New Hope for Diabetes: A Discussion with Dr. Simi AhmedNews
This November, National Diabetes Month yielded some early holiday cheer as the FDA approved an exciting preventative treatment for type 1 diabetes (T1D). This work was spearheaded by JDRF, a leading type 1 diabetes research organization, alongside its partners. To get the inside scoop on this breakthrough, we sat down with NYSCF’s own Simi Ahmed, PhD, who spent 10 years at JDRF prior to joining the NYSCF team. During her tenure, Simi led JDRF’s portfolio in Disease Modifying Therapies for T1D, with significant emphasis on developing immune therapies to impact disease course.
First of all, congratulations to you and to everyone who helped make this happen! Could you tell us a little bit about this new treatment; what is it and how does it change the paradigm for type 1 diabetes treatment?
Tzield, or Teplizumab is an antibody that binds to a molecule (CD3) on the surface of a type of immune cell, called an ‘effector T cell’, which mistakenly recognizes and kills insulin-producing beta cells in the pancreases of type 1 diabetic subjects. By binding to CD3, Tzield de-activates the T cell and can trigger an extended immune protective state in the body by rendering these cells ‘exhausted’ and therefore unable to effectively carry out beta cell killing.
The approval of Tzield is a watershed moment for T1D on many levels. First, it is approved for Stage 2 disease, which means it will be administered before clinical onset/diagnosis, which is a high bar for regulatory approval and a tremendous achievement for the clinical community.
Second, it is approved for ages 8 and older, which means it includes the pediatric population. This is profound. The calculus for ascertainment of prospect of direct benefit in the pediatric population – in other words, the risk to benefit ratio, as it pertains to approval of any drug for this group – is non-trivial for any stage of disease, and a huge feat.
And third, perhaps most gratifying to me as an immunologist, is the unambiguous validation through this approval that if one can effectively fix a misbehaving immune system, one can basically fix autoimmune disease (and any other disease that involves immune related aberrations at its core).
What would you say is the most remarkable thing about this drug?
What is truly remarkable about this achievement is that, as the first drug approved for T1D, Tzield has already overcome aspects of some of the perceived challenges within drug approval for the field. It validates the T1D scientific community’s long-standing conviction of the power of disease modification – one that has fueled decades of tireless effort – centered on the premise that targeting autoimmunity therapeutically at the earliest stages, when the mechanisms of disease unleashed have not yet given rise to symptoms, ought to produce a tangible clinical outcome (with Tzield, specifically, slowing down disease process; perhaps even permanently halting progression in some).
In my mind, this achievement is also a celebration of the regulatory process, whereby thoughtful, and data-supported approval for the full age range of subjects who stand to benefit from a drug (including pre-symptomatic pediatric subjects!) should stand as a beacon of hope for the approval path of future disease modifying and/or curative therapies for T1D. The floodgates for the next bench-to-bedside journeys are now finally open for T1D therapies and should be embraced with much enthusiasm by the entire community committed to preventing and curing this disease.
Translating basic research into clinical outcomes is a long and difficult endeavor. What were some of the main challenges that the team faced throughout this process?
Thank you for asking this question. In many ways the story of Tzield feels bigger than Tzield itself. This therapy was pioneered by scientists early in their careers who are now leaders in the T1D field: Jeff Bluestone, Kevan Herold, and Lucienne Chatenoud. Grants from funding agencies such as JDRF enabled these pioneers to collect early data in preclinical models using teplizumab and subsequently in multiple small trials involving newly diagnosed (Stage 3) T1D subjects that indicated potential slowing down of pancreatic beta-cell decline in responders. The drug was licensed by Macrogenics, who subsequently entered a co-development partnership with Eli Lilly including sponsorship of a phase 3 trial (PROTÉGÉ) that did not meet its endpoint, due to multiple considerations, including trial design. Unfortunately, at that time (2010) development of this drug was discontinued.
It’s impressive that JDRF was able to bring this drug ‘back to life’ so to speak, how did that happen?
In the decade that followed, multiple non-commercial stakeholders, including funding coalitions (JDRF, NIAID funded Immune Tolerance Network (ITN), NIDDK funded TrialNet, ADA), scientists and clinicians committed to conducting and completing clinical studies with teplizumab, exploring treatment cohorts accompanied with extensive mechanistic and clinical analysis to generate critical data to further elucidate that type 1 diabetics can respond to this therapy and for those who respond, the T cell exhaustion signature is clearly detectable. It is during this period that the TrialNet prevention trial with Teplizumab in Stage 2 subjects was launched.
In the 2017-2018 period, and with the blessing of fortuitous timing, venture philanthropy in the form of the JDRF T1D Fund came into play with equity funding to Provention Bio who acquired exclusive license to Teplizumab from Macrogenics and launched a newly designed phase 3 trial in Stage 3 T1D called PROTECT (nearly a decade since the reporting of PROTÉGÉ), which is currently ongoing. The seminal outcome from the Stage 2 TrialNet trial was reported in the NEJM in 2019 and kicked off the process that led to today’s approval for the use of Tzield in preventing symptomatic disease.
In recent times, Sanofi has entered into a partnership with Provention Bio for further development of Tzield, hopefully ensuring its continued trajectory into the commercial realm with access and affordability that must now become front of mind. Interwoven within all these integrated and coordinated efforts have been numerous meetings of stakeholders with the FDA, where the voice of the patient held a central space and was ever well received alongside science.
Quite an odyssey! Do you think there’s a bigger lesson here for the broader biomedical community?
As I reflect on this journey that I was privileged to be part of during my tenure at JDRF, I cannot but marvel at the power of partnership and a community coming together to keep hope alive, to never give up, and to strategically build foolproof data packages with advocacy at the helm, all of which ultimately shepherded this therapy to the finish line and placed it firmly in the hands of commercial developers. It takes a village!
So where do we go from here? What are some of the most promising research avenues for a permanent cure?
The future of T1D therapies shows me endless possibilities and the opportunity to meet still unmet needs for cures. First, for those with established disease, who have pretty much lost all or most of their functional beta cells, an immune therapy like Tzield will not be of help. For these subjects, there is need to replace lost beta cells or to regenerate or transdifferentiate other pancreatic cells into beta cells inside the human body. Regenerative medicine, therefore, is a necessary and still unmet cure for those with advanced disease.
In addition, it might be clever to safely modify the replacement cells to enhance their survivability. For example, the cameo cell technology that NYSCF is developing may allow insulin-secreting cells to evade the immune system altogether and be suited for universal recipients without the worry of short or long term rejection. For earlier stages of T1D, I strongly believe that combination therapy potentially involving beta cell and immune targeted therapies will be the way to go.
Are there any other treatments we should look for in the near term?
I am encouraged by the diverse monotherapy candidates for T1D that are approaching or are already in clinical testing at this time. With novel preclinical and clinical development strategies, combination therapies that address different pathogenic features of T1D should be on the horizon far in advance of the lengthy road it took for Tzield. In addition to combination therapies, the regulatory path for cell replacement therapies and in-vivo regenerative therapies will be the next challenge to overcome.
If anything, Teplizumab has shown us that we must convene in true partnership from all corners of our ecosystem to make cures for T1D (and all incurable diseases of our lifetime) a reality. I firmly believe that effective partnership among scientists, clinicians, nonprofits like NYSCF, JDRF, government funders, and the commercial, regulatory, and reimbursement sectors will become the cornerstone for getting future cures to patients in the most effective, efficient, and equitable manner.