After posting positive Phase 2b results with its oral insulin drug candidate, ORMD-0801 in Type 2 diabetes, Oramed Pharmaceuticals (NASDAQ:ORMP) hopes to meet with the FDA before the end of 2016 to discuss proceeding with a Phase 3 clinical trial in 2017.
“We believe that our data set shows that oral insulin works, which is a first in history,” Josh Hexter, COO and VP of business development, says in an interview with BioTuesdays.com.
“While currently under development, our Phase 3 program will focus on safety and long-term HbA1c lowering efficacy, and will include both active comparator and placebo controlled trials,” he adds. HbA1c is an important three-month average of plasma glucose concentration in blood.
Oral insulin has been an elusive challenge because proteins and peptides do not survive as they travel through the digestive system, beginning with harsh stomach acidity. In addition, most therapeutic proteins fail to be absorbed via the intestinal wall. As a result, diabetic patients have been forced to rely on insulin injections into the bloodstream to maintain glucose control.
Mr. Hexter explains that Oramed’s technology includes a pH-sensitive enteric coating that has the potential to protect the insulin capsule through the stomach so that it dissolves only when it reaches the small intestine. Protease inhibitors stave off and protect the active agent from protease attack, and absorption enhancement assists in the permeation of insulin across the intestinal membrane and into the bloodstream, he adds.
One-in-12 people on the planet have diabetes, with 4.9 million deaths in 2014 attributed to the disease.
About 10% of patients have Type 1 diabetes, an autoimmune disease, where the body destroys its insulin-producing beta cells in the pancreas, leaving patients completely dependent on external sources of insulin before meals.
Type 2 diabetes, on the other hand, is a metabolic disease, where some patients become insulin resistant. Injections may be used to make up for the pancreas’ inability to make enough insulin to keep blood sugar at normal levels.
Oramed is targeting ORMD-0801 both for Type 1 diabetes, a projected market of $13-billion by 2023, and for Type 2 diabetes, a projected market of $39-billion by 2019. There are some 371 million patients worldwide with Type 2 diabetes.
In the current treatment paradigm for Type 2 diabetes, insulin injections represent a late-stage therapy after oral therapies fail. However, guidance from the American Diabetes Association suggests that earlier use of insulin leads to better outcomes.
Mr. Hexter points out that natural insulin is delivered directly from the pancreas to the liver to control blood glucose. The drawback of injected insulin, he says, is that not all of it reaches the liver, causing excess sugar to be stored in fat and muscle, which often results in weight gain and may also cause hypoglycemia.
He contends that oral insulin, like natural insulin, is delivered first to the liver, which should lead to better blood glucose control as well as reduced hypoglycemia and hyperglycemia, and weight gain.
In an earlier Phase 2a study with Type 1 patients, the company demonstrated that ORMD-0801 was safe and well tolerated, and reduced levels of post-meal and daytime glucose.
Mr. Hexter says the Type 1 program is on hold until the company meets with the FDA later this year. “We think the FDA may want a Phase 3 clinical trial with oral insulin to include both Type 1 and Type 2 diabetic patients.”
Oramed’s first indication with regular human insulin, encapsulated in the form of ORMD-0801, is to reduce excessive nighttime glucose production in the liver by acting in the same way as natural insulin.
“Excessive production of glucose at night is a significant challenge in diabetes management, as patients often begin the day with elevated blood glucose readings,” he adds. “Reducing nighttime blood glucose levels can significantly slow down the progression of diabetes and life-threatening comorbidities.”
Last month, Oramed reported statistically significant data from a four-week Phase 2b study of ORMD-0801 with 180 Type 2 patients at 33 clinical sites in the U.S.
Among other things, oral administration of multiple bedtime doses of ORMD-0801 capsules resulted in a clinically relevant anti-hyperglycemic effect lasting throughout the day. “This is striking considering there is no insulin depot as is the case with subcutaneously injected insulin, and once absorbed, regular human insulin is very rapidly cleared from the bloodstream,” Mr. Hexter points out.
In addition, the reduction in 24-hour glucose was highly significant. In the placebo arm, 24-hour glucose increased to 187 mg/dL from 173, while in the pooled active treatment arm, the 24-hour glucose level remained at baseline of 168 mg/dL throughout the study.
These results suggest we should observe a further and clinically meaningful reduction in HbA1c in longer studies, he adds.
Analyst Dr. Christopher James of FBR & Co. said in a report that although challenging to extrapolate from a four-week study, the statistically significant change in HbA1c for the pooled ORMD-0801 cohorts versus placebo is promising.
“Overall, we believe the Phase 2b data further supports the use of ORMD-0801 in the treatment of Type 1 and Type 2 diabetes and we shift our focus to updates on an end-of-Phase 2 meeting [with the FDA] expected in the coming months,” he said.
Dr. James rates Oramed “outperform” with a $20 price target. The stock closed at $7.69 on Friday.
Dr. James also notes that Oramed plans to seek a partner in order to advance ORMD-0801 in late-stage development, noting the size and scope of a Phase 3 program in diabetes.
Last fall, Oramed licensed exclusive rights in China to its oral insulin to Hefei Tianhui, which jointly owns a state-of-the-art GMP insulin manufacturing facility in the country. Mr. Hexter says Oramed has received about half of the $50-million in upfront and investment payments from Hefei and also is eligible to receive 10% royalties on net sales of ORMD-0801 in China.
According to the American Medical Association, some 12% of the adult population in China, or 114 million people, have diabetes, making China the largest single country with Type 2 diabetes in the world. In addition, 50% of the adult population, or 500 million people, are known to be prediabetic.
Oramed also is developing an oral version of GLP-1, or glucagon-like peptide 1, a new class of drugs with far ranging benefits for the treatment of Type 2 diabetes.
GLP-1 agonists have been shown to improve insulin secretion, decrease glucagon production, which serves to keep blood glucose levels high, help decrease food intake and may help patients lose weight. GLP-1 agonists also effectively reduce HbA1c, preserve beta-cell function in the pancreas, and may also have cardiovascular benefits as well.
Oramed’s oral GLP-1 product, ORMD-0901, has been shown to preserve the biological activity of orally-delivered exenatide, which is sold as BYETTA and is the first and only FDA-approved GLP-1 receptor agonist for the treatment of Type 2 diabetes. ORMD-0901 also successfully curbed blood sugar excursions following a glucose challenge.
Mr. Hexter says Oramed expects to file an IND with the FDA in early 2017 and begin a 90-day Phase 2b study with ORMD-0901, with HbA1c control and safety as the primary endpoints.