Objective
Zucara Therapeutics Inc. (Zucara) is developing a novel first-in-class therapeutic to prevent hypoglycemia (low blood sugar) for people with Type 1 diabetes (T1D), which is a primary barrier to optimum glucometabolic control, associated with worse health outcomes, and causes disruption to the lives of people with diabetes and their caregivers. Zucara believes that its therapeutic ZT-01, which recently completed Phase 1 safety and proof-of-concept studies will become an important adjunctive therapy to insulin to enhance glucometabolic control.
Study Objective:
The objective of the proposed trial is to show that ZT-01 can effectively reduce the extent to which people experience hypoglycemia in the overnight hours. These nocturnal hypoglycemia episodes are among the most troubling for people with T1D who struggle with low blood sugar. The trial seeks to show a reduction in the rate of hypoglycemia where blood sugar levels fall below 54 mg/dL, called “Level 2” hypoglycemia, which can cause uncomfortable symptoms, disrupt sleep, and impact morning blood sugar levels. Experiencing recurrent Level 2 hypoglycemia also puts one at risk for more severe potentially life-threatening episodes of hypoglycemia.
Clinical experts agree that Level 2 hypoglycemia should be avoided for optimal blood glucose control and have established a target of spending not more than 1% of time (<15 minutes/day) with this blood sugar level.
Our trial aims to reduce this occurrence and will test the drug’s effect in people struggling with nocturnal hypoglycemia, who have a recent history of experiencing at least 1 episode per week, on average, of Level 2 hypoglycemia lasting longer than 15 minutes between midnight and 6 AM.
Another objective of the trial is continued safety assessment of ZT-01. ZT-01 is in early development and its safety profile will be determined through all stages of human testing to fully understand its potential for unwanted side effects.
Overall, long term objective:
Testing the drug in a group with elevated risk for experiencing hypoglycemia will allow us to efficiently complete this first test for the efficacy of ZT-01. Success in this trial would support expanding the testing of ZT-01 to evaluate it in the broader general population of people with T1D. This first study focuses on nocturnal Level 2 hypoglycemia events; however, Zucara’s overall objective is to improve glucometabolic control overall for people with T1D. If the data from this Phase 2 study is supportive, future trial designs could also include reducing hypoglycemia rates occurring throughout the entire day, and reducing the occurrence of less severe “Level 1” episodes (ie blood sugar concentration <70 mg/dl) which can precede Level 2 hypoglycemia and should also be avoided. (Current recommendations from clinical experts is to spend <1¼ hours/day with Level 1 hypoglycemia). Effects over 24 hours, including both Level 1 and Level 2 hypoglycemia will be evaluated in an exploratory fashion in this first efficacy trial, but are not a primary goal at this stage of development.
In addition, severe (Level 3) hypoglycemia will not be evaluated in this first efficacy study. However later stages could include rates of severe episodes as well, and as reduction in Level 2 episodes can result in fewer future severe episodes, we are hopeful that this most troubling form of low blood sugar will also be preventable with treatment. Our long-term objective in developing ZT-01 is to reduce the overall burden of hypoglycemia for people with T1D, enabling improved glucometabolic control and better health for people with T1D.
Background Rationale
Zucara is developing a first-in-class drug for hypoglycemia prevention in type 1 diabetes (T1D) patients. Based on novel discoveries made by our company founders, we are developing a somatostatin receptor 2 (SSTR2) antagonist as a prophylactic therapy to improve defective glucagon counterregulation in T1D. They discovered that SSTR2 expressed on the alpha cell of the pancreas can inappropriately regulate glucagon secretion in T1D, resulting in reduced glucagon release in times of hypoglycemia leading to counterregulatory failure. They showed that this failure can be reversed by blocking the receptor. Based on this, we have developed a clinical candidate, ZT-01, to block the SSTR2 receptor.
The problem of hypoglycemia: Hypoglycemia remains a longstanding and significant barrier to optimum glycemic control in T1D. Fear of hypoglycemia affects ~70% of T1D patients, impacts self-care, and negatively affects metabolic control and quality of life. Hypoglycemia is not only worrying and dangerous for patients, it is linked with adverse vascular outcomes and dementia in older patients with type 2 diabetes (T2D) and poorer cognitive function with lower brain volume in T1D children. The incidence of severe hypoglycemia (requiring another’s help) ranges from 1-3 events/patient/year. Premature death where hypoglycemia is implicated is sadly also increased among people with T1D. Among the most troubling forms is nocturnal hypoglycemia (NH), which impacts all ages, can be prolonged, and result in seizures. NH has worse symptoms and impact on quality of life than daytime hypoglycemia and has been linked to “Dead in Bed” syndrome. Use of CGMs and insulin pumps offer some protection, but hypoglycemia remains a major concern for even the most vigilant. Our approach is to restore glucagon counterregulation in T1D.
Failed counterregulation: A major cause of hypoglycemia in T1D is defective hormone counterregulation when glucose levels drop below 70 mg/dL. Glucagon is normally the key early response hormone when glucose levels drop but its secretion is lost in T1D within just a few years of diagnosis. Counterregulatory failure occurs due to inappropriate signalling in the pancreas by a hormone called somatostatin which blocks glucagon release, despite people with T1D retaining healthy and functional glucagon-secreting α-cells in the pancreas.
We hypothesize that, ZT-01, a SSTR2 antagonist will normalize the glucagon response to hypoglycemia and help restore glucose homeostasis in T1D patients.
In progress to date, nonclinical studies of ZT-01 funded in part by a previous JDRF grant and completed in in 2018-20 have enabled the start of human studies. Toxicology studies of ZT-01 in rats and dogs established a safe initial dose for human testing, and pharmacology studies in rat models of T1D with a defective glucagon counterregulation system showed a dose-dependent effect to both increase glucagon secretion and reduce the frequency of insulin-induced hypoglycemia.
Based on our readiness to begin clinical development, Zucara raised $21M from the Perceptive Xontogeny Venture Fund in 2020, to complete Phase 1 and Phase 2 studies. Since this time, costs have increased as the design was refined resulting in a funding gap which this grant is aimed to address. We have completed three Phase 1 studies (2020-22) assessing the safety, tolerability, and pharmacokinetics of ZT-01, and demonstrated, in subjects with T1D, that glucagon secretion during hypoglycemia can be increased, resulting in counterregulation of glucose (ie trigger a rise in blood glucose levels during hypoglycemia).
Based on these positive results from Phase 1 studies, including our proof-of-concept study that restored glucagon secretion in nearly 90% of subjects, Zucara is preparing for a Phase 2 study to show the effect of ZT-01 in reducing the frequency of Level 2 nocturnal hypoglycemia (NH) in people with T1D who are at significant risk for these episodes.
Description of Project
Zucara Therapeutics Inc. (Zucara) is developing a novel first-in-class therapeutic to meet a significant unmet need for people with Type 1 diabetes (T1D): prevention of hypoglycemia (low blood sugar) due to insulin therapy. Hypoglycemia is a primary barrier to optimum glucometabolic control, associated with worse health outcomes, and causing disruption to the lives of people with diabetes and their caregivers. Zucara believes that its therapeutic ZT-01, which recently completed Phase 1 studies, will become an important adjunctive therapy to insulin to enhance glucometabolic control.
The proposed clinical trial focuses on nocturnal hypoglycemia (NH, occurring between midnight and 6 AM) which is among the most troubling forms of hypoglycemia, occurring frequently and impacting all ages. It causes worse symptoms and impact on quality of life than daytime hypoglycemia and can be fatal, as a precursor to sudden cardiac arrhythmia. Use of continuous glucose monitors (CGM) and insulin pumps offer some protection, but hypoglycemia remains a major concern for many.
ZT-01 is a ready-to-use injection. It blocks the somatostatin receptor subtype 2 (SSTR2) present on alpha cells in the pancreas, allowing them to secrete glucagon in times of hypoglycemia. In turn, glucagon stimulates the liver to release glucose, effectively countering the glucose-lowering effect of insulin. Together these two hormones should ideally prevent both highs and lows, keeping blood glucose within the normal target range.
Too much somatostatin in the pancreas inhibits glucagon release, resulting in the impaired counterregulatory response to hypoglycemia observed in T1D. Accordingly, treatment with a SSTR2 antagonist may reverse this somatostatin effect, should increase glucagon secretion in hypoglycemia in patients with impaired counterregulation, preventing hypoglycemia events.
ZT-01 significantly increased glucagon secretion and reduced the frequency of hypoglycemia in multiple animal models. It has shown no systemic adverse effects in animal toxicology studies at doses many times higher than is used in human clinical trials. The most significant findings in animal studies were reversible reactions (such as inflammation) at the injection site.
Three Phase 1 studies have assessed safety and pharmacology of up to 30 mg ZT-01 single or daily doses in people with and without T1D. ZT-01 was safe and well tolerated, with no serious adverse events reported. Minimal or mild injection site reactions (redness, swelling and pain), resolved within a few hours after dosing. Injection site reactions tended to be more frequent and took longer to resolve at the highest dose tested.
In hypoglycemia intentionally induced with insulin, up to 20 mg ZT-01 increase glucagon release compared to placebo and evidence of increasing blood glucose was observed. Based on the positive results from these initial human trials, this Phase 2 trial will test the effect of ZT-01 on decreasing hypoglycemia rates.
The objective of this grant is to complete the Phase 2 trial of ZT-01 administered nightly at bedtime for 28 days, using CGM to show a significant decrease in the rate of NH in people at higher risk for NH, experiencing on average ≥1 NH event per week. Treatment will be compared to a placebo for each subject. Each subject will receive one of three dose levels tested in the trial, and a placebo. Order of treatment (active/placebo) and dose level for each subject will be randomized and blinded to both subject and study site personnel.
The trial will demonstrate a novel mechanism of action by which ZT-01 reduces hypoglycemia in T1D, and inform the design of larger scale Phase 3 trials of ZT-01 to further evaluate its efficacy. If successful, ZT-01 may offer a much-needed treatment option for better glucometabolic control in people with T1D who struggle with hypoglycemia.
Anticipated Outcome
In this grant, we propose to conduct a Phase 2 clinical trial of ZT-01, a first-in-class inhibitor of somatostatin receptor 2 which is hypothesized to prevent hypoglycemia in people with T1D. The trial will test a novel mechanism of action by which ZT-01 reduces hypoglycemia in T1D, namely that blocking somatostatin receptor 2 in the pancreas will enable normal glucagon secretion which is the body’s response to falling blood glucose levels, to avoid hypoglycemia. Based on promising data from rat models of T1D and Phase 1 human testing in people with T1D in which the glucagon response to hypoglycemia can be , and that blood glucose levels can be made to rise in hypoglycemia, we believe that nightly treatment with ZT-01 should result in a decrease in the rate of hypoglycemic events which occur while the subject is asleep, between the hours of midnight and 6 AM (“nocturnal hypoglycemia”).
We will evaluate the efficacy of ZT-01 in people with an elevated risk for experiencing nocturnal hypoglycemia. The Phase 2 trial will be designed to show at least a 30% reduction in the hypoglycemia rate, which is considered to be a clinically meaningful change. In addition to this primary measurement for the trial, we will also evaluate other metrics for overall control of blood glucose, and frequency and extent of hypoglycemia episodes. In addition, we will evaluate the safety of ZT-01. ZT-01’s safety profile will be determined through all stages of human testing to fully understand its potential for unwanted side effects.
Testing the drug in a group with elevated risk for experiencing hypoglycemia will allow us to complete this first test of ZT-01’s efficacy in a relatively small group of volunteers over a relatively short time. Success in this trial would support expanding ZT-01’s testing to evaluate it in the broader general population of people with T1D. This study focuses on nocturnal hypoglycemia events in which blood glucose drops below 54 mg/dL (defined as “Level 2” events), which can be symptomatic, and may precede a more severe future event. However, Zucara’s overall desired outcome is to improve glucometabolic control overall for people with T1D. If the data from early Phase 2 studies is supportive, future trial designs could also include reducing hypoglycemia rates occurring throughout the entire day, rather than only at night, and reducing the occurrence of less severe “Level 1” episodes (ie blood sugar concentration <70 mg/dl) which can precede Level 2 hypoglycemia and should also be avoided. Effects over 24 hours, including both Level 1 and Level 2 hypoglycemia will be evaluated in an exploratory fashion in this first efficacy trial, but are not a primary goal at this stage of development.
In addition, severe hypoglycemia (when symptoms are extreme, including a decline in cognitive ability such that assistance is required from a third-party, such as an emergency medical responder) will not be evaluated in this efficacy study. However later stage clinical trials could include rates of severe episodes as well, and as reduction in Level 2 episodes can result in fewer future severe episodes, we are hopeful that this most troubling form of low blood sugar will be preventable with this treatment. Our long-term objective in developing ZT-01 is to reduce the overall burden of hypoglycemia for people with T1D, enabling improved glycemic control and better health for people with T1D.
If successful, ZT-01 may offer a much-needed treatment option for better glucometabolic control in people with T1D who struggle with hypoglycemia.
Relevance to T1D
Hypoglycemia remains a longstanding and significant barrier to optimum glycemic control in Type 1 diabetes (T1D). Fear of hypoglycemia affects ~70% of T1D patients, dramatically impacts self-care, and negatively affects control of blood glucose, and quality of life. Hypoglycemia is not only worrying and dangerous for patients, it is linked with adverse vascular outcomes and dementia, and poorer cognitive function with lower brain volume in T1D children. As such, hypoglycemia risk is a mandatory study endpoint for new diabetes treatments. The incidence of severe hypoglycemia (requiring another’s help) ranges from 1-3 events per patient/year in T1D. Premature mortality where hypoglycemia is implicated is sadly also high in T1D patients; estimates range from 4-10% of all deaths. Among the most troubling forms is nocturnal hypoglycemia, which occurs while the subject is asleep, between the hours of midnight to 6 AM. Nocturnal hypoglycemia impacts all ages and occurs approximately 1 night out of 14 per patient, regardless of insulin injection mode. Severe nocturnal hypoglycemia can be prolonged, and result in seizures. Simply snacking at bedtime does not effectively prevent it. Nocturnal hypoglycemic events can go undetected (asymptomatic), even for long periods of time, or alternately (symptomatic events) can occur with worse symptoms than daytime episodes, resulting in even greater impact on quality of life. Nocturnal hypoglycemia has also been linked to “Dead in Bed” syndrome as a precursor to sudden cardiac arrhythmia. Use of continuous glucose monitors (CGM) and insulin pumps offer some protection but do not fully address the issue and it remains a major concern for even the most vigilant. Many CGM users remain bothered by frequent disruptive alarms at night, further interrupting sleep for people with T1D and their family members. Administering glucagon with insulin, in a bi-hormonal pump likely offers the best hypoglycemia protection in ‘pump users’ with T1D, but the uptake of this emerging technology may be low for several reasons. An alternate approach is to restore glucagon counterregulation in T1D. For severe episodes, glucagon rescue formulations are available, but there are no treatments available to prevent hypoglycemia from happening in the first place.
Zucara is developing a first-in-class drug for hypoglycemia prevention in T1D. Based on discoveries that implicate somatostatin, a hormone in the pancreas, as an important suppressor of glucagon release, we have been developing ZT-01, a somatostatin receptor 2 antagonist, which is hypothesized to restore glucagon release in hypoglycemia to allow for normal counterregulation of falling blood glucose levels. In T1D, it is well known, that within 5 years of diagnosis, patients develop a defective counterregulatory response. Therefore, a drug that aims to restore this defect should help to normalize blood glucose control for those with T1D.
This hypothesis is supported by pharmacology studies in multiple rat models of T1D in which a defective glucagon counterregulation system was restored and rates of insulin-induced hypoglycemia were reduced. These and other non-clinical data supported the start of human testing. Phase 1 studies in both non-diabetic and people with T1D have shown that ZT-01 was safe and well tolerated, and importantly, that glucagon secretion could be increased in insulin-induced hypoglycemia, and increasing blood glucose levels, evidence of counterregulation, was observed. Based on these positive results, Zucara is proposing in this grant project to conduct a Phase 2 study in people with T1D who are at elevated risk for nocturnal hypoglycemia, to demonstrate for the first time in humans that ZT-01 treatment can reduce the incidence of nocturnal hypoglycemia.