Memorandum

Dr. Jeffrey Bluestone on past challenges and future opportunities for anti-CD3 – February 3, 2016

Executive Highlights

  • Leading anti-CD3 researcher Dr. Jeffrey Bluestone (UCSF, San Francisco, CA) discussed the main factors contributing to the failure of the class in previous phase 3 trials in type 1 diabetes, his definition of success over the next five years, and the main obstacles standing in the way of future programs.

Our team had the opportunity to speak with highly regarded immunologist Dr. Jeffrey Bluestone (UCSF, San Francisco, CA) on the past and future of anti-CD3 therapies in type 1 diabetes. Dr. Bluestone was heavily involved in the development of the anti-CD3 therapy teplizumab with MacroGenics and Lilly (as disclosure, he retains a financial interest in the drug as part of an agreement with MacroGenics). The drug showed promise in early clinical trials but Lilly dropped it after the phase 3 Protégé trial failed to meet its primary endpoint in 2010. Tolerx/GSK’s otelixizumab met a similar fate, initially showing promise but missing its primary endpoint in the phase 3 DEFEND trial in 2011. Five years later, the field is fairly divided on whether this class is worth continued study. On the one hand, anti-CD3 therapies were once considered one of the most promising areas of immunological research in type 1 diabetes, and certain subsets of patients did respond well in the phase 3 trials. On the other hand, funders are understandably hesitant to invest in candidates that have already failed in phase 3, and others have expressed concerns about toxicity, at least at higher doses. In our interview, Dr. Bluestone expressed continued optimism about the class’ future and cited lack of funding as the main obstacle standing in its way. Read on for our top highlights from the conversation.

1. Dr. Bluestone suggested that a combination of external factors including recruitment, patient selection, and choice of endpoints contributed to the failure of past anti-CD3 trials.

2. Dr. Bluestone’s “home run” for the next five years would be a drug (anti-CD3 or otherwise) that stabilizes C-peptide production and slows disease progression in the majority of people with type 1 diabetes.

3. In Dr. Bluestone’s view, lack of funding is the main hurdle for anti-CD3 efforts at this point.

Top Three Highlights

1. Dr. Bluestone suggested that a combination of external factors including recruitment, patient selection, and choice of endpoints contributed to the failure of past anti-CD3 trials. He noted that the majority of patients in the Protégé trial were enrolled outside the US and EU. As a result, their baseline characteristics such as A1c and insulin production were different compared to the typical new-onset type 1 diabetes patient in Western countries. He also acknowledged that recruitment was very challenging, with over 300 sites and sometimes only one or two patients recruited at each location. Dr. Bluestone also noted that the recent progress in type 1 diabetes management can pose a challenge for clinical trials because the control group is too well-controlled in terms of endpoints like A1c. He advocated for the use of C-peptide production, measured using a mixed-meal tolerance test, as a major component of the primary composite endpoint in future trials. Finally, he explained that given the field’s increasing understanding of the heterogeneity of type 1 diabetes (“we’re learning over time that type 1 diabetes is not a single disease”), an ideal trial would use biomarkers as enrollment criteria to ensure a drug is being studied in the patients most likely to benefit from it. In this case, factors that predicted a good response in previous trials (younger age, to take one example) could be used as enrollment criteria for the next phase 3 trial.

2. Dr. Bluestone’s “home run” for the next five years would be a drug that stabilizes C-peptide production and slows disease progression in the majority of people with type 1 diabetes. Such a drug could then serve as a foundation to which additional treatments like antigen-specific therapies or drugs that target beta cells could be added. Dr. Bluestone firmly believes that combination therapy represents the future in type 1 diabetes, a sentiment we have also heard from others in the field. In his vision, an effective combination would contain (i) a drug that eliminates the pathogenic cells that are attacking beta cells; (ii) a drug that regulates the immune system to prevent pathogenic cells from reappearing; and (iii) a treatment that repairs or replaces beta cell activity. He believes the biggest hurdle at this point is developing a foundational drug that impacts one or two of these areas and that anti-CD3 agents represent one of the most promising approaches, though by no means the only one. He noted that it is difficult to evaluate the clinical efficacy of combination therapies without any previous approvals because the FDA’s safety concerns are so great. In his view, achieving an approval for the first compound could go a long way toward allowing studies of more innovative combinations.

3. In Dr. Bluestone’s view, lack of funding is the main hurdle for anti-CD3 efforts at this point. He remains confident that the existing data for the class is promising enough to warrant future studies and optimistic that a more appropriately designed phase 3 trial could produce better results. He noted that his efforts with MacroGenics to recruit sites for a future clinical trial of teplizumab have been fairly successful, with 36 sites in the US and Europe expressing interest. The main barrier has been an almost complete lack of interest from pharmaceutical companies or nonprofit funders to provide the estimated $40-$50 million that would be required for another phase 3 program. Dr. Bluestone acknowledged that some of this hesitation is quite legitimate – “investing another $50 million into a failed drug is not an enticing proposition” – but he also suggested that some of the negativity around the class is due more to misleading headlines than to the actual data. However, he remains optimistic that some companies or foundations will see it as essential to their mission to “take every shot they can” on a drug that has shown some real promise in type 1 diabetes. He also noted that anti-CD3 agents could also have potential for many other indications beyond type 1 diabetes, which could perhaps make the class more appealing to investors.

--by Emily Regier, Maxwell Votey, and Kelly Close