Amalgam Rx launches with iSage Rx, basal insulin titration app with FDA clearance; Founded by former WellDoc Execs Ryan Sysko and Dr. Suzanne Clough – May 1, 2017

Early this morning, Amalgam Rx – a new digital health company from WellDoc founders Ryan Sysko and Dr. Suzanne Clough – announced its launch and its first product: a basal insulin titration app called iSage Rx. This report includes highlights on the app (we got a demo last week), Amalgam Rx’s pipeline, the insulin titration landscape, and more, complete with screenshots and Q&A from an interview with CEO Mr. Ryan Sysko. 

Top Ten Highlights

1. Amalgam’s iSage Rx is a prescription-only, basal insulin titration software for type 2 diabetes that launched on Google Play and the iTunes store early this morning. It is the first app on the market, to our knowledge, to support titration of all basal insulins – Lantus, Levemir, Toujeo, Tresiba, and Basaglar. In a web interface, prescribing physicians can select from multiple clinically-validated algorithms and tailor them to the specific needs of the patients. Patients then receive an activation code and the app runs on its own, using fasting glucose readings to constantly update basal insulin dose recommendations. iSage Rx also offers behavioral, clinical, and educational support in the form of short videos, trivia, and messages to help users overcome the obstacles associated with insulin therapy.

2. We were very impressed by iSage’s ease of prescribing and simple user experience. Once set up is complete, it should take “less than a minute” for the office staff to complete the prescription. The patient is presented with a simple, friendly interface with reminders to check fasting blood glucose (what the titration is based on), insulin dose, and to watch an educational video of the day and answer a trivia question (both optional). The patient-facing app is very encouraging, for example, explaining that the user should be patient, because it could take up to three months to see blood glucose readings reach goal. Providers can see how patients are doing on the back-end and be alerted to those with very high or low readings.

3. Amalgam Rx has begun recruiting for an initial proof of concept clinical trial to demonstrate the product’s ability to bring patients to optimal dose and improve outcomes. The trial, which will be loaded onto clinicaltrials.gov shortly, will aim to enroll ~30 patients in the intervention arm with a matched, retrospective control arm according to Mr. Sysko. He expects that the study will wrap up this year and hopes that the company will have data to share in 2018.

4. The development timeline for iSage Rx is remarkable: Amalgam Rx was founded in 1Q16, and FDA granted 510(k) clearance in March 2017, putting the whole regulatory process at about one year. The FDA review was nine months (submitted in ~June 2016), meaning the whole app was built and submitted to the FDA in just four months!

5. Said Mr. Sysko in a call with us: “We don’t want to be the operating system for type 2 diabetes. Our ultimate goal is to become the “Intel Inside” to provide insulin titration as a service.” Amalgam hopes to announce at least one partnership with a life sciences company this year. We imagine a range of partners could benefit from the FDA-cleared insulin titration platform: insulin companies (Novo Nordisk, Lilly, Sanofi), BGM/CGM players (Abbott, Ascensia, Dexcom, J&J, Medtronic, Roche), data management/app/coaching companies (Glooko, Livongo, mySugr, One Drop), connected pen players (BD, Companion Medical, Common Sensing), etc.

6. In the short term, Amalgam will work with providers, health systems, payers, and PBMs to drive adoption and generate real-world efficacy data. Since iSage is prescription-only, a direct-to-consumer model is unlikely. Amalgam plans to operate within a value-based framework and receive payments based on outcomes. We imagine a lot of business model learning from WellDoc’s BlueStar (app prescribed as a drug) will be leveraged here.

7. In the pipeline, Amalgam hopes to have basal + GLP-1 titration cleared in the next 60 days (~by the end of June) and basal-bolus titration cleared by the end of the year. A large pivotal study that is currently being designed will include all of these systems.

8. Mr. Sysko and Dr. Clough (a brother-sister duo) were two of three cofounders of WellDoc back in 2005, where Mr. Sysko then served as CEO and Dr. Clough as CMO for many years. The company held a small seed round previously with backing only from private individuals. The team will likely hold another financing round this year, and already has an existing revenue stream from an undisclosed partnership. BCG’s Chris Bergstrom (a former leader at WellDoc) is an advisor.

9. Why not build this at WellDoc and incorporate into BlueStar? Confidentiality agreements prevent Mr. Sysko and Dr. Clough from being totally candid, but they shared a desire to do something new and focus on this clear area of need.

10. The press release notes that iSage is the first of several new digital therapies being developed. Amalgam Rx is actually a “holding company” with multiple subsidiaries focused on different disease states.

Top 10 Highlights

1. Amalgam Rx’s iSage Rx is a prescription-only, basal insulin titration software for type 2 diabetes that launched on Google Play and the iTunes store early this morning. It is the first app on the market, to our knowledge, to support titration of all major basal insulins – Lantus, Levemir, Toujeo, Tresiba, and Basaglar. Prescribing physicians can select from multiple clinically-validated titration algorithms and tailor them to the specific needs of the patients. Clinicians can simply set up the standard algorithm or even customize their own algorithm. The app also offers behavioral, clinical, and educational support in the form of short videos, trivia, and messages to help users overcome the obstacles associated with insulin therapy.  

2. We were very impressed by the ease of prescribing for healthcare providers and the app’s simple user experience. To get set up, providers need to contact Amalgam and get trained on the system. Once set up is complete, it should take “less than a minute” for the office staff to complete a prescription. When the provider logs into the web portal, a button pops up saying “prescribe iSage Rx”; at this point, the provider is prompted to enter some basic demographic information about the patient (though the company is actively working on EMR integration). The provider then selects an insulin, a titration algorithm for that insulin, and a maximum dose, and hits prescribe – the titration scheme can be adjusted by the provider (e.g., target range, dose steps, alarm notifications), but iSage Rx pre-populates the algorithm based on the published clinical trial evidence. Once the doctor hits “prescribe,” the patient receives a text with an activation code and can download the app on the iTunes or Google Play stores. After an easy setup, the patient is presented with a simple, friendly interface with reminders to check and manually enter fasting blood glucose readings (what the titration is based on), insulin doses, and to watch an educational video of the day and answer a trivia question (both optional). We like that the system runs on its own for patients, giving updated dose recommendations and without provider involvement unless significant hypoglycemia/hyperglycemia presents. The obvious area for improvement is connected device integration to passively collect the blood glucose and dose data.

• The patient-facing app is very encouraging, for example, explaining that the user should be patient, because it could take up to three months to see outcomes, and offering engaging education to help patients get accustomed to using insulin. The developers are considering including social network aspects and/or reward systems in future iterations.
• Mr. Sysko believes that Amalgam Rx is set apart from other titration products by going beyond the number to deliver self-management support, education, and by ultimately getting people comfortable: “We know from large global studies, like the DAWN Study, that type 2 patients, in particular, have a real fear of insulin. The DAWN study highlights that patients’ reluctance to use insulin is underpinned by psychological fears that are often founded on myths and misconceptions. The AADE put a finer point on it in its 2011 Strategies for Insulin Injection Therapy in Diabetes Self-Management; we need to address the real and perceived patient, provider and system barriers to initiating and optimizing insulin dosing. This is where we believe we differentiate ourselves. We’ve developed specific learning objectives from expectations setting, insulin basics, insulin administration, etc. and deliver education and support to patients in real-time as they’re using the app. We supplement the education with trivia questions and proprietary educational videos to try and make the system as engaging as possible.”

iSage Rx Screenshots

Provider View

Patient-Facing App

3. Amalgam Rx has begun recruiting for an initial proof of concept clinical trial to demonstrate the product’s ability to bring patients to optimal dose and improve outcomes. We couldn’t find the trial on clinicaltrials.gov, but it will aim to enroll ~30 patients in the intervention arm with a matched, retrospective control arm according to Mr. Sysko. He expects that the study will wrap up this year and hopes that the company will have data to share in 2018 (ATTD? ADA?). In addition, Amalgam Rx is designing a larger pivotal study that will include this basal only version, along with in-the-pipeline basal+GLP-1 and basal-bolus algorithms. To date, the company has already conducted multiple rounds of human factors testing with 30+ patients, and the main feedback is that it is “SO easy” to use.  

4. The developmental timeline for iSage Rx is quite remarkable: Amalgam Rx was founded in 1Q16, and FDA granted 510(k) clearance in March 2017, putting the whole process at about one year. The FDA review was nine months (submitted in ~June 2016), meaning the whole app and HCP backend was built and submitted to the FDA in just four months! We were amazed by the timeline, but Mr. Sysko casually maintained that it’s not a huge app (“this is just Google Maps, a highly specific feature, one component of insulin delivery”), and that he and his team didn’t have to invent any algorithms – they leverage published dose titration algorithms like ATLANTUS. Further, he touted great, open lines of communication with FDA that allowed both sides to brainstorm and address potential challenges along the way. Still, just over a year from inception to first product launch is an incredible feat, even for such an experienced team.  

• Noted Mr. Sysko on the FDA process: “It was close to a nine-month process. The last few months required a lot of discussion and interaction with the agency. Overall, we were really pleased with the agency’s willingness to work with us to find solutions to challenges that were raised throughout the process. It wasn’t easy or simple, but we appreciated the agency’s approach to working with us. In many respects, we simplified the regulatory process by starting with publicly available algorithms in our initial filings. The core algorithms have been studied with thousands of patients, with one of the studies dating back to 2002-2003. The data from the published manuscripts show the algorithms to be safe and effective. In fact, many of them are included on the insulin manufacturers’ FDA labeling; there’s nothing confidential or proprietary about the algorithms. The regulatory challenge was how to digitize them and allow a provider to control multiple safeguards through the online prescription process and ongoing use of the product. As we move forward, we’re focusing on using machine learning and other data science techniques to create adaptive, dynamic and personalized algorithms that take into consideration a patient’s glucose response to their recorded doses. We always viewed the FDA process as requiring two-steps: Step one, get our foot in the door and develop a deeper understanding of the Agency’s requirements relating to titration and, step two, leverage our understanding of the Agency’s requirements to enhance our treatment protocols.”

5. Said Mr. Sysko in a call, “We don’t want to be the operating system for type 2 diabetes. Our ultimate goal is to become the “Intel Inside”; to provide insulin titration as a service.” Aka, while the app can stand alone, Amalgam Rx would ultimately like to see iSage incorporated into a variety of platforms from many different types of organizations. To make this possible, the young company has created SDKs and APIs to allow partners to easily integrate iSage into their own products (potential partners can learn more at www.isageapp.com/partners). According to Mr. Sysko, Amalgam plans to announce at least one partnership with a life sciences company this year. Similarly, because iSage is launching solo, it requires manual entry of blood glucose and insulin dose data for now, but the company already has agreements with “several” companies and expects BGM and CGM device integration to be cleared by the FDA this year. Multiple integrations with dose capture devices are expected in 2018.

• We imagine a range of partners could benefit from the FDA-cleared insulin titration platform: insulin companies (Novo Nordisk, Lilly, Sanofi), BGM/CGM players (Abbott, Ascensia, Dexcom, J&J, Medtronic, Roche), data management/app/coaching companies (Glooko, Livongo, mySugr, One Drop), connected pen players (BD, Companion Medical, Common Sensing), etc.

6. In the short term, Amalgam will work with providers, health systems, payers, and PBMs to drive adoption and generate real-world efficacy data. Since iSage is prescription-only, a direct-to-consumer model is unlikely. The company hopes to operate within a value-based framework, where it receives payments based on outcomes – Mr. Sysko noted that A1c and/or fasting blood glucose levels are two natural starting points. The software-as-a-service model makes a lot of sense here, especially if Amalgam can show outcomes relatively quickly and get payer or insulin company buy-in.

7. Though this initial product launch entails only basal insulin titration, Amalgam Rx hopes to have basal + GLP-1 titration cleared in the next 60 days and basal-bolus cleared by the end of the year. Wow! If these timelines are met, then Amalgam may be the first to offer this three-product titration portfolio. (Voluntis has basal-only and basal-bolus, but we’re not sure about basal+GLP-1.) A large pivotal study that is currently being designed will include all of these insulin systems.

8. Mr. Sysko and Dr. Clough (a brother-sister duo!) were two of three cofounders of WellDoc back in 2005, where Mr. Sysko then served as CEO and Dr. Clough as CMO for many years. Both clearly have ample experience building clinically-validated digital Health tools, and have shown proficiency generating outcomes at WellDoc (both in the clinic and real world) and forging critical bonds with payers and FDA. Plainly, they know the field. We don’t know anything about the rest of the company’s size or sources of funding. Amalgam held a small seed round previously with backing only from private individuals. The team plans to hold another round this year to raise additional funds, and also has an existing revenue stream from a current undisclosed partnership. The press release notes that the team is led by physicians, behaviorists, technologists and digital health pioneers, but Mr. Sysko only disclosed that the team is small and that BCG’s Chris Bergstrom (a former colleague at WellDoc) is an advisor. We can’t wait to learn more about the personnel under the hood of this company…

• What would be a 2017 homerun for Amalgam? 2018? 2019? Mr. Sysko: “There are a few dimensions that will define success for Amalgam in 2017. First, from an iSage perspective, we want to build the infrastructure for future success (e.g., demonstrate efficacy, integrate with devices, integrate with EMRs, work with payers/providers, etc.). Second, we want to continue to execute and grow our non-diabetes partnerships. I think that success in 2018 and beyond will be determined by our ability to effect change in patients’ outcomes at scale which ultimately will be the standard for all digital health products.”

9. One of our initial questions was: Why not build the titration service within WellDoc? Amalgam’s responses suggested that, while WellDoc is focusing on growing BlueStar and now going direct-to-consumer with BlueStar C, Mr. Sysko and Dr. Clough wanted to develop clinically and behaviorally validated products that could more easily achieve scale. While they are still passionate about the WellDoc mission, they feel that they can scale more quickly by enlisting large life sciences/pharmaceutical companies (as well as payers, employers, and PBMs), which “have largely been on the sidelines.” They also emphasized WellDoc’s broader focus on chronic disease, which will enable the company to optimize medication and provide support and education in other disease areas. We also like the idea of focusing a company on insulin titration, an area with so much potential and so much need for innovation.

• Said Mr. Sysko: “As you can read from WellDoc’s press releases, the company is focused on commercializing BlueStar and BlueStar C. Last year, as Suzanne and I began to discuss “what’s next,” we felt like we were ready to focus on new projects. We’re both still so passionate about and believe in the potential for digital health to transform the way that care is delivered and we wanted to apply our knowledge of clinical and behavioral technology platforms in new and different areas. One of the major challenges we wanted to solve was developing clinically and behaviorally validated products that could more easily achieve scale. In order to do so, we felt like we needed to find a way to tap into the large scaling mechanisms in healthcare. As it relates to digital therapeutics, our perspective is that many of those scaling mechanisms, including life sciences/pharmaceutical companies, have largely been on the sidelines. Pharma companies have built lots of tracking and adherence apps but haven’t invested heavily in broader self-management support. Part of our mission is to work with life sciences companies that want to move “beyond the pill.” Our team brings so much experience from a development, testing, regulatory, and commercialization perspective that we think we can be an accelerant. Insulin titration fit into the central thesis we were developing: targeting digital therapeutics that leveraged clinical and behavioral science to improve patient outcomes and cost while, at the same time, create the potential to significantly impact the P&L of life sciences companies. If we can get patients to not only take their medication but also optimize their therapy, we have the opportunity to create a massive win-win throughout the healthcare ecosystem.”

10. The press release notes that iSage is the first of several new digital therapies being developed. In fact, Amalgam Rx is actually a holding company with multiple subsidiaries focused on different disease states. On our call, CMO Dr. Suzanne Clough teased that the next project will be designed to build resilience, social connection, confidence, goal-setting, and coping strategies for people with chronic disease. The emphasis for this application will be strictly on the human – there will be no regulated aspect, just literature-backed modules to improve stress, gratitude, and positivity. How awesome! Dr. Clough said that while some pharmaceutical companies might call this “soft,” she is amazed at the beneficial physiological impacts mindset can have. (Read a lot more on this in Adam’s upcoming book, Bright Spots & Landmines!)

Insulin Dose Titration Landscape

• Below is a non-exhaustive landscape of players currently delivering or hoping to bring insulin titration to the market. The landscape is certainly heating up (we didn’t even include smart pens/caps), but we are certain that there is ample room for many of these companies to be successful, and we love the degree of partnering.

-- by Brian Levine, Adam Brown and Kelly Close