We recently spoke with Dr. George Savage, chief medical officer at Proteus Biomedical. The company raised $32 million in VC funding last year and is applying semiconductor and MEMS technologies to ingestible and implantable devices and pharmaceuticals with the initial focus on increasing the efficacy of treatments for heart failure.
Almost a million patients are hospitalized in the US each year for the failure of the heart to maintain adequate circulation because of various stresses upon it. Heart failure is the single largest expense for hospitalizations in the United States, costing $30 billion per year.
MEMS Investor Journal: What is "heart failure" as opposed to, for example, "cardiac arrest" and approximately how many people suffer from it?
Dr. Savage: Heart failure is a progressive disorder in which damage to the heart causes inadequate blood flow to tissues. This leads to fluid congestion and further deterioration in the pumping function.
Cardiac arrest is the sudden, abrupt loss of heart function. The victim may or may not have diagnosed heart disease. It is also called sudden cardiac arrest or unexpected cardiac arrest. Sudden cardiac death occurs within minutes after symptoms appear.
According to the National Heart Lung and Blood Institute, heart failure afflicts five million Americans and results in more than 300,000 deaths per year. It is the single largest expense for hospitalizations in the United States, costing $30 billion per year.
MEMS Investor Journal: Are there different types of failure and if so, which types are most serious and must be treated in order to avoid death?
Dr. Savage: Heart failure classification reflects the severity of symptoms and heart function. Some people have only right-side heart failure. But all people who have left-side heart failure also have right-side heart failure. Treatments for right-side heart failure alone differ from treatments for both right-side and left-side heart failure.
MEMS Investor Journal: What are the commonly applied treatments for heart failure?
Dr. Savage: Pharmaceutical therapy and device-based cardiac resynchronization therapy (CRT) targeted toward reducing the heart’s workload and improving quality of life are the standards of care for a significant number of patients.
Symptomatic heart failure patients are prescribed a daily regimen of multiple pharmaceuticals, typically including angiotensin converting enzyme (ACE) inhibitors, beta-blockers and diuretics. 85 percent of heart failure patients are treated by pharmaceuticals and all patients that are symptomatic are treated by pharmaceuticals.
CRT provides electrical stimulation to the heart in order to help relieve patient symptoms by improving coordination of the heart’s contractions. Over time, CRT can return the heart’s structure and function to more normal states.
CRT devices consist of an implanted pulse generator (IPG) placed under the skin in the upper chest as well as three electrode wires, or leads, that carry electrical signals to the heart. It is not 100 percent effective, however, because approximately 30 percent of patients receiving it fail to show improvement after receiving a CRT device.
MEMS Investor Journal: Do all cases of heart failure require therapy?
Dr. Savage: Patients at risk for heart failure without symptoms may only require monitoring and careful attention to diet and exercise. Once a patient experiences symptoms, or if they have co-morbid conditions like diabetes, or have had a previous heart attack, they are frequently prescribed pharmaceutical therapy. Implanted device therapy is currently only indicated for moderate to severely ill patients with specific clinical indications.
MEMS Investor Journal: How many or approximately what percentage of patients suffering heart failure are undergoing device therapy?
Dr. Savage: One study reported in Circulation: Journal of the American Heart Association found that 12.4 percent or 120,000 of the hospitalized heart failure population was discharged with cardiac resynchronization therapy. But according to previous studies, 30 to 50 percent of hospitalized heart failure patients would have been eligible for CRT. According to its authors, the later study suggests that hospitals need to have systematic practices to employ best evidence, including treating patients with CRT. Patients should also investigate their condition of heart failure and be their own advocate to get optimal care.
MEMS Investor Journal: What therapies now being employed? How do they differ from each other and what are the advantages and drawbacks of each?
Dr. Savage: There are pharmaceutical and device options for treatment and heart transplant for the most severely ill. The typical patient will start with pharmaceutical therapy, move to device therapy, and if those options fail, may be recommended for heart transplant.
The several types of drugs, surgical and medical device solutions that have proved useful in the treatment of heart failure are listed in the accompanying table.
Some people have such severe heart failure that surgery or medications do not help. They may need to have their diseased heart replaced with a healthy donor heart.
MEMS Investor Journal: What, if any, is the main problem with conventional therapies?
Dr. Savage: A major problem with heart failure medications is patient adherence and dose titration. For pharmaceutical therapy to be effective it is vital that patients adhere to the prescribed regimen – that is taking required doses at appropriate intervals. Multiple clinical studies demonstrate that more than 50 percent of symptomatic heart failure patients do not receive guideline-recommended therapy, and of those who do, only 40 to 60 percent adhere to the regimen.
A major problem with CRT is the challenge of placing the left heart lead in order to optimally mechanically re-synchronize the heart, and to also avoid pacing the phrenic nerve. The latter is a significant complication that causes the patient to hiccup every time the heart is stimulated. This can occur about once per minute, and affects between 10 and 15 percent of patients either during or after the procedure.
One third to one half of all patients receiving CRT do not respond or receive a negligible benefit.
MEMS Investor Journal: How is Proteus approaching this market? How does your technology differ from conventional therapies? What led you to apply MEMS technology to heart failure therapy?
Dr. Savage: Our approach comprises two therapeutic technologies: implantable and ingestible. The implantable technology is being incorporated into CRT device leads as well as implanted devices for chronic pain and other disorders. Our ingestible technology is being incorporated into oral pharmaceuticals.
Our implantable technology is the cornerstone of the company’s therapeutic device products, which are currently in clinical development with our development partners; it applies MEMS technology to add intelligence to any implanted medical device – tiny active electronics that expand their performance. Examples include implanted medical catheters, or leads, that use electrical energy to stimulate, pace, or regulate body function.
In the example of cardiac resynchronization therapy, Proteus intelligence can significantly expand the number of pacing sites on the left side of the heart – from 2 or 4 to more than 16. Proteus intelligence can also add more sophisticated means of sensing cardiac function – think of this as an automated implanted ultrasound – so that physicians can optimize pacing site location in order to improve heart function.
Our technology addresses one of the significant challenges preventing widespread use of implanted medical device therapies – namely the disintegration of active electronics upon exposure to body fluids. We overcome this by providing an extremely thin and durable protective layer that ensures long-term survival and performance of millimeter-scale implanted devices. So instead of encasing electronics inside a titanium welded implanted pulse generator we can deposit the IPG on the active electronics, at the wafer scale. This enables any implanted medical device to contain active electronics.
MEMS Investment Journal: How does your implantable technology address the problem of stimulating the phrenic nerve? Also, if it is expected to improve the rather poor response rate to CRT mentioned above, how will it be accomplished?
Dr. Savage: Networked leads for CRT enable more sophisticated monitoring of heart function, and increase the number of options for pacing. As a result, physicians can have the option to program around the phrenic nerve, and to monitor an individual patient’s response to CRT and adjust the pacing location as needed to optimize outcomes.
MEMS Investment Journal: How does the ingestible therapy work?
Dr. Savage: Our ingestible event markers (IEMs), currently in clinical development, are tiny, digestible sensors made from silicon and food ingredients that are activated by stomach fluids after swallowing. Once activated, the IEM sends an ultra low-power, private, digital signal through the body to a microelectronic receiver that is either a small bandage style skin patch or a tiny device insert under the skin. Unlike RFID devices, which transmit signals indiscriminately outside of the body, and are expensive to produce, our technology utilizes transconduction, an inherently private, in-body signal that requires a receiver placed inside or on the body, and is extremely inexpensive to produce.
The receiver date- and time-stamps, decodes, and records information such as the type of drug, the dose, and the place of manufacture, as well as measures and reports physiologic indicators such as heart rate, activity, and respiratory rate. Information from the receiver is communicated securely via wireless technology to a Proteus server and then to a PC, mobile phone or other electronic device.
The initial application for our ingestible therapy system is intended for the treatment of patients with heart failure. As suggested earlier symptomatic heart failure patients take multiple drugs daily to reduce the heart’s workload and improve quality of life. We are also investigating this ingestible system with tuberculosis therapy, as a less-invasive replacement for the standard of care, directly observed therapy, as well as psychiatric disorders, as a more effective way to connect customers with their caregivers. Ultimately, we envisage this offering significant benefit to anyone who has a chronic disorder and wants to more effectively and less invasively manage their wellness.
MEMS Investor Journal: What pointed you in this direction? What was the "eureka" moment?
Dr. Savage: My co-founders and I noticed that medical technology innovation was increasingly characterized by diminishing returns. More and more time, money and risk were expended to drive specific therapies forward by smaller and smaller increments. In comparison, treatment systems — the way actual therapies are delivered and personalized for particular patients — seemed stuck in the stone age.
Ask any consumer and they will undoubtedly tell you that medical technology is great; their physicians and nurses do terrific work. What makes them unhappy is the fragmented, labor-intensive way therapies are delivered. Treatment systems need improvement. We determined that intelligent medicine, that is deploying in-body and on-body sensors and computers and leveraging widely available wireless technology, holds the promise of allowing more individuals to live fuller, healthier lives.
MEMS Investor Journal: Who are your partners in bringing these solutions to market and how are they contributing?
Dr. Savage: Our business model is to partner with leading medical companies and build our technology into market leading products and therapeutic franchises offering broad potential benefits across a range of care settings and therapeutic areas. Examples include cardiovascular, psychiatric, metabolic and neurologic disorders. We will continue to partner with major medical device, technology and pharmaceutical companies to co-develop and commercialize intelligent medical products.
Our strategic investors comprise venture capital and private equity firms, healthcare concerns and manufacturers of devices and technology. They include St. Jude Medical, Medtronic, Itochu, Kaiser Permanente Ventures, Carlyle Group, Essex Woodlands Health Ventures and Springridge Ventures.
MEMS Investor Journal: What components comprise the Proteus solution? What does each component do and how are they assembled?
Dr. Savage: The accompanying photos describe the components of our ingestible and implantable solutions.
Proteus' sub millimeter ingestible event markers add "intelligence" to pharmaceuticals and provide patients with information on their individual response to medications through a mobile computer like a smart phone.
Proteus' system comprises a sensor-enabled pharmaceutical pill, a skin patch receiver that detects pill ingestion and measures physiologic response like heart rate, respiratory rate and activity, and a mobile computer like an iPhone in order to help a person stay healthy by tracking his or her individual response to pharmaceutical therapies.
Proteus' implantable technology protects active electronics inside of the body at a sub millimeter scale, and add "intelligence" to any implanted medical device.
MEMS Investor Journal: What design challenges did you have to overcome in bringing your products to market and how did you overcome them?
Dr. Savage: The most significant challenge with our implantable technology involved designing a hermetic package at the wafer scale that could survive inside the body long-term. The most significant challenges with the ingestible technology involved designing a safe, digestible sensor and private in-body communications method. We are not prepared to go into detail on how these challenges were solved.
MEMS Investor Journal: What, if any, other players in this market are taking a similar approach and how does your system compare with theirs in terms of efficacy, cost and ease of use?
Dr. Savage: To the best of our knowledge the Proteus approach to intelligent medicine is unique in that we are focused on improving existing therapies and using a systems approach to add therapeutic context that can help patients, physicians and their caregivers in an actionable way. Moreover, our diverse management team has with a broad range of expertise that includes leaders in life sciences, materials science, and semiconductors; veterans of leading pharmaceutical, biotech and medical device companies, and two medical doctors and a Nobel prize winning physicist.
MEMS Investor Journal: When will your clinical trials be completed, and how soon after that do you expect to be marketing these solutions?
Dr. Savage: Our commercial partners are conducting all trials that are required for regulatory approval of our heart failure products. We expect our first products will come to market through partners in 2010.
MEMS Investor Journal: What feedback are you getting from these trials?
Dr. Savage: Proteus will continue to conduct its own clinical studies to demonstrate the value of its technology in specific applications. Thus far, the physician and patient response has been extremely positive.
MEMS Investor Journal: What will be the determining factors in a cardiologist recommending Proteus solutions?
Dr. Savage: Proteus is a leader in intelligent medicine. What our technology does is personalize proven therapies by embedding computers and sensors into drugs and devices and linking them to mobile computers. In that sense we do not compete with conventional therapies, which would call for physicians to make choices. Instead we make conventional therapies work better. We believe that this approach has the potential to substantially impact global healthcare, promoting access, value and sustainability.
For example, in the specific instance of cardiac resynchronization therapy for heart failure, cardiologists need accurate, timely, objective evidence of an individual patient’s response to therapy, along with the means to expand their options for therapy titration without having to re-operate. In the case of pharmaceutical therapy for heart failure, it is almost impossible to titrate the multiple medications for an individual patient to optimal effect, and to have any ‘early warning’ that a patient is beginning to decompensate and end up in the hospital. These are two large clinical needs that Proteus technology can address in an extremely cost-effective and non-invasive manner.
MEMS Investor Journal: Under what circumstances, if any, would the Proteus solution not be recommended?
Dr. Savage: Based on the idea of "improving existing therapies", it is likely that Proteus technology will not only improve the effectiveness of pharmaceutical and device therapy by expanding it to other populations, but it will also identify patients that are not responding to therapy so an alternative therapy can be initiated. So, for example, beta blocker dosages must be carefully titrated in order to mitigate side effects. By using our ingestible system, a physician can easily identify what doses correlate with which physiologic side effects and switch to a better tolerated dosage form.
MEMS Investor Journal: What are the cost elements of your solution?
Dr. Savage: Proteus technology is manufactured using wafer-scale fabrication processes, and is intrinsically low-cost, with costs decreasing as volumes increase. Our partners are ultimately responsible for the manufacture and distribution of the final products to customers. We ourselves have a 15,000 square foot state of the art advanced manufacturing facility, where the critical ‘intelligent’ MEMS product components are produced.
In the case of networked leads for cardiac rhythm management devices, these devices are implanted using substantially the same device form factor, and reimbursed using the same codes as similar products. What this means is that the consumer, the hospital, and the physician will receive the value of improved outcomes without any added cost.
The ingestible system is manufactured on silicon wafers, and is extremely economical to produce, costing a few cents per sensor in large quantities. The cost and the configuration of the System will vary by application and duration of use. So, a heart failure patient that is discharged from hospital may receive an ingestible system to help keep them out of hospital for a short-term period, whereas a severely ill heart failure patient may have their implanted CRT device also track their heart failure medications.
MEMS Investor Journal: Where do you see Proteus within 3 to 5 years in the treatment of heart failure?
Dr. Savage: Proteus technology is being built into two companies’ next generation rhythm management devices. We expect that networked leads will become a clinical standard of care in cardiology within the next three to five years, and in neuromodulation shortly thereafter.
MEMS Investor Journal: What do you see are future applications for MEMS technology in biotechnology? Where is Proteus going?
Dr. Savage: The rapidly expanding field of "intelligent medicine" has been driven in large part not only by the ubiquity of the mobile phone, but also advances in MEMS, nanotechnology and other semi-conductor-based processes. There are dozens of intelligent medicine companies that are using these approaches to create implantable, ingestible and wearable computers to enable highly cost-effective, personalized therapies. Proteus along with our strategic partners will continue to pursue its vision of intelligent medicine to help people with chronic disorders like psychiatric disease, intractable pain, hypertension, GI disorders and TB.
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Dr. Savage is a co-founder of Proteus. He is also a managing member of Spring Ridge Ventures. From 1994-1999, Dr. Savage co-founded FemRx and served as a director and senior vice president of research and development during which time FemRx completed an IPO and was subsequently acquired by Johnson & Johnson. Previously, Dr. Savage co-founded CardioRhythm and served as a director and vice president of clinical and regulatory affairs during which time CardioRhythm was acquired by Medtronic. He practiced medicine from 1985 to 1992, specializing in trauma and emergency medicine. Dr. Savage holds a B.S. (Magna Cum Laude, Tau Beta Pi) in Biomedical Engineering from Boston University, an M.D. from Tufts University School of Medicine, and completed postgraduate training in general surgery at the University of Massachusetts Medical School. He has an M.B.A. from Stanford University Graduate School of Business.
Copyright 2009 MEMS Investor Journal
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