The Age of Teplizumab: A New Era in Type 1 Diabetes

The fight to cure diabetes.

A phrase steeped in hope and optimism but uttered for too long and by too many.

Among those in the diabetes community, the fight for a cure has been a seemingly endless journey, often without a glimmer at the end of the tunnel. The journey has been so arduous, many in the community have begun to reference the phrase “a cure for diabetes is 5 years away” with a tongue in cheek mannerism.

Not because the need is no longer as pressing, but because, despite all the advances in medicine and technology, some in the community have heard this same platitude for more than half a century.

Although the story of type 1 diabetes management has undergone revolution upon revolution in the last several decades, which includes marked advances in insulin analogs as well as the introduction of metformin and newer antihyperglycemic agents, the most notable advance within the field is now more than 100 years old, with the successful isolation of the insulin hormone by Sir Frederick Banting and Charles Best in 1921.¹

The First Milestone

History would come to know Leonard Thompson, then a 14-year-old boy, as the first human to receive insulin in 1922 at Toronto General Hospital. In a dire state, Thompson presented malnourished, dehydrated, and stricken with diabetic ketoacidosis, all of which was common among people with type 1 diabetes at the time as they were often relegated to a starvation diet in an attempt to prolong their life expectancy.

With insulin injections, Thompson’s condition improved and he went on to live for another decade. Following this successful demonstration of the potential of insulin as a treatment for type 1 diabetes, Banting, along with colleague Professor John Macleod, received the Nobel Prize in Physiology or Medicine in 1923. To this day, it remains among the quickest turnarounds from discovery to awarding of the Nobel Prize.¹ By the time Banting and Macleod received the award, mass production of insulin had begun and the course of management had been altered forever.

In November 2022, the diabetes community was able to bear witness to an announcement at least a decade, but possibly more than 100 years in the making, with the US Food and Drug Administration’s approval of teplizumab (TZIELD) for delaying the onset of type 1 diabetes.² Though not a cure, the advent, and subsequent approval, of teplizumab represent a new era in type 1 diabetes management—an era that now includes prevention.

“I would do it for every patient I've ever seen.”

Despite the countless hours and money on research, the exact cause of type 1 diabetes remains unknown. An Fc receptor–nonbinding anti-CD3 monoclonal antibody, teplizumab’s mechanism of action is not yet fully understood either, but early clinical trials have demonstrated the agent’s ability to T lymphocytes and reduce the loss of beta-cell function in patients with type 1 diabetes.

Delivered via daily infusions over a 14-day period, initial results of the pivotal trial used in approval demonstrated use of the agent was associated with a median time to diagnosis of 48.4 months compared to 24.4 months in placebo arm. In a median of 2 years of follow-up, type 1 diabetes was diagnosed in 43% of teplizumab arm and 72% of placebo arm (HR, 0.41 95% CI, 0.22-0.78; P = .006).³ In extended follow-up data, investigators found the median time to clinical type 1 diabetes diagnosis was 59.6 months with teplizumab and 27.1 months with the placebo. In a median of 2.5 years of follow-up, type 1 diabetes was diagnosed in 50% of the teplizumab arm and 78% of the placebo arm (HR, 0.457; P=.01).⁴

For many trials, more than 50% of people randomized to an intervention going on to develop disease would be looked at as a failure. This alone made interpretation of the results difficult, but those familiar with the plight of type 1 diabetes saw the results as tremendous success with the potential to usher in a new era of care.

“Patients with diabetes, they think about their diabetes a lot. Every time they want to go to exercise, every time they eat, every time their body changes, or they have illness, they're under stress, when they're hydrated, when they're dehydrated,” explained Natalie Bellini, DNP, an endocrine nurse practitioner with R&B Medical Group.⁵ “There's so many decisions and, if we could take this away for 2 years, 3 years, 4 years, 5 years, maybe 10 years down the line. I would do it for every patient I've ever seen.”

A Winding Road to Approval

The road to launch for teplizumab was not a simple runway. Since the launch of the TN-10 At-Risk trial in 2009, the journey to approval featured bumps, hurdles, and turns to the point many were concerned it might halt the agent’s progress before it could be fully realized.

Initial results of the phase 2 trial were met with applause at the American Diabetes Association’s 79th scientific sessions and published in the New England Journal of Medicine in June 2019. Following the submission of a Biologics License Application (BLA) in January 2021⁶, Provention Bio’s anti-CD3 monoclonal antibody was the subject of an Endocrinologic and Metabolic Drugs Advisory Committee Meeting scheduled almost 2 years after the initial presentation at ADA 2019 and just over 3 months after follow-up data was published in March 2021.This meeting concluded with a 10 to 7 vote in support of teplizumab.⁷ However, this renewed excitement was short-lived, with Provention Bio reporting the receipt of a Complete Response Letter from the FDA in July 2021. In the CRL, the regulatory agency expressed concerns centered around the pharmacokinetic comparability.⁸

Provention Bio would go on to resubmit their BLA in February 2022.⁹ At the time of acceptance in March 2022, the FDA set a PDUFA date for the agent of August 17, 2022.¹⁰ After a June 2022 announcement disclosing the FDA’s decision to extend its review period by 3 months, teplizumab PDUFA date was extended to November 17, 2022, which would eventually become the day of the agent’s approval.²

The Road Ahead

With an option for delaying the onset of type 1 diabetes available, the most pressing and immediate need becomes the need for optimal education on the staging of type 1 diabetes. The specific language of the US FDA’s approval for teplizumab indicates teplizumab for delaying the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older who currently have stage 2 type 1 diabetes.²

At the current time, rates of type 1 diabetes are rising and as the community struggles to understand the cause, for many outside of endocrinology, staging of type 1 diabetes is a foreign idea.

• In Stage 1, individuals test positive for 2 or more diabetes-related autoantibodies. There are no symptoms and blood sugar remain normal.
• In Stage 2, individuals still have no symptoms of type 1 diabetes. These individuals will have 2 or more diabetes-related autoantibodies, but loss of beta cells is contributing to irregular blood sugar levels.
• In Stage 3, individuals generally show symptoms of type 1 diabetes, including frequent urination, excessive thirst, weight loss, and fatigue. At this stage, significant beta cell loss has taken place and is typically when a diagnosis of diabetes will take place.¹¹

This is just part of the issue surrounding education on type 1 diabetes. The other is a lack of awareness of at-risk populations and should be considered, which goes beyond those with an immediate family history of type 1 diabetes and with other autoimmune disorders and those with certain genes.¹² Further compounding these issues is a lack of knowledge on organizations that provide testing services can further compound this issue and highlights the role of optimized clinical processes in fulfilling the potential impact of teplizumab’s approval.

“In the [American Diabetes Association] Standards of Care, they talk about the different stages and there is also a couple of recommendations about screening,” said Diana Isaacs, PharmD, an endocrine clinical pharmacist and coordinator of the CGM Program at the Cleveland Clinic, in reference to the Standards of Care in Diabetes—2022.⁵ “And I imagine these could change now that we have a drug that can actually be used to delay type one diabetes. In the past, it was like, ‘Yes, you can screen and be more aware and pay closer attention’, but without any action that you could take, it was kind of harder to justify the screening.”

As with most medical advances, access and barriers related to cost became a primary concern regarding the potential uptake of teplizumab soon after the excitement from approval reached a fever pitch. In a conference call the day following FDA approval, Prevention Bio executives revealed the expected cost of a course of teplizumab: $200,000.¹³ Provention Bio announced the creation Provention Bio COMPASS of a patient support program that helps patients to gain access to TZIELD and provides patients with education and resources.¹⁴

Regardless of price or education needs, the approval of teplizumab represents the most significant achievement in type 1 diabetes since the discovery of insulin by Banting and Best more than a century ago and an impasse for a community already stretched thin by current demands.

As it stands, the community has the opportunity to wash away the tongue-in-cheek mannerism that has accompanied talk of a cure in recent years and renew hope around the fight for a cure for the current and future generations. The same way insulin altered the course of type 1 diabetes, the advent of teplizumab has the potential to usher in a new era in type 1 diabetes. The proposed opportunity with teplizumab has a hypothesized benefit for society directly commensurate with the effort put forth into education and access initiatives related to uptake.

In 1922, Banting and Best treating Thompson with insulin changed type 1 diabetes from a death sentence to a chronic, but manageable illness, which was inconceivable to many at the time. In 2022, teplizumab paves the way for a similarly revolutionary idea that, for the first time, type 1 diabetes might become a preventable disease.

“The idea of disease prevention and disease modifying therapy is really exciting,” said Emily Sims, MD, who served as an investigator on the pivotal trial for teplizumab and is an associate professor of pediatrics and physician scientist with the Center for Diabetes and Metabolic Diseases and the Herman B Wells Center for Pediatric Research at IU School of Medicine.¹⁵ “You can imagine it might really change the way we treat people with type 1 diabetes and those at high risk for developing the disease. This is just the beginning.”

References

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4. ^{Sims EK, Bundy BN, Stier K, et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Science Translational Medicine. 2021;13(583). doi:10.1126/scitranslmed.abc8980}
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8. ^{Provention Bio Receives complete response letter (CRL) to Biologics License Application (BLA) for teplizumab for the delay of Clinical Type 1 diabetes (T1D) in at-risk individuals. Provention Bio | Investor Relations. https://investors.proventionbio.com/2021-07-06-Provention-Bio-Receives-Complete-Response-Letter-CRL-to-Biologics-License-Application-BLA-for-Teplizumab-for-the-Delay-of-Clinical-Type-1-Diabetes-T1D-in-At-risk-Individuals. Published July 6, 2021. Accessed December 13, 2022.}
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