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Thursday, October 4, 2018

Weight Loss Drug Helped Prevent Diabetes in Overweight People


In overweight and obese patients with type 2 diabetes, lorcaserin (Belviq) helped improve blood glucose levels, according to the CAMELLIA-TIMI 61 trial.
After 1 year of 10 mg, twice-daily treatment, patients saw a significant 0.33% (95% CI 0.29-0.38%, P<0.0001) drop in mean HbA1c level compared with those receiving placebo, reported Erin Bohula, MD, DPhil, of Brigham and Women’s Hospital in Boston, and colleagues.
There was also a 19% risk reduction seen for incident type 2 diabetes among those who had prediabetes at baseline (HR 0.81, 95% CI 0.66-0.99, P=0.038), as well as a 23% risk reduction among those free of diabetes at baseline (HR 0.77, 0.63-0.94, P=0.012).
“We can’t say for sure there’s more than one potential mechanism [behind the glycemic benefit], although my suspicion is that much of it is related to weight loss,” Bohula stated during a press conference of the findings at the annual meeting of the European Association for the Study of Diabetes (EASD). The results were also simultaneously published in The Lancet.
Lorcaserin was originally FDA approved back in 2012 for chronic weight management as an adjunct therapy to lifestyle modification, although the drug is not available in Europe.
In the multicenter trial, lorcaserin only somewhat helped those with prediabetes achieve a normal glucose range, although this did not reach significance (HR 1.20, 0.97-1.49, P=0.093).
Not surprisingly, the patients who received lorcaserin also had a significant amount of weight loss compared with placebo, seen across all groups of diabetes status (P<0.0001 for all):
  • Diabetes: loss of 5.7 lb (95% CI 5.1-6.4 lb) [2.6 kg, 2.3-2.9 kg]
  • Prediabetes: loss of 6.2 lb (95% CI 5.5-7.1 lb) [2.8 kg, 2.5-3.2]
  • Normoglycemia: loss of 7.3 lb (95% CI 5.7-8.8 lb) [3.3 kg, 2.6-4.0 kg]
A total of 12,000 adults age 40 and older were included in the trial: 6,816 patients with diabetes, 3,991 who were identified as having prediabetes — defined as an A1c between 5.7% to <6.5% — and 1,193 with normoglycemia. All participants had a body mass index of 27+ at baseline with established atherosclerotic cardiovascular disease or other cardiovascular-related risk factors. All patients were encouraged to be involved in a weight management program that was freely available to them, but there was no further treatment given beyond the drug. The participants were then followed for a median 3.3 years.
Questions about Clinical Significance
In an accompanying commentary, Xabier Unamuno, MSc, and Gema Frühbeck, MD, PhD, of the University of Navarra in Pamplona, Spain, were somewhat wary of the findings: “From the endocrinologist’s point of view, both the design of the study and its results are somewhat puzzling — namely, in terms of the magnitude of the effect of lorcaserin and the anti-diabetes management of the patients.” Although there was statistically significant net weight loss seen across all groups, it was only moderate at best and “might not be clinically significant.”
Unamuno and Frühbeck said that ultimately, clinicians may find this weight loss “disappointing, especially if it does not lower the risk of cardiovascular disease,” as was seen in the trial’s previously reported cardiovascular outcomes, presented earlier this year at European Society of Cardiology.
The commentary noted that because not everyone will respond to lorcaserin, physicians may instead consider initially prescribing it only on a temporary basis of around 6-12 months in order to distinguish responders from non-responders. “It is difficult to quantify the risk of chronic use versus meaningful clinical improvement. Treatment on an intermittent basis, to maximize the benefits of the first months, might be considered.”
During the press conference, Bohula also noted that the renal outcomes — microalbuminuria, eGFR, and chronic kidney disease progression — from the trial will be presented later this year at the American Heart Association (AHA) meeting in November.
The trial was funded by Eisai.
Bohula reported financial relationships with Servier, Merck, Lexicon, Medscape, Academic CME, MD Conference Express, Paradigm, Novartis, Amgen, and AstraZeneca, as well as grants from the Natoinal Institutes of Health.
Unamuno and Frühbeck reported grants from the Spanish Health Institute ISCIII, Subdirección General de Evaluación and Fondos FEDER, and CIBEROBN.
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Mallinckrodt selloff on Praxair FDA approval seen as overreaction


Shares of Mallinckrodt (MNK) are sliding following the FDA approval of an abbreviated new drug application for Praxair’s (PX) Noxivent. Commenting on the news, Stifel analyst Annabel Samimy argued that the stock selloff is an overreaction as its competitor will face high commercial hurdles to displace the INOmax System and noted that consensus estimates have reflected potential commercial competition for well over a year. Voicing a similar opinion, her peer at BMO added that there are several important factors to consider that would appear to mitigate the generic risks and make the situation manageable for Mallinckrodt. SELLOFF AN OVERREACTION: Noxivent’s filing as a generic has given investors pause that the gas will be used as a substitute to Mallinckrodt’s nitrous oxide in the INOmax System, the leading nitric oxide vasodilator for respiratory failure in term/near-term infants, Stifel’s Samimy said in a research note. The analyst pointed out, however, that Noxivent cannot be interchanged with the nitric oxide gas used in the INOmax System, and thus far, she has not seen a 510(k) approval from the FDA for Praxair’s device. Furthermore, Samimy highlighted that the pending Praxair system will be another branded competitor and not a generic substitute as the Street reaction implies. The pending approval of this ANDA was well known, she contended, adding that she believes estimates have reflected potential competition for well over a year. Overall, the analyst sees the stock move as an “overreaction to a known event” and believes Mallinckrodt is well-positioned to defend its share. Samimy reiterated a Hold rating and $30 price target on the latter’s shares. Also commenting on Praixar’s Noxivent news, BMO Capital analyst Gary Nachman said in a research note of his own that the generic was expected to be approved at some point, although the timing was uncertain. Moreover, the analyst highlighted that there are several important factors to consider that would appear to mitigate the generic risk and make this situation manageable for Mallinckrodt. Praxair will need its device to be approved in order to have a generic version of INOmax, he noted, adding that he fully expects the device to be approved sometime soon. Additionally, the analyst pointed out that litigation is still ongoing with Mallinckrodt’s appeal of the decision that favored Praxair regarding the INOmax patents, with the former indicating that the appeal is expected to be resolved sometime in the first half of 2019. A Praxair generic launch before then would be “at risk,” Nachman argued. The analyst believes “this is a very challenging market” with many natural barriers including all the support that Mallinckrodt provides the neonatal intensive care units at hospitals. Nachman reiterated an Outperform rating and $37 price target on Mallinckrodt. PRAXAIR APPROVAL REINFORCES OVERHANG: Noting that INOmax is Mallinckrodt’s second largest product, representing approximately $131M of sales in the second quarter, Wells Fargo analyst David Maris told investors that the approval of a generic version of its gas was something that was expected, although the exact timing was unexpected. The analyst pointed out that he was already modelling a slowdown in growth in 2019 for Mallinckrodt but is not modelling “a major loss” of market share. Overall, Maris believes that the Praxair approval “certainly reinforces an overhang issue” and brings market share risk closer to reality, and as such will likely have a negative impact on the shares. He reiterated a Market Perform rating and $30 price target on Mallinckrodt’s shares. PRICE ACTION: In afternoon trading, shares of Mallinckrodt have plunged over 18% to $25.43.
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Disgruntled Takeda alumni demand a window into $62B Shire buy


It’s no secret that Takeda’s pending Shire megadeal has plenty of critics, and some of them have penned a letter to company president Christophe Weber demanding behind-the-scenes information and documents to justify the buy.
The group of about 130 shareholders, including alumni of the Japanese drugmaker, requested that Weber serve up details on how Takeda plans to pay down the debt it’ll incur with the $62 billion acquisition. It also wants to know why Takeda offered a 65% premium for the rare-disease-focused target, and it’s asking for board-meeting minutes and executive statements, too, Nikkei Asian Review reports.
Dubbing itself, “Thinking about Takeda’s Bright Future,” the group gave Takeda an Oct. 31 response deadline.
Takeda’s deal first faced opposition well before the two parties shook hands. In March, the company’s shares plummeted after it revealed its interest in Shire, in part because of questions surrounding the hefty debt necessary to pull the deal off.

And since Takeda and Shire inked their pact back in May, more critics have joined the chorus. A descendent of Takeda’s founder publicly voiced his disapproval, predicting the takeover would prove detrimental to the Japanese drugmaker’s business. “Hasty decisions on big deals should be avoided. It will lead to disaster if there are large-scale mergers and acquisitions without careful consideration,” he said in September.
This isn’t the first time this particular shareholder group—which owns about 1% of the company, Nikkei says—has tried to pump the brakes on the Shire deal, either, Nikkei notes. During a June shareholder meeting, the group proposed a rule requiring that acquisitions of more than 1 trillion yen ($8.78 billion) win shareholder approval first. But the proposal garnered less than 10% support from shareholders.

Takeda has defended its buyout decision and particularly worked to ward off concerns about its lagging hemophilia business. At a June meeting, Weber reassured investors that Takeda had already factored next-gen competition from Roche into its financial models for the company after Shire joins the fold.
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Want a glimpse into pharma’s future? Look to cable television, Merck CEO says


If all the scrutiny on drug prices has taught us anything, it’s that there are a lot of intermediate players in today’s pharma supply chain. But expect that to change, Merck CEO Ken Frazier said Wednesday.
In comments made at the Economic Club of New York, Frazier foreshadowed pharma’s “disintermediation”—a.k.a., stops on that chain between drugmakers and patients—pointing to the cable television industry as an example.
“You could actually look at the cable industry at one point where the content providers—if you were Disney, you had to pay a lot of money to get your content to the other side,” Frazier said, as quoted by Yahoo Finance, adding, “I think that’s going to happen in this area.”
The way he sees it, nixing some of the middlemen can bring down costs, and the Trump administration—which is examining the role of various participants in the supply chain—is focused on it, too.
“I think at the end of the day, I’ll just be blunt here, I just don’t understand why we live in a world where 50% of the value goes into the supply chain,” Frazier said.

As drug pricing has come into the national spotlight—aided by high-profile scandals featuring Martin Shkreli and Mylan’s Epipen, as well as commercials from once-presidential candidate Hillary Clinton and ominous tweets from Trump—drugmakers and others have been quick to point the finger at one another for costs that have soared in recent years.
Lead PBM Express Scripts has been particularly vocal about pharma’s price hikes, and it’s patted itself on the back repeatedly for introducing formulary tactics that incentives pharma to hand over discounts.
“Despite promises to limit price increases, drugmakers are trying to game the market by delaying generic competition, blocking access to safe and effective biosimilars, and coyly deferring—not cancelling—list-price increases. This is why our work to expand access and maximize value is more important now than ever,” Express Scripts said in August.

But as PBM industry critics have been quick to point out, such moves help their bottom lines without reducing costs for consumers. Industry association PhRMA has spent big bucks the past couple of years on awareness ads that seek to both educate patients on the role of different players in forcing prices up—and to encourage them to probe deeper.
“I mean no disrespect to anyone else in the supply chain, but I know how hard it is to make my 50 cents on the dollar,” Frazier said. “I have to invent something that’s never existed in the history of the world. And I have to ask my shareholders to be patient with their capital. I think that the system has got to change.”
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Horizon Presents Follow-Up to Phase 2 of Thyroid Med Trial


Horizon Pharma plc HZNP, +1.16% announced new data from the Phase 2 clinical trial of teprotumumab for people living with moderate-to-severe active thyroid eye disease (TED) showing a majority of patients that had reductions in proptosis at week 24 maintained these reductions 48 weeks following the study completion, or nearly a year off therapy. The results of this investigational medicine were presented during an oral session at the American Thyroid Association (ATA) Annual Meeting, Oct. 3 – 7, 2018, in Washington, D.C.
TED is a rare autoimmune disease that is active for up to three years. During active TED the insulin-like growth factor 1 receptor (IGF-1R) is overexpressed on orbital fibroblasts, resulting in local inflammation and tissue expansion, which can in turn lead to proptosis, or bulging of the eye. This can result in stiffness of the muscles, displacement of the eyes so they are no longer in line with each other, and/or the eyelids are unable to close. The inability for people living with active TED to close their eyelids can lead to corneal ulcerations and potential blindness, and many also endure challenges with double vision, known as diplopia. Once TED is no longer active, the orbital muscles and tissues become fibrotic and, for some, changes due to local inflammation and tissue expansion can only be corrected with surgery.
“Proptosis creates numerous challenges for people living with thyroid eye disease and is the most important measure from a clinical perspective,” said George J. Kahaly, M.D., Ph.D., lead author and professor of medicine and endocrinology and metabolism, Johannes Gutenberg University Medical Center. “In addition to challenges with visual function and appearance, proptosis can lead to permanent structural changes around the eyes and is what drives the decision for surgery following active thyroid eye disease.”
The analysis of the Phase 2 data, 48-Week Follow-Up Of A Multicenter, Randomized, Double-Masked, Placebo Controlled Treatment Trial Of Teprotumumab In Thyroid-Associated Ophthalmopathy, shows that at four weeks following the initial 24 week treatment period, proptosis response was 73.8 percent for patients receiving teprotumumab versus 13.3 percent for patients receiving placebo (p<0.001). In addition, 53 percent of week 24 teprotumumab proptosis responders maintained at least a 2 mm improvement relative to baseline at week 72 (48 weeks following treatment period). Teprotumumab is an investigational medicine and its safety and efficacy have not been established.
“Teprotumumab has the potential to be an impactful treatment for people living TED and the first therapy to demonstrate reduction in proptosis,” said Elizabeth Thompson, Ph.D., vice president clinical development, rare disease, Horizon Pharma plc. “We are encouraged by these data, which suggest proptosis reductions could be maintained in a majority of responders for nearly a year off therapy. Through our ongoing confirmatory Phase 3 trial and extension study, we expect to gain a deeper understanding of the effect of additional treatment for those considered non-responders as well as those who may benefit from retreatment.”
Horizon Pharma will host an investor call at 10:30 a.m. ET to discuss these data, as well as provide an overview of TED and the current treatment landscape.
Additional data from the 48 week off-therapy follow-up will be presented during an oral session on Oct. 25, 2018, at the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) and on Oct. 29, 2018, at the American Academy of Ophthalmology (AAO 2018) meeting in Chicago, IL. The presentation is titled Diplopia Response in a Controlled Trial with Teprotumumab, an IGF-1 Receptor Antagonist Antibody for Thyroid Eye Disease.
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New Display Design May Create Lightweight, Compact Smart Glasses


Researchers have developed a fundamentally new approach to a see-through display for augmented reality, or smart glasses. By projecting images from the glass directly onto the eye, the new design could one day make it possible for a user to see information such as directions or restaurant ratings while wearing a device almost indistinguishable from traditional glasses.
“Rather than starting with a display technology and trying to make it as small as possible, we started with the idea that smart glasses should look and feel like normal glasses,” said research team leader Christopher Martinez of the Laboratoire d’électronique des technologies de l’information (Leti) in France. “Developing our concept required a great deal of imagination because we eliminated the bulky optical components typically required and instead use the eye itself to form the image.”
In Optica, The Optical Society’s journal for high-impact research, the authors detail their new retinal projection display concept and report positive results from initial optical simulations. Although glasses using this new approach wouldn’t be useful for showing videos, they could provide information in the form of text or simple icons.
“Although we are focused on augmented reality applications, the new display concept may also be useful for people with vision problems,” said Martinez. “The disturbance present in the eye could be integrated into the projection, giving visually impaired people a way to see information such as text.”
Forming an image in the eye
The unconventional display design rapidly projects individual pixels, which the brain puts together to form letters and words. “We don’t bring an image to the surface of the glass, but instead bring information that is emitted in the form of photons to make the image in the eye,” explained Martinez.
According to the design concept this feat would be accomplished by sending photons from a laser or other light source through a light-guiding component into a holographic optical element created within the lens of the glasses. Holographic optical elements that are significantly smaller than their traditional counterparts can be made in light-sensitive plastics using the same laser light interactions that make holograms such as those that protect credit cards from forgery.
For the concept to work, it is critical that all the projected photons have synchronized phases and match in coherence. Otherwise, a noisy image is formed, akin to what you would hear if the members of a choral group were singing the same song but starting and stopping at different times. The researchers used the holographic element to synchronize the phase, like a cue that helps the singers start at the same moment.
“It is very complicated to use traditional methods such as a mask with an optical structure to adjust the phase of photon emitters that are separated from each other by just hundreds of microns,” said Martinez. “Our design uses a unique holographic element to synchronize the photons by matching the phase with a reference beam.”
The design also includes a grid of lightguides that makes the photons coherent, akin to making sure the singers all sing at the same speed. This component was made using an integrated photonics approach that incorporates the same semiconductor fabrication techniques used to make computer chips and fabricate optical components in silicon.
The researchers say that their display concept is an important example of the new opportunities for retinal projection that will now be possible thanks to recent developments in integrated photonics, which have moved from applications using telecommunication wavelengths into visible wavelengths that can be used in displays.
Seeing outside the box
Because of the limited space available in glasses’ lenses, the first prototype will likely have a resolution of 300 by 300 pixels, which the researchers say could be improved by stacking two displays on top of each other. Importantly, the design enables completely new ways to use the pixels available, which are not constrained to a square shape like traditional displays.
“Using a holographic element to form a retinal display is quite different from the traditional grid of pixels used for traditional displays,” said Martinez. “For example, information could be projected to the left and right portions of the field of view with no information in between, without increasing the complexity of the display.”
A detailed optical simulation of the new design validated the new approach and revealed that a clearer image would be created if the points where light is emitted were arranged randomly rather than with a periodic pattern. The researchers are now figuring out how to best accomplish this random arrangement. They also point out that although the device should be safe because very little light will be needed to form the image on the eye, safety studies will be needed as development progresses.
The researchers plan to make and test the individual components before creating a working prototype. The first prototype will display static monochromatic images, but the researchers are confident that the retinal projection approach can be used for a dynamic multi-color display.
Paper: C. Martinez, V. Krotov, B. Meynard, D. Fowler, “See-Through Holographic Retinal Projection Display Concept,” Optica, 5, 10, 1200-1209 (2018).
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Richmond Vascular Center 1st to Use Non-Surgical Dialysis Fistula System


Richmond Vascular Center, Central Virginia’s state-of-the-art treatment center for Radiology Associates of Richmond and Surgical Associates of Richmond, is the first US site to offer the Ellipsys® Vascular Access System, a game-changing innovation for patients with End-Stage Renal Disease (ESRD).
The newly FDA-approved Ellipsys System is a minimally-invasive, single catheter-based system designed for ESRD patients requiring hemodialysis. Pioneered by local interventional radiologist and the Director of Richmond Vascular Center (RVC), Dr. Jeffrey Hull, the new procedure and technology bring patients a unique non-surgical option for arteriovenous fistula (AVF) creation, a procedure that had previously not changed in over 50 years.
A significant advancement for dialysis patients and clinicians, the Ellipsys System, developed by Avenu Medical (San Juan Capistrano, CA), transforms an open surgery connecting an artery to a vein into a minimally invasive procedure using a needle and a catheter. Using a percutaneous approach, the Ellipsys procedure replaces an incision with a needle puncture, ultrasound imaging replaces surgical dissection, and sutures are replaced with tissue fusion. The procedure can be performed in the physician office, but will also be used in hospitals and ambulatory surgery centers. After the procedure, the patient leaves with just a band aid.
Since 1966, the AV fistula was surgically created in an operating room by sewing a major arm vein and artery together in the arm. When this is done, blood from the artery will pass through the vein increasing its flow rate and diameter. This makes the vein suitable for the insertion of the needles required for hemodialysis treatment. The AVF is the best method for vascular access reducing hospitalization and mortality with the additional benefits of longer term patency, improved flow rates and fewer complications than other methods of vascular access.
“We are very encouraged by the consistent positive results we’ve been seeing in patients,” said Dr. Hull. “And it is rewarding to be able to offer a faster, more efficient and less-invasive option for patients requiring vascular access. We’re proud to be the first in the nation to provide this quality of life improvement opportunity for ESRD patients.”
Located at 173 Wadsworth Drive, in the Midlothian Center in North Chesterfield, Richmond Vascular Center (RVC) is committed to serving its community with the utmost compassion and respect. Offering a state-of-the art facility, our outpatient center and its entire staff recognize the importance of compassion, privacy, and dignity in the delivery of these services. RVC can be reached at 804-864-8346.
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