 KEYNOTE PRESENTATION:
Harnessing the Functional Selectivity of GPCRs for Drug Discovery
Michel Bouvier, Ph.D., Professor, Department of Biochemistry, University of Montreal
G protein-coupled receptors can engage multiple signaling cascades that may or may not involve G protein activation. This functional selectivity of GPCRs is controlled by the ligand that binds the receptor. Such ligand-biased signaling can be exploited for the development of new drugs with increased selectivity profiles and less undesirable effects. I present approaches we used involving both BRET-based biosensors and label-free methods that hold promise for large scale drug discovery applications.
9:40 GPCR Biased Ligands: Translating Theory to Improved Therapies
Jonathan Violin, Ph.D., Head of Biology, Trevena
Biased GPCR ligands selectively engage or elude distinct receptor signaling mechanisms, and may provide a strategy for designing safer and more efficacious GPCR-targeted drugs. Two examples illustrate how biased ligands can elicit novel pharmacological profiles: TRV027, a beta-arrestin biased ligand of angiotensin II type 1 receptor, and TRV002, a G protein-biased ligand of the mu opioid receptor. These compounds highlight the concept, mechanism of action, and utility of biased ligands.
11:10 Discovery and Characterization of a Novel Chemical Class of GABA-BR Allosteric Potentiators
Geraldine Parenty, Ph.D., Senior Scientist, in vitro Pharmacology, Addex Pharma
The allosteric modulation of GABA-BRs is offering an attractive and novel approach to identify new drug candidates for the treatment of disorders such as anxiety, depression, schizophrenia, pain or GERD, that are devoid of side effects associated with GABAB receptor agonists (e.g. baclofen), and represent a major advance in the drug discovery process. Addex has recently demonstrated in vivo efficacy of such novel PAMs in pre-clinical models of anxiety, inflammatory pain and osteoarthritis pain models.
At June 30, 2015, we had cash and cash equivalents of $214.7 million, a majority of which is invested in money market funds at several highly rated financial institutions.
Common Stock March 31, 2015 29.3 million.
Cash per Share is $7.33.
Austin, TX's microRNA replacement specialist Mirna Therapeutics last week announced its up to $81 million Nasdaq IPO plans on the same day that the Nasdaq Biotechnology Index plummeted 23%, though it ended the day down 4%.
The company is developing a tumor suppressor or known as MRX34 that inhibits multiple oncogene pathways to fight cancer while (hopefully) limiting the development of drug resistance. The candidate is in currently in a Phase I dose escalation study to determine its maximum tolerated dose against a variety of cancers, including primary liver cancer, lymphoma and melanoma.
The microRNA is delivered using the Smarticles platform and formulation, licensed from Marina Biotech, which describes its tech as "amphoteric liposomes composed of unique combinations of lipids having anionic and cationic groups that work together to enable cell uptake, to provide serum stability, and to provide pH-triggered endosomal escape."
We license the technology related to SMARTICLES from Marina. Our license with Marina imposes various development, regulatory, commercial diligence, financial and other obligations. If we fail to comply with our obligations under the agreement with Marina, or otherwise materially breach the agreement with Marina, and fail to remedy such failure or cure such breach, Marina may have the right to terminate the license. The loss of the license from Marina would affect a portion of the patent portfolio for MRX34, which would adversely affect our ability to proceed with any development or potential commercialization of MRX34, and could subject us to claims of patent infringement by Marina if MRX34 is covered by the affected patents.
We determined that the SMARTICLES formulation technology, owned by Marina Biotech, Inc., or Marina, had a favorable combination of efficient systemic delivery of miR-34 mimics to solid tumors in mice, a high therapeutic activity of formulated miR-34 in mouse models of cancer, low or no toxicity, and low or no cytokine stimulation in both animal models and an ex vivo human whole blood assay.
Efficient Systemic Delivery
The SMARTICLES formulation demonstrated key benefits in preclinical studies, including the ability to deliver very high numbers of microRNA mimics to tumors.
We have paid Marina approximately $2.1 million in the aggregate to date in up-front and milestone payments (including the milestone prepayment under the May 2015 amendment) and as consideration for the inclusion within the license of the three additional compounds. As we progress development and commercialization of products covered by the license, we will be required to make payments to Marina based upon the achievement of certain development and regulatory milestones, totaling up to $6 million in the aggregate for each licensed product. We are also required to pay up to an additional $4 million per licensed product upon the achievement of certain regulatory milestones for a specified number of additional indications, leading to a maximum cap on all milestone payments of $10 million per product. The exception to this is for our lead therapeutic product, MRX34, where the aggregate of all remaining development and regulatory milestone payments due to Marina, including for all additional indications, is $3.7 million. In addition to milestone payments, we will be required to pay low single digit royalties on net sales of licensed products other than MRX34, subject to customary reductions and offsets. As a result of our 2013 amendment to our agreement with Marina, we are no longer required to pay a royalty to Marina with respect to sales of our lead therapeutic product, MRX34.
M Fool says, re Vivent " If the buyout goes through the downside will be less than SunEdison's plunge, but SunEdison's stock drop lowers Vivint Solar's buyout price. "
The Fed’s rate hike plans are on a collision course with the economic cycle. In fact, the Fed is signaling a rate hike this year – if not by September, then by December – clearly expecting a pickup in growth. ECRI’s leading indexes suggest the opposite.
Indeed, a service sector slowdown has already joined the manufacturing slowdown that started last fall, and so the slowdown in overall growth is likely to intensify in the coming months. As such, hopes for a “second-half rebound” are likely to be dashed.
ECRI’s indicators show that the U.S. economy is in a GRC downturn that is poised to persist. The key question is whether there is a significant risk of recession in the context of possible shocks, including those from China, the Fed, or any other source. The answer from our indicators is that, for the time being, the U.S. economic expansion is in a cyclically resilient phase where it is resistant to shocks that could tip the economy into recession.
Prosensa's drug failed to beat a placebo in significantly improving boys' ability to complete a 6-minute walk test--the classic measure of success in this field. But left to its own devices the biotech completed fresh analysis of new extension study data that backed a theory that providing the drug earlier while extending treatment could delay disease progression. The biotech held what it called "positive" reviews with the FDA and began a rolling submission of the application just weeks ago. Evidently BioMarin has high hopes of success where GlaxoSmithKline saw nothing but failure. November 24, 2014.