New clinical trials that repurpose drugs already approved by the US Food and Drug Administration (FDA) for other diseases could help preserve insulin production in people recently diagnosed with type 1 diabetes (T1D). Currently, the first trial, funded by the National Institutes of Health, is enrolling participants, and the second is well into the design phase, thanks to the generosity of UCSF donors and friends.
“There’s a pressing need to find something that fundamentally addresses the underlying cause of type 1 diabetes,” said Stephen Gitelman, MD, the Mary B. Olney, MD/KAK Distinguished Professor of Pediatric Diabetes and Clinical Research and director of UCSF’s pediatric diabetes program. “Currently, there is no drug approved after diagnosis that preserves beta cells and extends the remission or honeymoon phase.”
Dr. Gitelman notes that in a series of clinical trials conducted over the past few decades, researchers have had modest success with some monotherapy (single-drug) treatments that target the immune response.
During remission, beta cells in the pancreas continue to control blood sugar levels and produce the right amount of insulin for proper function. These therapies will extend the remission phase and preserve the beta cells, resulting in better overall blood sugar control and lowering the amount of supplemental insulin a patient may need.
“It's an incredibly exciting time. We're showing that we can alter the course of type 1 diabetes, but we need to find more robust and durable therapies that have more clinically meaningful outcomes,” Dr. Gitelman said. “Families dealing with type 1 diabetes want answers, and I want to eventually have a standard clinical treatment that can extend the honeymoon phase after diagnosis and preserve those precious beta cells.”
The Latest Clinical Study: T1D RELAY
When used by themselves, immune therapies such as rituximab (Rituxan) and abatacept (Orencia) have been shown to help delay beta-cell loss in people newly diagnosed with T1D. By combining these established drugs, researchers anticipate that people with new-onset T1D will have longer honeymoon phases during and potentially after treatment.
“What's unique about the T1D RELAY study design is, there's no placebo group,” Dr. Gitelman said. “You're randomized to either receive the combination of the beta-cell treatment (rituximab) followed by the T-cell treatment (abatacept), or rituximab followed by an injection of a placebo.”
The primary endpoint for most of these efforts is 12 months after study enrollment, but Dr. Gitelman and colleagues are now looking for a longer-lasting effect, with the primary endpoint at 24 months.
This novel combination therapy approach is also safe and effective in treating rheumatoid arthritis. Dr. Gitelman considers T1D RELAY as the first rationally designed combination trial in T1D, meaning researchers based the study on metabolic and immunologic analyses from previous studies on each drug alone.
“We studied the responses in people who've had these different drugs by themselves and realized that beta cells and T cells talk to each other and that by targeting each of these arms in the immune system, we expect a more robust, durable response,” Dr. Gitelman said. "That’s one foray into combination therapy, and we're very excited to see what we'll learn.”
Another Approach Boosted by Philanthropy
With philanthropic support, Dr. Gitelman and a team of investigators have agreed on a second promising approach that involves a combination therapy that includes an initial induction therapy phase followed by a maintenance phase. This method has not been tested in T1D.
They will first use a standard T-cell treatment called antithymocyte globulin (ATG), then follow up in the maintenance phase with either tumor necrosis factor-alpha (TNF-a), a mainstay therapy for various autoimmune disorders; or verapamil, a treatment previously approved for high blood pressure but that more recently has been shown to lower stress and improve the function of beta cells.
“Each of these therapies has been FDA-approved and evaluated as a monotherapy in new-onset type 1 diabetes, with promising results,” Dr. Gitelman said. “We think these novel combinations will be far more effective than any monotherapy effort conducted to date.”
While one-time treatments like ATG may delay disease progression, Dr. Gitelman said the effects wear off, and not everyone responds to it. He’s optimistic that the benefits of preserving beta cells will be especially impactful for newly diagnosed children and adolescents who want to return to their usual, carefree daily lives.
“If you look in other fields like rheumatoid arthritis, multiple sclerosis, or inflammatory bowel disease, combination therapies are the norm,” Dr. Gitelman said. “We’re now testing drugs that had modest success when used as a monotherapy to try to achieve an additive or synergistic response that is more meaningful clinically.”
With any study, the process of planning and then conducting a clinical trial is often long and slow; however, this trial is moving more quickly because of philanthropic contributions to UCSF investigators.
“Philanthropy really accelerates things for us – opening doors to important opportunities and allowing us to take on projects that may be higher risks but also offer higher potential rewards,” Dr. Gitelman said. “We’re getting there, but we still have important work to do.”
To learn more about the T1D RELAY study, call TrialNet at 800-425-8361. If you would like to contact UCSF about the study, email clinicalresearch@diabetes.ucsf.edu or call 844-813-8273. | 
