Our Development of a Glucagon Rescue Product
We believe that the complexity of the currently available rescue kits and the training required for proper administration of glucagon using those kits has resulted in the underuse of glucagon as a rescue treatment for diabetes patients experiencing severe hypoglycemia. We also believe that the development of room temperature stable presentations or liquid formulations of glucagon can overcome the limitations resulting from the rescue kits. In June 2013, we announced plans to develop a novel glucagon rescue product to treat severe hypoglycemia using a proprietary device from Unilife Corporation. The device, which is being customized for use in emergency situations by patient caregivers with no medical training, is a dual-chamber design that automatically reconstitutes lyophilized glucagon with a liquid diluent immediately prior to injection, and it features automatic needle retraction on full dose delivery. We expect to submit an Investigational New Drug application to the FDA for our dual-chamber glucagon rescue product during the next nine months and anticipate conducting a pivotal clinical trial in the second half of 2014. We are also using other proprietary technologies to develop a liquid glucagon formulation that does not require reconstitution and could, therefore, be administered using a pre-filled syringe in an autoinjector or similar device.
Development of Additional RHI- and Insulin Analog-Based Formulations
Based upon the complete response letter and subsequent feedback that the FDA provided to us, we decided to study newer RHI-based formulations in earlier stage clinical trials. After reviewing the results of a Phase 1 clinical trial of two newer formulations, BIOD-105 and BIOD-107, we determined that the overall pharmacokinetic and pharmacodynamic profiles of these formulations did not demonstrate our target product profile. We subsequently conducted a Phase 1 clinical trial of two additional formulations, BIOD-123 and BIOD-125, and announced top-line results from that trial in April 2012. We determined that both formulations achieved our target pharmacokinetic, pharmacodynamic and toleration profiles.
The Phase 1 clinical trial of BIOD-123 and BIOD-125 evaluated the pharmacokinetic, pharmacodynamic and injection site toleration profiles of these product candidates relative to Humalog ® , a rapid-acting insulin analog. The objective of the clinical trial was to identify an RHI-based formulation with pharmacokinetic and pharmacodynamic profiles similar to the Linjeta TM formulation, but with improved injection site toleration characteristics. The clinical trial was a single-center, randomized, double-blind, three-period crossover trial in 12 patients with Type 1 diabetes. Each study drug was administered subcutaneously on separate days with a washout period between injections. In the Phase 1 clinical trial, absorption rates of BIOD-123 and BIOD-125 were significantly faster than that of Humalog ® as indicated by 64% and 54% reductions, respectively, in mean times to half maximal insulin concentrations (p < 0.001 for both BIOD-123 and BIOD-125 compared to Humalog ® ). Both RHI-based formulations and Humalog ® were well tolerated, with injection site toleration generally perceived by patients to be similar to that of their usual mealtime injections used at home. As measured on a 100 mm visual analog scale, or VAS, in which 100 mm is defined as the worst possible injection discomfort, local toleration was not significantly different for BIOD-123 compared to Humalog ® (BIOD-123 mean VAS 3.6 ± 2.1 mm, Humalog ® 1.8 ± 1.1 mm, p=NS). The VAS score for BIOD-125 was slightly higher as compared to Humalog ® (mean VAS 6.8 ± 2.9 mm, p < 0.05).
In the third calendar quarter of 2012 we began enrolling patients in a Phase 2 clinical trial of BIOD-123. The clinical trial was a randomized, open label, parallel group study conducted at 32 investigative centers in the United States. In the clinical trial, 132 patients with Type 1 diabetes were randomized to receive either BIOD-123 or Humalog® to use as their mealtime insulin during an 18-week treatment period. Both arms of the study used insulin glargine, sold as Lantus®, as the basal insulin. The clinical trial was designed to evaluate HbA1c control as the primary endpoint, and secondary endpoints included postprandial glucose excursions, glycemic variability, hypoglycemic event rates and weight changes. Following randomization, subjects entered a six-week dose titration period during which basal insulin and then prandial insulin doses were titrated in order to reach standard ADA recommended preprandial glucose targets. Upon completion of the titration period, patients entered a "relative stable dosing period" for an additional 12 weeks. The trial completed patient dosing in the second calendar quarter of 2013.
The Phase 2 clinical trial of BIOD-123 completed patient dosing in the second calendar quarter of 2013, and in September 2013 we announced preliminary results from the trial. BIOD-123 achieved the primary endpoint of noninferiority for HbA1c relative to Humalog®. The mean HbA1c change from baseline in the BIOD-123 group was -0.08 ± 0.064% and -0.25± 0.063% in the Humalog® group. The 95% confidence interval (-0.01, 0.35) of the between group differences in change from baseline HbA1c did not exceed the FDA-designated threshold of 0.40%, thereby establishing non-inferiority. HbA1c change during the stable dosing period was similar in both treatment groups. During this period, the mean change in HbA1c in the BIOD-123 group was -0.01% and in the Humalog® group was +0.02%. Additionally, we observed comparable weight gain, mean hypoglycemia event rates and postprandial glucose excursions between the treatment groups, as well as some trends in favor of BIOD-123 in regard to postprandial glucose excursions to a liquid meal challenge test and weight gain during the stable dosing period. Comparable safety and adverse event profiles were observed in the clinical trial, with the exception of an increased frequency of injection site pain associated with BIOD-123, which appeared to be clinically minor, short-lived and distinctly superior to the toleration profile we observed with Linjeta™ in our earlier Phase 3 clinical trials. We expect to provide an update on our further development plans for BIOD-123 after completing our analysis of the data from the Phase 2 clinical and following discussions with FDA on clinical trial design, safety and chemistry, manufacturing and controls relating to potential future studies.
In addition to BIOD-123, we have other RHI-based formulations in earlier stages of development. In particular, we are developing ultra-rapid-acting formulations of concentrated insulin that are characterized by a rapid onset of action and a prolonged duration of action. We believe these formulations could address an unmet medical need for an insulin with an initial rate of absorption superior to that of Humulin® R U-500 and prandial/basal pre-mixed insulins. In November 2013, we announced that we had initiated a Phase 1 clinical trial with BIOD-531, our lead candidate for an ultra-rapid-acting concentrated insulin formulation. BIOD-531 contains 400 units of RHI per milliliter (instead of the standard 100 units per milliliter), and is formulated with EDTA, citrate and magnesium sulfate. In preclinical studies in diabetic swine, BIOD-531 demonstrated a more rapid rate of absorption and onset of action, along with a similar duration of action, when compared to Humulin® R U-500, a presentation containing 500 units of RHI per millimeter. In other preclinical studies, BIOD-531 also demonstrated a more rapid rate of absorption and onset of action when compared to Humalog® pre-mixed prandial/basal formulations. In the Phase 1 clinical trial of BIOD-531, we will evaluate and compare the onset and duration of action and injection site tolerability of BIOD-531 to Humulin® R U-500 and to Humalog® prandial/basal pre-mixed insulin. We anticipate reporting top line data from the clinical trial in the first calendar quarter of 2014.
We also continue to develop ultra-rapid-acting insulin analog-based formulations. In January 2013, we announced top-line results from our Phase 1 clinical trial of two insulin analog-based formulations, BIOD-238 and BIOD-250. These formulations, which were manufactured using commercial preparations of Humalog®, use the same combination of or similar excipients as BIOD-123 and were intended to be optimized for rapid absorption and injection site toleration. The trial, which was conducted in Australia, was designed to compare the pharmacokinetic and injection site toleration profiles of BIOD-238 and BIOD-250 relative to Humalog®. In the trial, both formulations met our target pharmacokinetic profile for an ultra-rapid-acting insulin analog-based formulation, and BIOD-250 met our target injection site toleration profile. We do not expect to study these formulations in additional clinical trials because they were formulated by adding our proprietary excipients to the marketed formulation of Humalog® and because they do not demonstrate stability characteristics consistent with our target product profile. Accordingly, we are continuing our insulin analog-based formulation work to develop formulations using insulin lispro as the active pharmaceutical ingredient, rather than a marketed presentation of Humalog®.
Insulin Therapy and Its Limitations
Because patients with Type 1 diabetes produce no insulin, the primary treatment for Type 1 diabetes is daily intensive insulin therapy. The treatment of Type 2 diabetes typically starts with management of diet and exercise. Although helpful in the short-term, treatment through diet and exercise alone is not an effective long-term solution for the vast majority of patients with Type 2 diabetes. When diet and exercise are no longer sufficient, treatment commences with various non-insulin medications. These non-insulin medications may be limited in their ability to manage the disease effectively and can have significant side effects. Because of the limitations of non-insulin treatments, many patients with Type 2 diabetes deteriorate over time and eventually require insulin therapy to support their metabolism.
Insulin therapy has been used for more than 80 years to treat diabetes. This therapy usually involves administering several injections of insulin each day. These injections consist of administering a long-acting basal injection one or two times per day and an injection of a rapid-acting insulin at mealtime. Although this treatment regimen is accepted as effective, it has limitations. First, patients generally dislike injecting themselves with insulin due to the inconvenience and pain of needles. As a result, patients tend not to comply adequately with the prescribed treatment regimens and are often inadequately medicated.
More importantly, even when properly administered, insulin injections do not replicate the natural time-action profile of insulin. In particular, the natural spike of the first-phase insulin release in a person without diabetes results in blood insulin levels rising within several minutes of the entry into the blood of glucose from a meal. By contrast, injected insulin enters the blood slowly, with peak insulin levels occurring within 80 to 100 minutes following the injection of recombinant human insulin.
A potential solution is the injection of insulin directly into the vein of diabetic patients immediately before eating a meal. In studies of intravenous injections of insulin, patients exhibited better control of their blood glucose for 3 to 6 hours following the meal. However, for a variety of medical reasons, intravenous injection of insulin before each meal is not a practical therapy.
One of the key improvements in insulin treatments was the introduction in the 1990s and 2000s of rapid-acting insulin analogs, such as Humalog ® , NovoLog ® and Apidra ® . However, even with the rapid-acting insulin analogs, peak insulin levels typically occur within 50 to 70 minutes following the injection. Because the rapid-acting insulin analogs do not adequately mimic the first-phase insulin release, diabetic patients using insulin therapy continue to have inadequate levels of insulin present at the initiation of a meal and too much insulin present between meals. This lag in insulin delivery can result in hyperglycemia early after meal onset. Furthermore, the excessive insulin between meals may result in hypoglycemia.
Additional complications of insulin therapy can arise if a patient's response to insulin diminishes with the progression of the disease. Some patients with Type 2 diabetes have severe insulin resistance, resulting in the need to take more than 200 units of insulin per day to control blood glucose elevations. In order to reduce the volume of insulin needed for each injection, many of these patients use Humulin® R U-500, a presentation of Humulin® R containing 500 units of RHI per milliliter (instead of the standard 100 units per milliliter). Humulin® R U-500 has a long duration of action, but its onset of action is very slow and therefore is not ideally suited to cover the elevation of glucose levels associated with meals. Humulin® R U-500 is currently the only concentrated insulin on the U.S. market. Many other patients with Type 2 diabetes and lesser degrees of insulin resistance use mixes of prandial and basal insulins, which offer a combination of shorter- and longer-acting insulins in the convenience of one injection. However, the mealtime component of these "pre-mixed" insulin formulations is typically absorbed more slowly than what is required to optimally cover the elevation of glucose levels associated with meals. Examples of these "pre-mixed" insulins include Humalog ® Mix 75/25, Humalog® Mix 50/50 and NovoLog ® Mix 70/30.
Glucagon Rescue Treatment and Its Limitations
Hypoglycemia is often treated by the oral administration of carbohydrates, such as orange juice or glucose tablets. However, in the case of severe hypoglycemia, the patient often experiences neurologic compromise, such as loss of consciousness or seizure. In these emergency cases, it is typically unsafe for carbohydrates to be administered by mouth and the patient requires the assistance of another person. In such cases, an injection of glucagon can be administered to help quickly raise the patient's blood glucose concentration.
Glucagon, like insulin, is a hormone secreted by the pancreas. Glucagon opposes the action of insulin by promoting the breakdown of glycogen into glucose in the liver, thereby raising the levels of blood glucose. Although glucagon injections are useful in treating severe hypoglycemia, glucagon is inherently unstable in a liquid solution. Therefore, injectable glucagon for the treatment of severe hypoglycemia is currently available only as a rescue kit consisting of a vial containing a dry powder of glucagon and a syringe containing a liquid solution. To administer glucagon with this kit, the liquid solution must first be injected into the vial with the dry powder, the contents need to be adequately mixed and then the solution is drawn back into the syringe. After the glucagon powder is dissolved, it is injected into the patient. In order to properly administer the glucagon, a caregiver must follow this multi-step process in a situation typically made challenging by the patient's condition.