By Stacy Lawrence, Staff Writer
Boston Scientific Corp. will acquire Symetis SA for $435 million in cash in an effort to broaden its transcatheter aortic valve replacement (TAVR) portfolio. The Ecublens, Switzerland-based company had been expected to list publicly at the end of this month on the Euronext Paris market in an offering slated to raise €55.8 million (US$59.9 million).
Instead, the Marlborough, Mass., cardiovascular giant has scooped up Symetis, which has two EU marketed TAVRs with a next-gen iteration in the clinic. Wall Street evinced some concern that the addition of Symetis' Acurate platform to Boston Scientific's existing Lotus TAVR platform signals continued problems for the latter.
Last fall, during an initial European launch, Boston Scientific had to pull its latest TAVR, Lotus Edge, due to a problem with the deployment pin that later was found to be a larger manufacturing issue also affecting other Lotus products. The company, however, reiterated that it remains on track with resolving the manufacturing issue and that Lotus Edge is still slated to both re-enter the EU market and to have a PMA submission in the fourth quarter. A U.S. launch is targeted for mid-2018.
DOING IT ALL IN TAVR
"Our cornerstone Lotus valve combined with Symetis' Acurate platform are highly differentiated from competitors and highly complementary, addressing a broader range of patient pathologies and anatomies as well as physician preferences," said Boston Scientific chairman and CEO Mike Mahoney on a conference call about the deal, which is expected to close in the second quarter. He noted that TAVR is a higher growth segment with an overall market that's expected to exceed $4 billion by 2020.
"This is an attractive asset in the fast-growing TAVR space, with Symetis having made significant strides in the last two years with their Acurate TAVR platform," he added. Mahoney highlighted that the company's revenue growth rate has exceeded 50 percent in each of the last two fiscal years, and that it has a "very attractive" gross margins in the mid-60 percent range.
Symetis markets its Acurate TA and Acurate neo/TF systems in Europe to treat high-risk patients with severe and symptomatic aortic valve stenosis. Acurate TA is for transapical use, while Acurate Neo/TF is for transfemoral. Its next-gen Acurate neo/AS is currently in a clinical trial that's intended to be the basis for another CE mark.
Symetis had CHF38 million in 2016 sales, up from CHF25 million in 2015, which is roughly equivalent to the same amounts in U.S. dollars. Germany, Austria and Switzerland account for 70 percent of Symetis sales; during the fourth quarter it achieved a 13 percent market share in Germany and an 8 percent market share in Europe overall.
"We'll be able to uniquely offer customers both supra-annular and intra-annular valves, help expanding and mechanically expanding valves as well as transapical and transfemoral access routes, plus other accessory products," explained Mahoney, adding that the Symetis acquisition "builds on" certain recently acquired Neovasc assets.
That suggests that biologic tissue based on those Neovasc capabilities may be a coming attraction in Boston Scientific's TAVR program. In December, Boston Scientific bought Neovasc's advanced biologic tissue capabilities and certain manufacturing assets for $75 million and made a 15 percent equity investment.
CAUTIOUS WALL STREET OPTIMISM
Initial response on Wall Street to the Symetis acquisition was muted at best, with Boston Scientific shares edging down 1 percent in early trading on the news. Analysts evinced some concern that the addition of a second TAVR platform called into doubt continued progress on the existing Lotus platform, which has been troubled.
"According to BSX, the acquisition of Symetis is about having a broader product offering and not a hedge on Lotus," noted Wells Fargo analyst Larry Biegelsen in a note. He went on to observe, as did Boston Scientific on its call, that having more than one TAVR platform technology is hardly unique and cited Edwards Lifesciences as an example with its dual TAVR platform approach, including balloon-expanding Sapien 3 and its self-expanding Centera.
Symetis' devices are self-expanding nitinol devices, like Medtronic's Corevalve and Abbott's Portico, while Lotus has a nitinol frame and is mechanically expanding, pointed out Biegelsen. He was upbeat about the potential for Symetis' products, including their potential in the U.S., projecting 2017 Symetis sales of roughly $50 million to $60 million.
"Symetis' devices have relatively low pacemaker rates for self-expanding TAVR devices and are known for their ease of use. Symetis has not yet started a pivotal US trial, however, they recently started the SCOPE I trial which is a head-to-head comparison of its Acurate Neo/TF vs. EW's Sapien 3. The company also plans a second trial, SCOPE II, as well as a mitral program," outlined Wells Fargo's Biegelsen.
Stifel's Rick Wise was even more upbeat on the company's Lotus reassurances and Symetis' potential, citing the latter's "innovative X-shaped" device structure, very low paravalvular leak rates as well as a low pacemaker rate.
Mahoney offered extensive reassurance on the Lotus recall and the resolution of related manufacturing issues. "It's the one single issue that first presented with Edge; you'll recall last fall we found it, this early pin release, which we founded on the classic Lotus and Lotus with Depth Guard platforms in February."
"So it's the same single issue. It has to do with excessive pin tension and the root cause is well understood by our teams in Ireland. We are in implementation mode, in terms of revalidations and such and it remains, as we said before, a combination of relatively minor process and then specification changes, along with a final inspection step that we think will be very robust," he concluded.
Boston Scientific expects a return on invested capital (ROIC) from the Symetis deal of 10 percent at year three. It anticipates the deal will be accretive to earnings in 2018 and beyond.
Summed up Mahoney on the deal rationale, it "helps us continue to build upon and execute our category leadership strategy in structural heart, in addition to our leading Watchman Left Atrial Appendage closure device. We're excited to offer both Lotus Valve and the complementary Symetis Acurate platform and TAVR to physicians. Given our proven track record of providing broad and compelling product innovation, supported by commercial and clinical excellence, we believe we can drive synergistic growth by offering all three platforms."
By Stacy Lawrence, Staff Writer
New research published in the BMJ finds that total knee replacement may be most useful in osteoarthritis patients with the most severe symptoms, with little quality of life or economic benefit from the use of the procedure in the less severe patient population.
The researchers suggested that a more rigorous assessment for individual patients of the potential risks and benefits of knee replacement, as well as better optimization of more conservative interventions, could help to improve population-level outcomes and the economic utility of the procedure. The study authors call for further research to advance these benefit/risk prediction tools as well as the relative efficacy of other kinds of interventions.
"You could say we used a more unique approach to look at before and after to compare outcomes for patients who did not have the knee replacement or had knee replacement later and we looked at similar patients to compare outcomes," Bart Ferket, assistant professor at the Department of Population Health Science and Policy at the Icahn School of Medicine at Mount Sinai and lead study author, told Medical Device Daily.
"We did the same, at the same time points, for patients who did not have knee replacements. We found that the improvements are, on average, generally lower than found in other studies and we conducted a cost-effectiveness analysis using those improvements," he added.
An estimated 12 percent of U.S. adults have osteoarthritis of the knee. There are more than 640,000 knee replacements a year in this population for a total estimated cost of about $10.2 billion. The annual rate of the procedure has doubled since 2000, mostly due to the expansion into patients with less severe physical symptoms, but the Mount Sinai researchers questioned the usefulness of that treatment strategy.
There has only been one randomized, controlled trial to evaluate total knee replacement as an adjunct to optimized nonsurgical treatment; and that prior study did not take into account relative symptom severity.
"What would happen if we allocate only knee replacement only to patients with severe symptoms? Cost decreases if we only performed it in severe patients; costs would go down but that would not lead to the loss of total population efficacy," concluded Ferket.
The researchers analyzed data from two U.S. cohort studies. One with 4,498 participants with or at high risk for knee osteoarthritis from the Osteoarthritis Initiative (OAI), and the other 2,907 patients from the Multicenter Osteoarthritis Study (MOST). Patients were followed up for nine years in the former study and two years in the latter one.
Overall quality of life was assessed using a standard measure of physical and mental function, known as SF-12, as well as with other osteoarthritis-specific quality of life scores. Based on that data, the study then estimated quality adjusted life years (QALYS) and assessed them in context of lifetime costs.
The research found that improvements increased with decreasing patient functional status at the initial baseline data. But, taken as a whole amongst all levels of severity, total knee replacement had minimal effects on quality of life and QALYs at the group level.
"Our findings show opportunity for optimizing delivery of total knee replacement in a cost-effective way, finding the patients who will benefit the most, delivering the treatment at the correct point in their disease progression, and optimizing the cost so we can deliver the benefit to all who need it," said Madhu Mazumdar, director of the Institute for Healthcare Delivery Science at the Mount Sinai Health System and Professor of Biostatistics in the Department of Population Health Science and Policy at the Icahn School of Medicine at Mount Sinai and study co-author.
The researchers argue that little effort is made to exhaust non-surgical medication and other options prior to proceeding to knee replacement, and that better use of these could help to manage symptoms in less severe patients.
These non-surgical options include osteoarthritis pain medication included acetaminophen (paracetamol), non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors. Beyond drugs, other options include massage, chiropractic and acupuncture treatments.
It's worth noting that funding for the cohort studies used in the analysis was provided by the National Institutes of Health, Merck Research Laboratories, Novartis Pharmaceuticals Corporation, Glaxosmithkline plc and Pfizer Inc.
"For current practice, our study has a take-home message that not all patients with osteoarthritis are expected to benefit from total knee replacement. That likely depends on the severity of physical symptoms that these patients experience," said Fekert. "We believe that more research should be done looking at more conservative treatments with proper education to patients, recommended exercise and weight loss in patients who are overweight."
Weight loss and exercise to strengthen the knee and improve aerobic fitness, as well as using the best medication, could be sufficient for less severe patients, eliminating or extending their need for an eventual knee replacement.
"Acetaminophen or topical NSAIDs, alternative treatments such as hot and cold compresses and transcutaneous nerve stimulations – patients should be using these in an optimal way before being treated. But in many cases, conservative treatment options have not been optimized before surgery. We need to identify how to better deliver conservative treatment programs," Fekert added.
He would also like to see physicians routinely using predictions tools that can evaluate the potential benefit, as well as the harms and health care costs associated with pursuing a particular path. There are several studies that have proposed such prediction models, but Fekert noted that they need to be validated to ensure their usefulness more broadly outside of their particular study sample.
Fekert cautioned that this analysis doesn't give answers to individual patients. He noted that individuals must decide for themselves if they will be happy with what will perhaps be a small improvement, despite the risks and costs. But the data do speak to broader usage trends – and their appropriateness.
"There's a variation in utilization of the procedure, so it's very difficult to put your finger on it," he said. "Even considering the prevalence of disease across countries, you still end up with questions and use is not in concordance with distribution. In the U.S., utilization is probably the highest among all Western countries."
By Omar Ford, Staff Writer
Organogenesis Inc. is set to acquire Nutech Medical Inc. a private company and supplier of tissue products used in spinal and orthopedic surgeries. Financial details surrounding the deal were not disclosed.
Canton, Mass.-based Organogenesis has been waiting to enter the amniotic tissue market, which led to it picking up Nutech Medical.
"The acquisition expands Organogenesis' product profile into the surgical, orthopedic, spine and amniotic wound care markets and unites two pioneering companies, each with decades of experience in bringing quality biologics products to patients around the world," Gary Gillheeney, president and CEO of Organogenesis, told Medical Device Daily. "The acquisition of Nutech Medical enables Organogenesis to drive significant growth in both the advanced wound care and surgical biologics markets, through our combined R&D programs and distribution networks."
Birmingham, Ala.-based Nutech Medical will continue existing operations as a new division of Organogenesis focused on the surgical biologics arena. Nutech will continue to develop and distribute its product line from existing facilities in Birmingham with plans to grow its existing surgical sales network of about 150 representatives. Nutech's president and CEO Howard Walthall will take the role of president for Organogenesis' surgical division and as senior vice president for strategy and development for Organogenesis.
Nutech Medical's portfolio includes an amniotic product line for both soft tissue and bone repair, used in multiple markets including wound healing and surgery, Walthall told Medical Device Daily.
He added, "Nutech has four randomized controlled trials and nine other clinical trials currently ongoing to demonstrate the benefits of its products across several applications."
Nutech's product line includes, Affinity, a fresh amniotic allograft; Nushield, a dehydrated terminally sterilized allograft that comprises both the amnion and chorion layers; and Nucel and Renu, cryopreserved allografts derived from human amnion and amniotic fluid, as well as other complementary products. In addition, the Nutech's Bioloc process preserves the native structure of the amnion and chorion membranes. Its Allofresh process allows for the fresh hypothermic storage of amniotic tissues.
It has been a busy week for Organogenesis. The company also reported it was launching its Puraply Antimicrobial clinical research program, which will comprise multiple studies and a nationwide patient registry. Puraply is intended for the management of both acute and chronic wounds; and as an effective barrier to resist microbial colonization within the wound dressing and reduce microbes penetrating through the dressing.
Organogenesis was founded in 1985 as a Massachusetts Institute of Technology spin-off. The company went public a year after it was founded, but resumed its status as a private firm back in 2002.
Nearly a year ago, Organogenesis raised about $30 million in capital from existing investors to support a significant expansion of the company's commercial operations, sales force, Puraply product line and new product development in the wound care and surgical fields. (See Medical Device Daily, April 15, 2016.)
The company has faced off against several competitors in the regenerative medicine space. Mimedx is one of its chief rivals, and the two have crossed paths in the courts. Two years ago, the Marietta, Ga.-based company filed a federal lawsuit alleging Organogenesis engaged in malicious actions that "tortiously interfered" with its contractual relationship selling into the Department of Veteran's Affairs. (See Medical Device Daily, Jan. 5, 2015.)
In May 2014, Mimedx reported that it had declined to participate in an adjudication of an advertising challenge filed with the National Advertising Division of the Council of Better Business Bureaus. That challenge was initiated by Organogenesis. Specifically, the company claimed that by comparing Mimedx's allografts to Organogenesis' products, Mimedx implied that its allografts had been FDA approved through the same premarket approval process as Organogenesis products. Organogenesis alleged at that time that only PMA-approved products may be marketed to promote wound healing, but Mimedx argued against both allegations.
Mimedx's Epifix allograft competes with the Apligraf and Dermagraft skin substitutes made by Organogenesis.
By Stacy Lawrence, Staff Writer
iCAD Inc. has secured a PMA approval from the FDA for the computer-aided detection product for digital breast 3-D tomosynthesis that is based on deep learning. The product is already available via Chicago-based partner GE Healthcare; the Nashua, N.H., start up is working now to make it available to other major tomosynthesis providers.
Known as Powerlook Tomo Detection, it received a CE mark and Health Canada approval last year. In Europe, it's already in use at multiple high-volume breast imaging centers.
APPLYING DEEP LEARNING
"The way the product works is that we have developed a deep learning algorithm that scans each of the digital breast tomosynthesis planes. Our algorithm looks at every one of those areas and takes that information, which gets presented to a radiologist who is reading the study. It takes those areas and blends them into a synthetic 2-D image," iCAD Vice President of Marketing Rodney Hawkins told Medical Device Daily.
"It is the first product of ours to incorporate deep learning technology, a subset of machine learning," he noted.
The approach is effective in reducing the reading time necessary for radiologists – without sacrifices when it comes to sensitivity, specificity or recall rate, according to the pivotal U.S. trial data. The study was of 240 tomosynthesis cases read by 20 radiologists. It found that reading time was reduced by up to 37 percent with Powerlook. A European study of six radiologists with 80 cases had similar results.
Deep learning enables the development of sophisticated algorithms developed by the computer itself as it processes more and more images. The Powerlook was initially developed with 500 cancer cases and many more normal breast images, Hawkins said, that made a total of thousands of images. That enabled the system to achieve a detection rate of 92.3 percent.
"This innovative workflow solution detects suspicious areas on the tomosynthesis planes and that information is used to deliver an enhanced image that focuses the radiologist on the specific areas that need further investigation," said Justin Boatsman, medical director and diagnostic radiologist at Intrinsic Imaging LLC, who took part in the U.S. clinical trial. "This not only helps reduce the reading time and improve the reading experience for radiologists, but it can also provide radiologists with an added level of confidence," he added.
NEED FOR 3-D
A study last year in the Journal of Clinical Oncology found that adding 3-D mammography or ultrasound to regular screening mammograms can detect more cancers in dense breasts, although ultrasound has a slightly better detection rate.
Roughly 43 percent of women who are 40 to 74 are classified as having dense breasts; these patients have both a lower rate of detection and a six times higher risk of developing cancer.
"The algorithm itself was fully developed within iCAD, we did partner with GE to blend detected areas into the synthetic ones to make sure that blending was accurate and looked natural," Hawkins said.
The GE partnership was solely around this product. The imaging giant will market the newly approved product as part of its own tomosynthesis offerings, including their own branded version of it. iCAD will also be marketing directly to GE customers, and eventually to those from other tomosynthesis makers.
"We're working to expand the current product to other ventures, with our immediate focus to cover other tomosynthesis providers in the U.S. We are also exploring how we can leverage the core technology," Hawkins said.
iCAD went public in 1984 and has long lingered among the ranks of the sub-$200 million valuation companies. The FDA approval gave its valuation a bit of a boost in early trading, adding 10 percent to bring to roughly $77 million.
It had revenues of $6.9 million in the fourth quarter, a gain of 15 percent from the same quarter one year prior. iCAD reported $26.3 million in revenue last year, with a GAAP net loss of $10.1 million.
The company markets computer aided detection for breast, prostate and colorectal cancer, as well as a treatment system known as iCAD's Xoft Axxent electronic brachytherapy system a noninvasive technology that delivers high dose rate, low-energy radiation to target cancerous tissue in non-melanoma skin cancer, early-stage breast cancer and gynecological cancers.
Earlier this year, it closed a deal to sell its magnetic resonance software products Versavue and DynaCAD for $3.2 million to Invivo Corp., which is part of Royal Philips NV. iCAD and Invivo had partnered in 2013 to develop MRI analysis products.
iCAD is optimistic that its newly FDA approved product will help it gain revenue traction, making it more appealing to Wall Street.
"As the use of 3-D mammography continues to grow in the U.S. and abroad, iCAD remains committed to delivering innovative solutions that help radiologists be more efficient and confident when reading tomosynthesis exams," said iCAD CEO Ken Ferry.
He added, "FDA approval of Powerlook Tomo Detection is a significant milestone for the company, and we are positioned to rapidly advance our commercial plan for this innovative technology in the U.S. with the potential to greatly improve clinical workflow and patient care in the years ahead."
By Omar Ford, Staff Writer
Newly published guidelines from the American College of Cardiology (ACC), the American Heart Association (AHA), and the Heart Rhythm Society (HRS) support cardiac monitoring devices in evaluating syncope patients.
The "2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope" was recently published online in the Journal of the American College of Cardiology, Circulation and Heartrhythm. American College of Emergency Physicians and the Society for Academic Emergency Medicine also helped draft the guidelines.
The new measures point out the choice of a specific cardiac monitor should be determined on the basis of the frequency and nature of the syncope events.
Both external and implantable cardiac monitors (ICM) are recommended based on symptom frequency in the new guidelines. Implantable cardiac monitors have a stronger recommendation as a result of the strong evidence and randomized controlled trials that support the use of ICMs in unexplained syncope patients.
Earlier this month, Dublin-based Medtronic plc expanded its offerings into the space when it received FDA clearance for its Reveal Linq insertable cardiac monitors with Trurhythm Detection. (See Medical Device Daily, March 14, 2017.)
Medtronic has also developed the Seeq Mct system, an adhesive-backed and water resistant external cardiac monitor that is applied to the chest and can be worn discreetly under clothing, without the need for removal during exercise, showering or while sleeping.
"The new ACC/AHA/HRS syncope guidelines were published to drive better informed clinical decisions and improved patient outcomes," Chris Landon, vice president and general manager of diagnostics, for Medtronic, told Medical Device Daily.
Landon added, "Patients who have experienced frequent symptoms may benefit the most from a short-term external heart monitor such as the Seeq Mct System. Patients who experience less frequent symptoms – more than 30 days between symptoms – may be better suited for long-term cardiac monitors such as the Reveal Linq implantable cardiac monitors with Trurhythm Detection, which can monitor the heart for up to three years."
Medtronic's Reveal Linq for the monitoring of syncope patients was evaluated in the PICTURE clinical study. Data from the trial showed that long-term cardiac monitoring with Reveal Linq led to diagnosis and specific treatment for 78 percent (170 of 218) of patients who experienced recurrent syncope. Of those diagnosed, 75 percent of patients were shown to have had a cardiac cause of their syncopal event. In addition, the study found that patients were evaluated by an average of three different specialists for managing their syncope and underwent a median of 13 inconclusive tests before a Reveal device was implanted.
The cardiac monitoring space is a market teeming with competitors. Other key players in the market are Abbott Laboratories Inc., Boston Scientific Corp., GE Healthcare Inc., Philips Healthcare NV, Biotronik AG, Livanova plc, Cardiac Science Corp., Mortara Instrument Inc. and Schiller AG.
Abbott Laboratories has been making some noise in the space with its Cardiomems HF system. Last week, results were revealed from an observational analysis of Cardiomems system that showed the device could have the potential to reduce heart failure hospitalizations and costs. (See Medical Device Daily, March 21, 2017.) But critics of the study noted it wasn't definitive due to its lack of a control group.
Cardiomems is a battery-free device that monitors blood pressure in the pulmonary artery and wirelessly transmits the results to a bedside monitor, which sends the data along to a doctor's office.
Abbott gained access to Cardiomems through the $25 billion acquisition of St. Jude Medical Inc. The St. Paul, Minn.-based company had actually obtained the technology about two years earlier, as a result of its $455 million Cardiomems Inc. buy. (See Medical Device Daily, June 3, 2014.)
By Omar Ford, Staff Writer
Biostable Science & Engineering Inc. received FDA clearance for its Haart 300 product, an annuloplasty device designed for aortic valve repair. The Austin, Texas-based company said it will launch the device in select heart centers this summer. The company has had CE mark for the Haart 300 since March 2016. (See Medical Device Daily, March 9, 2016.)
Heart valve repair is a procedure to repair native valve function instead of replacing it with a mechanical or biological replacement device. Valve repair may be more durable than biological valve replacement and avoids the complications associated with anticoagulation medications required with mechanical valve replacement.
Haart 300 replicates the anatomy of the normal aortic valve. The device is designed to resize, reshape, and stabilize the aortic annulus to restore valve competence and help prevent recurrent aortic regurgitation.
"We know that if we could successfully repair the valve instead of replacing it, that it would be a better answer for patients," John Wheeler, president and CEO of Biostable Science & Engineering, told Medical Device Daily. "We hope our technology helps make aortic valve repair an easy or reproducible procedure. We're trying to offer a better patient solution through valve repair."
Data from a study of the Haart 300 indicated that patients who underwent aortic valve repair using the company's device showed significant improvements in aortic insufficiency grade and New York Heart Association scores, with a reported 89 percent freedom from valve reoperation and a 95 percent rate of freedom from all-cause mortality.
Biostable is a private company and was formed in 2008. Wheeler did not discuss specifics regarding Biostable's funding.
However, Wheeler was clear on the fact Haart 300 wasn't targeting patients in the transcatheter aortic valve replacement (TAVR) market.
"From our perspective TAVR really isn't indicated in our patient population for the most part," he said. "Our patients don't have [calcification], which is really a key characteristic of TAVR. Our patients are typically much younger than an aortic stenosis patient."
In addition to aortic valve repair, the company is also eyeing the mitral valve repair market, with its Haart 200 model.
"Patients are extremely young when they develop problems in the mitral valve," he said. "No one wants to put either a tissue valve or mechanical valve in a young patient with a long life expectancy. There is lots of time for problems to develop. A repair solution there would be a really great option."
Biostable said it hopes to file for CE mark approval for the Haart 200 in the near future. Once that process is underway, the company would seek approval for Haart 200 in the U.S.
Treatment of the mitral valve through either repair or replacement has become an attractive opportunity for many med-tech companies. The space has seen a great deal of mergers and acquisitions activity in the past few years.
Late last year, Edwards Lifesciences Corp. took a deeper dive into the transcatheter mitral valve replacement market when it revealed plans to acquire Or Yehuda, Israel-based Valtech Cardio Ltd. for $340 million, with the potential for $350 million in additional milestone payments. (See Medical Device Daily, Nov. 29, 2016.)
With Valtech, Irvine, Calif.-based Edwards gains access to Cardioband, a transcatheter ring technology and sets the company firmly against Abbott Park, Ill.-based Abbott Laboratories' Mitraclip device.
In July 2015, Abbott Laboratories reported plans to pay $225 million for the equity of Roseville, Minn.-based Tendyne Holdings Inc. that it did not already own at the time, making the total deal worth $250 million plus potential regulatory-based milestone payments. The company closed on that deal in September 2015. (See Medical Device Daily, July 31, 2015.)
In a separate deal, Abbott said it had invested in mitral valve repair company Cephea Valve Technologies Inc., of Santa Cruz, Calif., with an option to buy.
Nearly two years ago, Dublin-based Medtronic plc jumped into the transcatheter mitral valve replacement pool and agreed to pay up to $458 million to acquire Redwood City, Calif.-based Twelve Inc. (See Medical Device Daily, Aug. 26, 2015.)
By Omar Ford, Staff Writer
Treatment has begun on the first patients in Origin Inc.'s U.S. dose-ranging GENESIS trial. The Princeton, N.J.-based company has developed a technology to produce and deliver plasma-generated nitric oxide for the treatment of chronic diabetic foot ulcers (DFU).
Origin, which was formed in 2010 and was formerly called Advanced Plasma Therapies Inc., has developed a device with a hand-held, computer-guided system that generates nitric oxide from ambient room air within a defined plasma stream. From there, nitric oxide is generated and targeted toward the patients wound for about six to 12 minutes.
"From an external source, we're able to deliver a critical mechanism to the body, to allow healing to begin," Betsy Hanna, chief operating officer of Origin, told Medical Device Daily.
In the GENESIS study, the company will recruit up to 100 patients across 15 clinical sites in the U.S. After a two-week run-in period, patients will be randomized into one of four different dosing regimens or a standard of care treatment arm to assess efficacy and safety. Patients will be treated over 12 weeks and monitored for 12 weeks post treatment.
Standard for care treatment for chronic wounds includes dressing changes, wound cleansing, pressure relief (off-loading) and wound debridement.
Effectiveness will be measured by wound closure rate and wound closure percentage. Safety will be measured by wound-related adverse events, which include adverse events of all causes that affect the wound. The company said it would provide an update and initial readout of the interim results in 4Q17.
"We're going to do an analysis of the data at the mid-point of the trial to see the differences of the arms and the efficacy vs. the standard of care," Hanna said. "That data will [determine] the time in which we file for a new IDE for a pivotal trial."
Because of the nitric oxide component, the technology is being treated like a combination product by the FDA.
"The FDA has put us in the device division," Hanna said. "But because of the mode of action of nitric oxide, we do have in our review process and our regulatory process members from the [Center of Drug Evaluation and Research] are also involved in the discussions of the safety and efficacy of the therapy."
Plans eventually call for the company to seek approval in Europe.
"Our target initially is going to be looking at wounds that have failed the standard of care," Hanna said. "There are a number of different products out ... [but] nothing with an overwhelming clinical success in treating these kinds of ulcers. You've got a market out there for advanced wound treatment products and the market is more than $13 billion."
She added, "We see this as a wide open opportunity, and our job is to get the first use and indication approved for our device, to demonstrate we can make a difference in that healing."
Origin isn't alone in its goal to get secure FDA approval for a diabetic foot ulcer technology.
One of the most notable companies in the space is Sanuwave Inc. The Alpharetta, Ga.-based firm has been vying to gain FDA approval for its Dermapace technology for a number of years. The device has CE mark approval and uses a noninvasive, biological response for the repair and regeneration of skin, musculoskeletal tissue and vascular structures.
Sanuwave initially hit a major snag in its plans to bring the device to market back in 2011, after it was revealed in the 206-patient trial that there was no statistically significant difference regarding wound closure after 12 weeks between the sham treatment and the treatment with Dermapace. Sanuwave has been notably quiet with its progress in the U.S., but last month it launched a blog on its website to update key developments with its product line.
Integra Lifesciences Holdings Corp. also has applications in soft tissue repair and regeneration applications. The Plainsboro, N.J.-based company broadened its strength in the space when it acquired Tei Biosciences and Tei Medical for $312 million. (See Medical Device Daily, June 30, 2015.)
By Mark McCarty, Regulatory Editor
WASHINGTON – Payers are quite interested in technologies that determine whether a patient really needs an expensive treatment, but fractional flow reserve (FFR) might have to take a back seat to instantaneous wave-free ratio (iFR) for determining the need to revascularize the coronary arteries, according to two presentations at ACC 2017.
Among the companies whose fortunes might be affected by any conclusions drawn from these studies is Heartflow, which reported at the 2016 edition of the American College of Cardiology annual meeting that it had wrapped up a study intended to nudge payers off the sidelines regarding the FFRct system. Heartflow's chief medical officer, Campbell Rogers, told Medical Device Daily that the company's cloud-based software, which employs CT imaging as source data, deferred invasive imaging for nearly a third of patients with no adverse clinical events at one year as a consequence of the deferral. (See Medical Device Daily, April 6, 2016.)
Justin Davies of Imperial College London said iFR avoids the need for adenosine used in FFR as a vasodilator, adding that the Define Flair study randomized the nearly 2,500 patients across almost 50 centers evenly to iFR and FFR. iFR also requires the insertion of a catheter to insert a pressure sensor wire to capture blood flow data, but the avoidance of adenosine sidesteps some serious, albeit rare side effects, depending on the route of administration.
"In total, more patients were deferred in the iFR arm," Davies said, noting that the 652 deferrals in the iFR arm constituted 53 percent of that group, while the 583 deferrals in the FFR arm accounted for only 47 percent of that side of the study. Bypass was performed on 25 patients in the iFR arm, compared to 42 in the FFR arm, while percutaneous intervention was likewise lower in the iFR group (565 total to 625).
"All these numbers are statistically significant," Davies said, noting that the rate of major adverse cardiac events (MACE) was 6.79 on the study article and 7.01 among controls, which Davies remarked was sufficient to demonstrate non-inferiority.
Define Flair is "the largest randomized controlled trial to date" comparing iFR and FFR, Davies continued, noting that this comparison was "performed in a study population reflecting real-world clinical practice."
The Instantaneous Wave-Free Ratio versus Fractional Flow Reserve guided intervention (IFR-SWEDEHEART) study, which enrolled slightly more than 2,000 in three northern European nations, also appeared at ACC 2017. This study also randomized the enrollment roughly equally to iFR and FFR, and disclosed "significant" lesions of the coronary arteries in 29 percent of patients whereas FFR located lesions in 37 percent.
Both studies appeared in the New England Journal of Medicine, which featured an editorial by Deepak Bhatt of Brigham and Women's Hospital in Boston, who remarked that FFR has not attained widespread use despite "strong data in its favor."
Bhatt noted that clinicians are wary of the risk that adenosine might trigger heart block or bradycardia, but patient discomfort and increased treatment times are also a factor (Davies said iFR shaves nearly five minutes off the 45 minutes ordinarily incurred in FFR).
Bhatt concluded that these two studies are not applicable to patients with acute coronary syndrome, but said that while FFR "has been the evidence-based standard for invasive evaluation of such lesions . . . it now appears that iFR may be the new standard."
TAVR LEAFLET THROMBOSIS RESURFACES
Two registry studies dealing with leaflet thrombosis for both transcatheter and surgical aortic valve replacements found their way to the dais at ACC 2017, the Savory and Resolve registries.
Raj Makkar of Cedars Sinai Medical Center in Los Angeles said subclinical leaflet thrombosis has up to now been reported as occurring at between 10 and 15 percent of transcatheter aortic valve replacement (TAVR) cases, although surgical aortic valve replacement (SAVR) is not immune to this problem. The two registries covered more than 930 patients total, more than two thirds of which were in the Cedars' Resolve registry. There was a large difference in mean time to CT, with 58 days elapsing on average for the TAVR enrollees, while the delay for SAVR patients was on average more than 160 days.
Reduced leaflet motion was defined in both registries as a restriction of motion of at least 50 percent, and about 13 percent of the TAVR patients were diagnosed with reduced motion, while the same could be said of only 3.4 percent of the SAVR patients. Reduced motion was actually associated with a lower rate of death in the two studies, although the rate of stroke/transient ischemic attack was significantly higher in the presence of this condition, 3.4 percent for normal leaflet motion compared to 10.4 percent for reduced motion.
The validity of these studies is hampered of course by their observational nature, but Makkar also acknowledged that the longer delay to CT for the SAVR group "makes it difficult to state leaflet thrombosis as the definitive cause" for stroke and TIA. And although the study was not sufficiently populated to contrast the rates of subclinical thrombosis across TAVR types, the Medtronic plc Corevalve incurred the nominally lowest rate at six percent, less than half the rate seen in the Sapien units by Edwards Lifesciences Corp.
By Mark McCarty, Regulatory Editor
WASHINGTON – The FDA broke an embargoed release of data for Abbott Laboratories' Absorb GT1 scaffold, advising clinicians that the rates of major adverse cardiac events in a large study were higher than seen with the comparator, but leading cardiologists at ACC 2017 were nonetheless unwilling to recommend that clinicians abandon the device.
The FDA's safety alert preceded the embargo placed on the news from the Absorb III study – sponsored by the Abbott Park, Ill.-based company – by nearly 50 minutes, but contained no information that was not included in the presentation by Stephen Ellis, one of the investigators in Absorb III. Ellis reminded that the primary non-inferiority endpoint for Absorb III in regulatory terms was based on one-year data, and that the company had hoped to keep data from years two through five under wraps until those data could be blended with Absorb IV data for longer-term assessment of target-lesion failure (TLF).
However, Ellis said the superiority of the GT1 over the Xience drug-eluting stent for TLF would not likely emerge until after the GT1 scaffold had absorbed, which is typically expected to occur at three years post-implant. Consequently, the company and FDA have agreed, after consulting with clinical investigators, to use years three through seven to test the TLF superiority endpoint, thus allowing the unblinding of data for ACC 2017.
Abbott has two-year data from Absorb III for roughly 98 percent of the nearly 2,000 patients in both arms of the study, and Ellis pointed out that the study article had met the non-inferiority endpoint for TLF at one year. As has been previously described, clinicians have been cautioned about implanting the device in patients with reference vessel diameters smaller than 2.5 millimeters, a predicament that colored the latest release of data.
The Absorb had a difficult time keeping up with the Xience for target-lesion failure for the 13-to-25 month interval (the actual period of elapsed time used for the nominal one- and two-year data collection set points), which occurred in 3.7 percent of all enrollees on the study article regardless of lesion size, while only 2.5 percent of Xience patients experienced TLF. After dividing the data by RVD as assessed by quantitative coronary angiography with vessel diameter of 2.25 milimeters as the threshold, the GT1's rate of TLF dropped to 3.2 percent in the larger set of vessels, but Xience also benefitted from this analysis, with only 1.9 percent experiencing TLF. More than eight in 10 of enrollees in both arms had RVDs in excess of 2.25 mm, according to Ellis.
At 25 months, the difference in TLF for the two arms for the entire study population had widened in absolute terms (11 percent for GT1 to 7.9 percent for Xience), as was the case for the subset with larger vessels (9.4 percent to 7.0 percent). However, the relative differences in TLF had actually narrowed.
Ellis said the generalizability of Absorb III is limited by inclusion of those with stable ischemic disease, and that the study is underpowered to evaluate low-frequency events. "Importantly, implantation technique was still evolving" as the study commenced with enrollment, he said, adding that the combination of predilatation of the vessel, appropriate vessel size selection, and postdilatation – an approach known colloquially as PSP – might go a long way toward resolving some of the differences between the two devices.
Antonio Colombo of New York Presbyterian said of the new Absorb III data, "I think you can look at the glass [as] half empty or half full." Colombo stated further, "with the proper technique and selection, you can make it non-inferior" to Xience, suggesting that if clinicians stay in bounds on vessel size, frequently invoke postdilatation with a noncompliant balloon inflated to at least 18 atmospheres, and routinely use intravascular ultrasound (IVUS) to guide the implant procedure, the device's performance should shape up well in contrast to the Xience.
Roxana Mehran of Mt. Sinai Hospital in New York said she was "somewhat comforted that the event rates are not extremely high" for the GT1, but that the data leave her "waiting for the promise of the future; superiority of this device" over Xience for TLF.
Mehran said the question of whether a patient with the GT1 should stay on dual antiplatelet therapy until the scaffold disappears is still unanswered. She said most of the patients in the study were not treated via the PSP protocol, and that it is not entirely clear how IVUS influences outcomes.
Ellis responded, "I think, based on these results, as long as you follow the inclusion criteria in Absorb III" and deploy the device in a technically appropriate fashion, "the results are similar to what you see in Xience." Nonetheless, he said, clinicians "should be up front with the patient" about the uncertainty.
Regarding the broken embargo, the FDA told Medical Device Daily that it has "interacted with Abbott to ensure it has the most up-to-date information on which to base its recommendations. As new information becomes available, the FDA will update its communications and recommendations as necessary."
By Mark McCarty, Regulatory Editor
The TAVR wars heated significantly at the annual meeting of the American College of Cardiology, where a new set of data for the Corevalve series of devices demonstrated that the Dublin-based Medtronic plc offering beats surgical aortic valve replacement on several scores for intermediate-risk patients, a population already served by a TAVR offering from Edwards Lifesciences Corp. of Irvine, Calif.
The 17th annual scientific sessions held by the American College of Cardiology commenced with the usual late-breaking clinical trial data releases, with the data from Surtavi serving as the premier device study presented on day one. Michael Reardon, a principal investigator in the 1,764-enrollee study, reminded that the study was conducted across more than seven dozen sites in the U.S., Canada and Europe. Numerically speaking, the Medtronic units outperformed surgical aortic valve replacement (SAVR) handily in terms of the primary endpoint of all-cause death and stroke (12.6 percent for TAVR and 14 percent for SAVR) at two years, but this measure failed to hit the benchmark for demonstrating superiority for the study article, although the Corevalve units' performance sufficed to hit the non-inferiority standard.
Despite the sheer volume of enrollment, Surtavi was a Bayesian trial that was principally populated by the legacy Corevalve in the device arm, while the successor, the Evolut R, accounted for 16 percent of the total TAVR devices used in the study. Operators handling the SAVR cases were allowed their pick of available surgical valve offerings in an effort to mirror real-world outcomes, which Surtavi replicated at least in one characteristic: Nearly one in four on the study article needed a pacemaker in this study, similar to a figure seen in a previous study of Medtronic valves in high-risk patients. (See Medical Device Daily, March 18, 2015.)
The enrollees, who on average were nearly 80 years of age in both the roughly numerically equal arms, were all in the range of 4.4 to 4.5 on the risk scoring system devised by the Society of Thoracic Surgeons. The TAVR arm included some patients who underwent percutaneous intervention for the coronary arteries while some of the SAVR patients also underwent bypass surgery, and one of the inclusion criteria was that the patient be in at least stage II heart failure.
Reardon, who had presented two-year Corevalve data for high-risk patients at ACC 2015, said the original enrollment had been winnowed to 1,660 by the time it came to attempt device placement. He said the 24-month data for all-cause mortality and disabling stroke presented "a very robust statistic for non-inferiority." The all-cause death at 30 days favored SAVR, which was 1.7 percent while TAVR's 30-day mortality was 2.2 percent. Of the SAVR figure, Reardon said "this is extraordinarily good surgery." The numbers flipped by two years, however, with TAVR all-cause mortality at 11.4 percent while SAVR yielded 11.6 percent. "TAVR stood toe-to-toe with surgery" and won on all-cause death at two years, Reardon emphasized.
Reardon remarked that this is the third consecutive study showing TAVR imposes a lower rate of stroke than SAVR, but he said the data do little to answer the question of whether hemodynamic performance is particularly important. Reardon said he was "very taken aback," by the persistence of the pacing problem, which he said will greatly affect patients who have a considerable life expectancy in front of them. "I think this is an engineering ... and site placement thing," Reardon continued, although he added that the ability to retrieve and re-place the Medtronic units gives the operator more breathing room to ensure proper device placement.
Among the other encouraging signs to come out of Surtavi is that the Medtronic devices imposed a stroke rate of 2.6 percent at two years, only slightly more than half the stroke rate of 4.5 percent of the SAVR arm. One of the confounders on the point of pacemaker in Surtavi was that the rates between Corevalve and the Evolut R iteration were very similar (25.5 percent for the legacy device and 26.7 percent for the newer edition), although the fact that the Evolut R made up only about one in six of the TAVR devices in this study complicates efforts to draw any conclusions on that point.
Reardon told Medical Device Daily that it can be difficult for less experienced operators to avoid placing a TAVR device without interfering with the function of the atrioventricular node, a predicament incurred when the device is positioned in such a manner as to impinge upon the outflow tract. Overcompensating for this hazard with the original Corevalve could lead to some problems with obtaining a proper fit of the device into the aortic annulus, he said.
Reardon said the clinical discussion for device selection revolves around several factors.
"We look at things such as whether there's a lot of calcium in the outflow tract," he said, noting that a self-expanding device is perhaps a better bet to avoid rupturing the annulus, which could prove lethal. On the other hand, he said, a practitioner might go to a balloon-expandable unit if the width of the aortic sinus exceeds a certain benchmark, although most of the variability in sinus width is indifferent to device type. Reardon said the ability to reposition the Medtronic offering is really the best argument for the Evolut R.
When asked about private payers, Reardon said, "most of them have been willing to cover [TAVR] in the high-risk group," although they are obviously less inclined at present to cover these devices for intermediate-risk patients. "The bigger problem is not the payer," Reardon said, explaining that a hospital's chief financial officer will say that SAVR "has one of the highest contribution margins in the hospital, and you want to replace it with a TAVR, which barely has a contribution margin." As for the patients, "they all want TAVR," Reardon shrugged.
The Evolut Pro is scheduled to debut at ACC 2017 on March 18, and Reardon said the device "has an external skirt to cut down on paravalvular leak. Stay tuned, it's going to move things forward," he advised.
TAVR WARS HEATING UP AGAIN
The competitive temperature was on display on March 17, as demonstrated by the full-page ad taken out by Edwards for its Sapien 3 TAVR device in the ACC.17 Daily, the circular published by the college each day during the ACC's annual scientific sessions. The Edwards advertisement bragged that the company currently has the only TAVR offerings approved by the FDA for use in intermediate-risk patients, although the numbers from Surtavi suggest Edwards will lay sole claim to that population for only a little while longer.
Larry Biegelsen of Wells Fargo of San Francisco said in an investor's note that the data from Surtavi should prod the FDA to expand the device's indications to intermediate-risk patients. Biegelsen pointed out that SAVR performed substantially better on the primary endpoint in this study than was anticipated, mostly because of a lower mortality rate than has been seen in other studies, such as Partner 2A, a study of the Edwards Sapien XT and Sapien 3.
Biegelsen noted that Edwards may argue that the data for the Sapien 3 device as seen in Partner 2A bested the Surtavi data for Corevalve units in terms of moderate to severe paravalvular leak and rate of pacemaker implant, but that Medtronic can resort to the assertion that those Sapien 3 data were drawn from an observational study that employed propensity matching to filter out bias. The problem for Medtronic with the Evolut R iteration is that the pacemaker rate was roughly double that of the Sapien 3 (nearly 26 percent versus 12.4 percent on the Sapien 3), and the rate of paravalvular leak was nearly triple for the Medtronic items against the Sapien 3. Still, Biegelsen observed, Medtronic has the Evolut Pro waiting in the wings, a device Medtronic is expected to bring to market later this year.
An investor note from Rick Wise at Stifel Financial Corp. of St. Louis, characterized Reardon's presentation as positive for both Medtronic and Edwards because the data "argue for continued, steady TAVR adoption" for intermediate-risk patients in the coming years. Wise commented that the Surtavi data might have been more persuasive had the entirety of the device arm had been populated by the Evolut R.
"Any lingering hesitancy about referring potential patients [for TAVR] should gradually diminish," Wise said, noting that the comparative stroke rate at 24 months was 2.6 percent for the TAVR units and 4.5 percent for the surgical arm. He said Medtronic has already forwarded the Surtavi data on to the FDA, stating that the approval process "would likely take three to six months." He rated Medtronic's shares a hold with a target price of $84.