JDRF and Sanofi announce expanded collaboration to support development of glucose-responsive insulin – February 25, 2016

JDRF and Sanofi just announced an expansion of their type 1 diabetes research collaboration (first announced in 2010) to include support for four researchers developing novel glucose-responsive insulin (GRI) approaches. The organizations will invest up to $4.6 million over three years to fund projects by Drs. Alborz Mahdavi (Protomer Technologies, Pasadena, CA), Christoph Hagemeyer (Monash University, Melbourne, Australia), Zhen Gu (North Carolina State University, Raleigh, NC/UNC Chapel Hill, Chapel Hill, NC), and Danny Chou (University of Utah, Salt Lake City, UT). The approaches range from engineered glucose-responsive insulin analogs (Drs. Mahdavi and Chou) to a glucose-responsive insulin patch (Dr. Gu) to glucose-sensing nanoparticles (Dr. Hagemeyer). According to Dr. Sanjoy Dutta (JDRF Associate VP for Translational Development), this initiative began as a solo JDRF RFA, but Sanofi approached JDRF during the review process and expressed interest in becoming involved. Both Dr. Dutta and Dr. Philip Larsen (Sanofi Global Head of Diabetes R&D) emphasized that JDRF and Sanofi will provide research and technical support in addition to funding, particularly since some of the investigators are fairly new to diabetes.

Dr. Dutta expressed great excitement about glucose-responsive insulin research during our conversation, noting that the area has long been a priority for JDRF and has attracted increased interest in the field in the past couple of years. He also emphasized that JDRF is “absolutely” open to other collaborations in this area and hinted that more announcements may be on their way in the next few months.  He suggested that JDRF’s goal is to build a “robust pipeline” of potential glucose-responsive insulin approaches (from this collaboration and others) within the next few years and then identify the most exciting/feasible candidates to move into clinical development. As Dr. Larsen noted, all of these projects are currently at a very early stage, and much exploratory research is needed to understand safety in particular. We are encouraged to see renewed efforts in this area following a number of years with little visible activity and hope that this potentially game-changing product can finally come to fruition.

• The selected researchers are all relatively young and new to diabetes – Dr. Dutta noted that bringing in “fresh blood” was one of the goals of the initiative. Drs. Gu and Chou have both published preclinical results for their glucose-responsive insulin approaches within the past year. Dr. Gu was a 2015 ADA Pathway grant recipient and published promising results for his smart insulin patch in a mouse model of type 1 diabetes in July. Dr. Chou was an earlier recipient of a prestigious JDRF post-doctoral fellowship; his synthetic glucose-responsive insulin formulation also demonstrated positive results in a mouse model in a paper published in February 2015. Drs. Mahdavi and Hagemeyer are newer to the field, though Dr. Mahdavi was one of three winners of the 2013 JDRF GRI Grand Challenge Prize (see more below). He wrote his PhD thesis on an innovative approach to protein modifications and founded the startup Protomer Technologies to translate that approach into therapies. Dr. Hagemeyer has fairly extensive experience in nanobiotechnology but has only recently ventured into diabetes with the goal of developing glucose-sensing nanoparticles.
• Dr. Mahdavi previously won JDRF’s Glucose-Responsive Insulin Grand Challenge Prize. The competition was announced in 2011 in partnership with crowd-sourcing company InnoCentive with a $100,000 total prize funded by the Agnes Varis Charitable Trust. The aim of the challenge was to solicit and identify novel theoretical ideas for a smart insulin, but it did not involve any preclinical or clinical research. Three winning ideas were announced in 2012, including one from a partnership between Dr. Mahdavi and Dr. Mohsen Chitsaz, who were both graduate students at CalTech at the time. The other two winning ideas were submitted by Dr. Luz Blanco (who has since joined the NIH and was unable to participate in the JDRF/Sanofi RFP due to her new position) and a team consisting of Drs. Xi Chen and Siqian Feng (who were doctorate fellows at the time and have now gone on to pursue fields outside of diabetes). The winning ideas themselves were not disclosed at the time and it’s unclear if Dr. Mahdavi’s current project is based on his idea from the theoretical challenge. While we are disappointed that the other winners are no longer involved in the diabetes field, we’re heartened to see Dr. Mahdavi’s continued commitment.
• The smart insulin field is beginning to heat up with Lilly’s acquisition of start-up Glycostasis’ technology earlier this month. The technology was invented by Dr. John Mulligan through the Urban Innovation Center at the Pacific Northwest Diabetes Research Institute (PNDRI), an “incubator” for biotech companies. Details on the acquired smart insulin are scarce, with the PNDRI announcement stating only that the technology aims to regulate blood glucose through glucose-responsive variations in insulin activity independent of patient input. This description could apply to anything from a newly bioengineered insulin molecule or a novel glucose-responsive delivery system. Lilly did not release an announcement on the acquisition and has not added any candidates to its clinical development pipeline (though we imagine the technology is in the very early preclinical stages). It’s unclear what Dr. Mulligan’s level of involvement will be moving forward. According to his LinkedIn page, he has founded a slew of small biotechnology companies in the last two decades and founded a new company – Good Therapeutics – just last month. It appears that the smart insulin research with Glycostasis has been his only diabetes-related project.
  
  • Lilly previously partnered with JDRF to fund a grant for research toward a glucose-responsive insulin. Grants through this partnership can be as high as $110,000 per year (innovative applications) or $200,000 per year (strategic research agreements). Funding decisions for this program will be made in May 2016. Lilly will have first rights to license any candidates developed through this funding.
• Merck’s smart insulin candidate MK-2640 is currently the most advanced glucose-responsive insulin candidate in the competitive landscape. The candidate entered phase 1 clinical trials in November 2014. Merck’s candidate is an insulin-oligosaccharide conjugate in which the oligosaccharide component can variably block the insulin molecule from binding the insulin receptor depending on glucose levels. Management expressed optimism about the candidate at a 2014 Investor Briefing. However, according to ClinicalTrials.gov, the estimated completion date of the trial (n=74) has been moved back twice: first from July 2015 to January 2016 and most recently from January 2016 to March 2016.
  
  • Merck was an early adopter in the smart insulin field with its acquisition of SmartCells in 2010. SmartCells’ SmartInsulin first appeared on the radar way back in 2008 when it received $1 million in JDRF funding. The candidate was based on an engineered complex that holds insulin molecules with an insulin polymer conjugate. At the time of the JDRF funding, SmartCells planned on separate formulations for type 1 and type 2 diabetes and expected to move the formulation for type 2 diabetes in phase 1 clinical development by mid- to late-2010. However, the candidate remained in the preclinical stages when it was acquired by Merck and it appears that Merck’s phase 1 candidate is a different formulation. We have heard that Novo Nordisk has smart insulin programs underway as well, but the company has not commented publicly on those efforts in the recent past.
• A successful “smart” insulin would represent a serious challenge to closed-loop systems, but the time horizons for the two are very different. In our interview, Dr. Dutta emphasized that closed-loop systems are very close to the market and predicted that they will lead to very meaningful improvements for many patients. However, he suggested that if a “true” glucose-responsive insulin candidate can successfully make it through the many scientific, clinical, regulatory, and pricing/reimbursement hurdles ahead, it may be more appealing to some patients than a device-based solution. Another open question is how the timelines and target populations for “smart” insulin will stack up against those for cell replacement and immunomodulatory therapies for type 1 diabetes. Dr. Aaron Kowalski (JDRF Chief Mission Officer) offered an informative take on the landscape at Friends For Life last summer, predicting the arrival of closed-loop systems within five years, macroencapsulation and smart insulin within ten years, and a “walk-away cure” farther out.

Close Concerns Questions

Q: Will some of the proposed projects eventually be combined together?

Q: How much collaboration might the funded researchers have with each other?

Q: What other companies are thinking about entering the smart insulin field?

Q: The JDRF announcement focuses on type 1 diabetes. Will the potential smart insulin candidates also be developed for type 2 diabetes? Would type 2 diabetes require a separate formulation as SmartCells was pursuing?

Q: How do the potential timelines for smart insulin compare to the timelines for type 1 cure therapies like beta cell encapsulation and immunomodulation?

Q: Would smart insulin obviate the need for next-generation glucagon formulations?

Q: Will it become more common for pharmaceutical companies to enter into similar joint funding agreements to explore a wide range of early preclinical candidates while limiting personal risk?

-- by Helen Gao, Emily Regier, and Kelly Close