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Tuesday, January 8, 2019

AcelRx Pushes Safety Analysis on Powerful New Opioid


Sufentanil sublingual tablets (Dsuvia) were found to be well tolerated for treating acute pain in a manufacturer-sponsored safety analysis, which follows the agent’s controversial November approval that saw healthcare leaders warning against the drug’s potential for abuse and diversion.
Among 804 patients across 10 studies, the adverse event rates were similar for individuals on the ultra-potent opioid and those on placebo (60.5% vs 61.4%, respectively), though more patients administered sufentanil tablets experienced treatment-related adverse events (43.8% vs 33.5%), reported James Miner, MD, of the Hennepin County Medical Center in Minneapolis, and colleagues.
Nausea was the most common adverse event (28.5%) for patients receiving any sufentanil dose, followed by vomiting (6.5%) and headache (5.0%), they wrote in Pain Management.
In total, 12 of the sufentanil-treated patients experienced a severe adverse event (nausea, headache, oxygen saturation decrease, procedural vomiting, and others) compared with 3 of the placebo patients.
Steven Meisel, PharmD, director of medication safety at Fairview Health Services in Minneapolis, said the results from this pooled analysis were similar to those discussed at the October 12 FDA advisory committee meeting, where AcelRx Pharmaceuticals presented data from the randomized phase III SAP-301 trial (he with two others voted against recommending approval of the drug at that meeting). In that trial, oxygen saturation was the most common reason for discontinuing sufentanil.
However, Meisel noted that this new study is not a formal meta-analysis and compiles varying doses and patient populations. For example, most patients received two 15 mcg doses (n=427) within 20 to 25 minutes, but in the U.S. the agent is approved at a single 30 mcg dose, he said. Additionally, only one open-label emergency department study was included, despite the fact that the drug was designed for use in emergency and military settings.
In the FDA’s approval, Commissioner Scott Gottlieb, MD, said this formulation would be particularly useful in battlefield situations when intravenous administration is not possible, stating that it was a “high priority” to ensure soldiers had access to treatment.
Meisel told MedPage Today that a fixed dose of medication for analgesia, particularly in trauma or postoperative settings “goes against any modern thinking of pain management” and is “problematic.” And the agent’s 45-minute latency period could increase the risk of dose-stacking, which is one of the most common factors in oversedation, he said.
“The fact that the authors reported relatively few oversedation events at the dose selected says nothing about what will be experienced when clinicians inevitably give higher, more effective doses,” Meisel wrote in an email. “At those doses, we should expect to see a higher rate of adverse events.”
In this analysis, 3.8% of patients on placebo discontinued treatment due to adverse events, as did 2.9% of patients receiving the active treatment — 1.5% due to respiratory-related events, including 6 patients with oxygen desaturation.
Oral Advantage?
Across the 10 studies, three patients administered the 30 mcg sufentanil dose required the opioid-reversal agent naloxone (Narcan), including one patient who experienced an oxygen saturation decrease. There were two deaths (renal failure, sepsis) involving patients administered the 15 mcg tablets, but both were considered unrelated to the treatment.
Meisel said the rationale that one of the advantages of the sufentanil sublingual tablets is that clinicians can avoid putting it in an IV line is “solving a problem that doesn’t exist” in postoperative settings, since any patient who goes into the operating room will already have an IV. He added that if there is a problem and a patient needs reversal medication, inserting an IV will complicate matters and delay the administration of drugs like naloxone.
Leading up to the agent’s approval, Raeford Brown, Jr., MD, chair of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee, expressed concern that the tiny tablets (0.5 mm thick and 3 mm in diameter), which are 10 times more potent than fentanyl, could be diverted and abused by healthcare professionals.
Shortly after the drug’s approval, watchdog group Public Citizen issued a statement claiming the FDA made the “wrong call,” and that this “super-strong opioid medication will be abused and kill people.”
Miner, who also works as a consultant to AcelRx, said concerns over the new agent being diverted were misplaced, explaining that it would be more difficult than with standard IV drugs, since they are small, solid tablets that cannot be broken up or taken partially without their absence being detected.
“From my perspective as a manager of an emergency department, I’m much less worried about this drug getting misused or abused by healthcare professionals than I am about standard IV drugs,” he told MedPage Today. “It’s at least as safe from my perspective, but probably better.”
Study Details
This pooled analysis collected data from patients with moderate-to-severe pain (pain intensity ≥4 on an 11-point numeric rating scale). Participants were a median age of 56 years and were mostly women (60.9%), white (79.4%), and with a body mass index <30 (58%).
The majority of patients had undergone abdominal (43.7%) or orthopedic (42.8%) surgery. Patients on 30-mcg sufentanil received a median 7.0 doses in the first 24 hours of treatment while those on the 15 mcg dose received a median 25.0 doses (these patients had more extensive surgeries).
Miner and his team noted that the main study limitation was the lack of an active comparator in most of the trials. Additionally, the 24-hour range of dosing in the group that received 15-mcg was 1.8-times higher than it was for those who received the 30-mcg dose, which could explain the higher number of adverse events experienced by the 15-mcg group. Lastly, consequences of opioid use, like tolerance and addiction, were not measured in this study.
The current study was funded by AcelRx Pharmaceuticals, while those included in the analysis were funded by AcelRx and in part by the Clinical and Rehabilitative Medicine Research Program of the U.S. Army Medical Research and Materiel Command.
Several of the authors are consultants, employees, or have stock ownership of AcelRx, and many received research funding from the company.
One co-author also received research funding from Avenue, Recro, and Trevena.
LAST UPDATED 
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Sleep tech at CES aims to beat Vegas at its own game


If there’s a town that fights harder to keep you from getting a good night’s sleep than this one, I sure haven’t found it. Which may help explain why the sleep-tech collection of exhibits at the massive CES trade show here has become so popular.
Companies aren’t sleeping on the growing popularity of sleep tech. Although total CES exhibit space is roughly flat from last year, the sleep-tech section has swelled 22 percent, making it one of the fastest-growing concentrations in the hot digital health, wellness and fitness area. And that doesn’t take into account the growing number of smartwatches and fitness trackers with sleep tracking at neighboring wearable, fitness and sports sections.
Even when we’re not hopelessly overstimulated in Vegas, many of us are concerned about the quantity and quality of the sleep we get. No wonder. Sleep plays such a critical role in our physical and mental well-being. And yet, more than a third of us don’t get enough sleep.
Here’s a roundup of tech at this year’s Consumer Electronics Show that can help you rest easier.

Fitbit scores

Popular fitness tracker Fitbit has a sizable private-meeting area just inside the entryway to the show floor at the Sands Expo & Convention Center, where all the digital health tech resides. The company has on hand its newest fitness band, the Charge 3, along with Versa and Ionic, its latest smartwatches. All three feature Fitbit’s latest sleep-tracking technology, which monitors sleep stages as well as total sleep and awake times.
Fitbit is currently developing a sleep-quality component to its shut-eye monitoring. Last month, Fitbit Labs launched its Sleep Score Beta program, which the company said proved to be popular. All 10,000 spots in the beta program filled up in just a week.
The beta program delivers a nightly quality score from 0 to 100, based on variables like time spent in REM and deep sleep, heart rate and restlessness. The program also watches for breathing disturbances that could signal underlying disorders like apnea — but only with newer devices, which are equipped with an SpO2 sensor to track blood oxygen levels.

Tag, you’re sleeping!

The wrist can be a challenging spot to collect data for wearable suppliers because the built-in artificial intelligence must sift through irrelevant hand motions like waving and scratching to pinpoint the true biometrics. So this year, some health-tech players are exhibiting new devices that monitor sleep from other locations on the body.
I’ve been testing one such device, a novel wearable that tracks sleep and stress by examining breathing patterns. It’s called the Health Tag, from Silicon Valley startup Spire, and it attaches to the waistband of your shorts or inside a bra strap and communicates via a smartphone app. The Tag comes in packs, so you can permanently attach each one to a different piece of clothing. That way, you don’t need to constantly do laundry just to track activity.
The Tag does track your heart rate and count your steps. It also tallies workout duration, calories burned and heart rate range.
Beddr, another Silicon Valley startup, is demonstrating its new SleepTuner. More of a stickable than a wearable, the unobtrusive device monitors sleep from the forehead. It attaches with hypoallergenic adhesive stickers. Like the newer Fitbits, SleepTuner can monitor SpO2 to spot sleep issues.
Both SleepTuner and the Health Tag pair with iPhone apps, with Android apps planned.

Taking action

Another class of devices pushes beyond monitoring and coaching to enhance sleep quality. They fall broadly into two categories: those that attempt to optimize sleeping conditions, and those that transmit sound waves to boost the restorative power of deep sleep.
Philips today unveiled the SmartSleep Deep Sleep headband. Part headband, part ear warmer, the device delivers “pink noise” to strengthen so-called “slow-wave” activity to enhance restoration once built-in sensors detect deep sleep.
I’ve been testing the headband for a couple weeks and found the device difficult to get accustomed to. When I moved during the night, the headband would shift, often waking me. Once I adjusted to wearing it, though, I did feel more refreshed in the morning.
After working late one night — and getting up early — the Philips’ SleepMapper app reported the headband boosted my Sleep Score from a terrible 56 out of 100 to a not-too-bad 72. I felt an odd combination of tired and refreshed in the morning, far better than the last time I only managed 4½ hours of sleep.
French startupDreem is exhibiting its second-generation, deep sleep-enhancing headband along with a new Dreem Coach app to help identify and tackle problems that lead to poor sleep. I tried the first-generation band last year and found that, like the Philips device, it did noticeably improve sleep after a difficult adjustment period. The second-generation device is more comfortable than the original and should be easier to get accustomed to, the company said.
And Urgotech, also a French startup, just announced a sleep-enhancing headband called Urgonight. The headband and companion app are used during the day to train your brain to produce more slow-wave activity at night. Three 20-minute sessions a week over three months will result in sustainably better sleep, the company says.

Just chillin’

Rather than enhancing the power of deep sleep, some devices aim to extend deep-sleep periods by maintaining temperatures in the 60- to 67-degree range, the best temperatures for falling — and staying — asleep.
North Carolina-based Kryo is previewing Ooler, a next-generation temperature-mattress cover that regulates temperature, as well as ChiliPad, its existing offering. And French startup Moona is exhibiting a temperature-controlled pillow by the same name.
Hopefully, with the right combination of monitoring, assessment and correction, we’ll all sleep well enough one day to beat Vegas at its own game.
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Dexcom tops revenue forecast as demand grows for wearable glucose monitors


San Diego’s Dexcom said this week that it expects fourth quarter revenue to surge 50 percent as more people with diabetes opt to wear continuous glucose monitors.
The company announced the year-over-year revenue spike ahead of its fourth quarter earnings report, which will come out Feb. 21.
It also boosted full-year revenue expectations for 2018 but maintained fairly conservative guidance for 2019, according to Wall Street analysts.
Still, the company’s shares surged nearly 12 percent over the past two days on the news. They closed Tuesday at $131.52 on the Nasdaq exchange.
“Our success in 2018 was driven by increasing awareness of the importance of continuous glucose monitoring in managing diabetes, supported by the approval and launch of Dexcom’s G6 Continuous Glucose Monitoring platform in the U.S. and internationally,” said Kevin Sayer, Dexcom’s chief executive.
The revenue gain came despite increased competition in the continuous glucose monitoring market, with Abbott Laboratories FreeStyle Libre monitor launching in the U.S. in late 2017, and Medtronic also rolling out new glucose monitors.
Dexcom executives have argued that the market for wearable glucose monitors is new, so the additional competitors would help raise awareness.
That appears to be the case so far, said Baird Equity Research Analyst Jeff Johnson.
“It seems increasingly obvious that FreeStyle Libre is, indeed, helping to expand the overall continuous glucose monitoring market,” said Johnson. “Dexcom is one of the clear benefactors, along with Abbott, of this strong market demand.”
Dexcom said Monday that fourth quarter revenue will top $331 million. Wall Streetanalysts had been expecting sales of $284 million.
For its full 2018 fiscal year, Dexcom said revenue is expected to reach $1.025 billion, up 42 percent from a year earlier. The company previously forecast annual revenue of $925 million.
“The fourth quarter was unequivocally a strong finish to the year, with Dexcom delivering record new patient additions and robust global revenue growth,” said Kyle Rose, an analyst with Canaccord Genuity.
“Looking forward, Dexcom remains in the early stages of rolling out the G6 and continues to drive patient awareness with direct-to-consumer investments, which we expect will support robust new patient additions through year-end,” said Rose in a research report.
Wearable continuous glucose monitoring devices place a sensor just under the skin to alert people with diabetes when their blood sugar is too low or two high.
To date, these devices have been mostly used by people with Type 1 diabetes, where spikes or falls in blood sugar levels can result in serious medical complications. The monitors are generally covered by insurance for Type 1 diabetics.
About 2 million people in the U.S. and roughly 40 million worldwide have Type 1 diabetes. Of those, only about a quarter in the U.S. use continuous glucose monitors, according to analysts. An even lower percentage use the devices globally.
As sensors become smaller and easier to use, Dexcom and its competitors are betting that the systems will eventually be adopted by the much larger group of people with Type 2 diabetes, which is typically controlled with medications, diet and exercise.
Last spring, Dexcom received regulatory approval for its sixth generation of glucose monitor, the G6, which does not require finger pricks for calibration for insulin dosing — improving the quality of life for patients.
Dexcom began selling the G6 last summer. High demand led to some delays in shipping monitors, as well as long wait times or an inability to connect with customer service personnel.
It is unclear whether those problems linger, though Dexcom has ramped up hiring to deal with the demand. Efforts to reach the company on Tuesday were unsuccessful.
Dexcom announced pricing for the G6 in June. A box of three sensors that last 10 days cost $349. Two transmitters are priced at $475 per bundle, and a touchscreen receiver goes for $365.
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Aceto amends, enlarges credit facility


On January 8, 2019 (the “Fourth Amendment Effective Date”), Aceto Corporation, aNew York corporation (the “Company”), amended its existing senior secured Credit Agreement (as defined below) to, among other things, allow the Company to resume access to up to $23.0 million of its revolving credit facility, in order to fund vendor and business partner purchases and other payments, the continuation of its previously announced strategic process and general working capital purposes, on the terms and subject to the conditions described below.
The amendment – constituting a Fourth Amendment and Limited Waiver (the “January Amendment”), by and among the Company, certain other loan parties party thereto (the “Loan Parties”), the lenders party thereto, and Wells Fargo Bank, National Association, as administrative agent (the “Administrative Agent”) – further amended the Company’s Second Amended and Restated Credit Agreement (the “Credit Agreement”), dated as of December 21, 2016, by and among the Company, the Loan Parties, the lenders party thereto and the Administrative Agent. All capitalized terms used herein but not defined herein shall have the meanings ascribed thereto in the Credit Agreement, unless otherwise defined herein.
The January Amendment contains certain amendments to the Credit Agreement relating to the revolver access and vendor and business partner payments, under which the Company is permitted:
(a) on or after the Fourth Amendment Effective Date, to request and borrow up to an additional $23.0 million as Revolving Loans; and
(b) to purchase, prior to the repayment of these newly borrowed Revolving Loans and during (x) the Company’s fiscal year 2019, assets in an aggregate amount not to exceed $6,500,000 or (y) the third quarter of the Company’s fiscal year 2019, assets in an aggregate amount not to exceed $3,105,000, in each case, consisting of intangible assets relating to strategic product acquisitions, certain data compensation expenses and certain capital expenditures.
The January Amendment also contains modifications to the Credit Agreement relating to cash management and liquidity. In general, further compliance with the minimum liquidity covenant from the Third Amendment to the Credit Agreement has been permanently waived, there is a cash anti-hoarding provision, and there are restrictions on the Company and Domestic Subsidiaries transferring funds to Foreign Subsidiaries and prohibitions on paying dividends and making similar distributions.
The January Amendment mandates certain milestones with respect to the Company’s strategic process. In general, the milestones require delivery to the Administrative Agent and Lenders of proposals and commitments from financially credible third parties, the proceeds of which would be sufficient and used to repay both the Revolving Loans borrowed on or after the Fourth Amendment Effective Date and the remaining Obligations. The Company has been taking steps to meet these milestones, but no assurance may be given that they will be successfully met. The January Amendment also revises both the Revolving Loan Maturity Date and Term Loan Maturity Date to June 30, 2019, the last day of the Company’s current fiscal year.
The January Amendment provides for a waiver of any event of default under the Credit Agreement arising as a result of the failure by the Company (x) to make certain principal and interest payments under the Credit Agreement that were due on or about December 31, 2018 (which were instead paid pursuant to the January Amendment on the Fourth Amendment Effective Date) and (y) to pay interest on certain deferred payment amounts to the sellers under the 2016 Citron product purchase agreement, and (z) as described above, the non-compliance by the Company with the liquidity financial covenant. The January Amendment provides for the payment of a fee equal to 2.0% of each Lender’s revolving commitment that is available or borrowed after the Fourth Amendment Effective Date, a 0.25% (of each such Lender’s aggregate exposure) consent fee to the Lenders who timely consented to the January Amendment, increases the waiver fees imposed under the Third Amendment from 4.0% to 6.0% but only under certain circumstances, and provides for reimbursement of certain third party expenses incurred by the Administrative Agent and Lenders.
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MediciNova Enrolls for Glioblastoma Trial


MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), today announced that the first glioblastoma patient has enrolled in the clinical trial of MN-166 (ibudilast) in combination with temozolomide (TMZ, Temodar‑®) for the treatment of recurrent glioblastoma (GBM). The principal investigators are Patrick Y. Wen, M.D., Professor of Neurology, Harvard Medical School and Director, Neuro-Oncology Division at the Dana-Farber Cancer Institute (DFCI) in Boston, and Kerrie McDonald, Ph.D., Associate Professor and Head of Biomarkers and Translational Research at the Lowy Cancer Research Centre, University of New South Wales, Australia.
The scientific rationale for this clinical trial is based on positive results from preclinical studies conducted by Dr. McDonald and her team. MN-166 (Ibudilast) and temozolomide (TMZ) combination treatment significantly increased GBM cell apoptosis and cell cycle arrest in an in-vitro study. Combination treatment of MN-166 (ibudilast) with TMZ resulted in significantly extended survival times compared to TMZ monotherapy in a GBM animal model study with complete tumor regression observed in two out of 16 mice.  This is the first clinical trial to evaluate the safety, tolerability and preliminary efficacy of MN-166 (ibudilast) in combination with temozolomide for the treatment of recurrent GBM.
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Array at JPMorgan


Array BioPharma’s (ARRY) transition into a commercial stage pharmaceutical company appears to be going smoothly, as the company reported an encouraging rollout of the Braftovi/Mektovi combination for metastatic melanoma. Importantly, the company announced that they’ve observed a large number of US prescribers switch their patients from the standard-of-care for BRAF-mutant melanoma, the combination of Tafinlar/Mekinist, to Braftovi/Mektovi, driven largely by results seen in the COLUMBUS trial. In this trial, Braftovi/Mektovi showed the best inclass numerical results for overall survival seen to date in BRAF-mutant patients, as well as a favorable toxicity profile.
Going into 2019, Array emphasized the importance of the Phase III BEACON trial, evaluating the combination of Braftovi/Mektovi/cetuximab in previously-treated BRAF-mutant colorectal cancer (CRC). As the number of treatable patients in this indication exceeds the number of treatable patients in melanoma, approval for this indication is seen by the company as a larger value-driver.
With enrollment for this trial completed, Array expects top-line results of an interim analysis to be release in H1 2019, and announced that they plan to seek accelerated approval in the US if results of this analysis are positive. The combination received the FDA’s Breakthrough Therapy designation for CRC in August of 2018 based on results from BEACON’s safety lead-in.
Array also discussed their partnerships with Bristol-Myers Squibb, Merck, and Pfizer, testing Mektovi combinations in previously-treated, RAS-mutant, microsatellite stable (MSS) CRC, first-or second-line MSS CRC, and previously-treated pancreatic cancer/non-small cell lung cancer, respectively. Though these trials are exploratory in nature, they have the potential to drive significant value for Array.
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CRISPR gene editing for muscular dystrophy


The gene editing technique known as CRISPR is a revolutionary approach to treating inherited diseases. However, the tool has yet to be used to effectively treat long-term, chronic conditions. A research team led by Dongsheng Duan, PhD, at the University of Missouri School of Medicine has identified and overcome a barrier in CRISPR gene editing that may lay the foundation for sustained treatments using the technique.
CRISPR gene editing is inspired by the body’s natural defensive ability to fend off viruses. The technology enables researchers to alter DNA sequences by cutting out and replacing a mutation in the genome, which has the potential to treat a variety of genetic diseases and conditions. Duan, along with his collaborators at MU, the National Center for Advancing Translational Sciences at the National Institutes of Health and Duke University, are studying how to harness CRISPR to treat Duchenne muscular dystrophy (DMD).
Children with DMD have a gene mutation that interrupts the production of a protein known as dystrophin. Without dystrophin, muscle cells become weaker and eventually die. Many children lose the ability to walk, and muscles essential for breathing and heart function ultimately stop working.
“CRISPR essentially cuts out the mutation and stitches the gene back together,” said Duan, who serves as the Margaret Proctor Mulligan Professor in medical research in the Department of Molecular Microbiology and Immunology at the MU School of Medicine. “In order to do this, the ‘molecular scissors’ in CRISPR, known as Cas9, must know where to cut. The location to cut is flagged by a molecule called gRNA. We were surprised to find that by increasing the quantity of flags, we could extend the effectiveness of the therapy from three months to 18 months in our mouse model.”
Duan’s lab treated 6-week-old mice with DMD intravenously using CRISPR and looked for improvements at 18 months. They initially employed a strategy widely used by many researchers. In this approach, similar amounts of Cas9 and gRNA were administrated. While it worked well when injected directly into the muscle, this strategy yielded poor outcomes when the team tried to achieve long-term correction in all the muscles in the body. They found no dystrophin restoration in skeletal muscle and low-level dystrophin restoration in the heart — the treatment failed to stop disease progression.
When reviewing the results, the team found a disproportionate depletion of gRNA flags, meaning there were not enough gRNA to tell Cas9 where to cut. The team increased the number of gRNA flags and repeated the experiment. This new strategy significantly increased dystrophin restoration in both heart and skeletal muscle and reduced muscle scarring at 18 months. Additionally, muscle function and cardiac function were improved.
“Our results suggest that gRNA loss is a unique barrier for long-term systemic CRISPR therapy,” Duan said. “We believe this barrier can be overcome by increasing and optimizing gRNA doses. While this has exciting possibilities for improvements to DMD therapies, we believe this principle may also be applied to other CRISPR therapies for a range of other diseases and conditions.”
The researchers will continue to test and refine the approach in a mouse model before other models are explored. With more study, they are hopeful this insight may help lay the foundation for improved therapies using CRISPR gene editing.
Story Source:
Materials provided by University of Missouri-Columbia. Note: Content may be edited for style and length.
Journal Reference:
  1. Chady H. Hakim, Nalinda B. Wasala, Christopher E. Nelson, Lakmini P. Wasala, Yongping Yue, Jacqueline A. Louderman, Thais B. Lessa, Aihua Dai, Keqing Zhang, Gregory J. Jenkins, Michael E. Nance, Xiufang Pan, Kasun Kodippili, N. Nora Yang, Shi-jie Chen, Charles A. Gersbach, Dongsheng Duan. AAV CRISPR editing rescues cardiac and muscle function for 18 months in dystrophic mice. JCI Insight, 2018; 3 (23) DOI: 10.1172/jci.insight.124297
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