New Drugs

Quizartinib: Surprising, Unprecedented Activity in Relapsed AML

January 29, 2013 Chemotherapy, Drug Informatics, Hematology, Pharmacotherapy, Therapeutics No comments , , , ,

ATLANTA, Georgia — The investigational agent quizartinib (Astellas/Ambit) has shown unprecedented activity in patients with relapsed and refractory acute myeloid leukemia (AML) in a phase 2 clinical trial.

On the basis of these results, larger phase 3 clinical trials with the drug are being planned, according to Astellas/Ambit.

Patients with AML can develop many different genetic mutations, but one of the most threatening is FLT3 internal tandem duplications (ITD), which makes the leukemia even more aggressive and typically leads to resistance to standard chemotherapy. This mutation develops in 34% of AML patients and is associated with more rapid relapse and reduced overall survival, explained lead author Mark Levis, MD, PhD, associate professor of oncology, pharmacology, and medicine at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, Maryland.

“Quizartinib is the first and only single-agent drug that has produced a clinical benefit in AML patients with this deadly mutation who have failed previous therapy,” he said. “It caught us by surprise how well it worked.”

Dr. Levis presented results from a large phase 2 study of patients with relapsed or refractory AML here at the American Society of Hematology (ASH) 54th Annual Meeting. Many patients achieved a complete response to quizartinib, and one third were stabilized with quizartinib for long enough to undergo potentially life-saving hematopoietic stem cell transplantation (HSCT).

“The number of patients bridged to a transplant was very significant,” Dr. Levis said in a statement. “We plan on using these encouraging results to design and conduct additional randomized trials that will hopefully lead to the approval of quizartinib to make it accessible for patients who previously had no hope for a cure,” he added.

“I am desperate to get this drug in the clinic…. I treat mainly a refractory patient population, and this is the drug that I want to use in them,” he explained.

Patients with a FLT3 mutation present a “major management problem,” said ASH president Armand Keating, MD, professor of medicine and director of hematology at the University of Toronto in Ontario, Canada. “You can put them in remission, but then they relapse…and the disease progresses so quickly that they don’t get a chance for transplant and for cure,” he said.

“This study is important because it shows that quizartinib can stabilize these patients for long enough to do a transplant. It shows that this is possible in about a third of patients,” Dr. Keating reported. It is another example of a new drug offering fresh hope for a hard-to-heal patient population, he said at a premeeting press briefing.

Mutation Is Like a Power Switch

“The FTL3 mutation is essentially a power switch that leukemia cells use to spread more aggressively and helps them to grow back immediately after chemotherapy,” Dr. Levis explained. “The only way to treat this type of mutation is to find a way to turn the switch off — a feat that has eluded researchers for far too long.”

Quizartinib appears to do just that. It was designed to “turn off” the mutated FLT3 enzyme, which forces the immature cancer cells to die immediately or to undergo maturation and then die. This eliminates enough cancer cells to stabilize the patient for long enough to offer them another treatment, including transplantation.

The phase 2 study of quizartinib was conducted in AML patients who had relapsed, did not respond to second-line therapy, or had relapsed after HSCT. The patients were divided into 2 groups: 133 were older than 60 years, and 137 were 18 to 60 years.

Dr. Levis presented data from the younger cohort. Of the 137 patients, 99 had the FLT3 mutation and 38 did not.

Oral quizartinib was used alone at a starting dose of 135 mg/day for men and 90 mg/day for women, and was given continuously in 28-day cycles. The difference in the dose between the sexes relates to an adverse cardiac effect of the drug; quizartinib can cause a prolongation of the QT interval on electrocardiogram, and women are more sensitive to this effect than men, Dr. Levis explained.

The drug elicited responses in patients with and without the mutation, but the responses were better in those with the mutation. The primary end point was a composite complete remission rate (CR), which included complete remission with no active disease, complete remission with incomplete platelet recovery (so no active disease but an incomplete platelet count), and complete remission with incomplete hematologic recovery (no active disease but abnormal red and white blood cells counts).

For the 99 patients who had the FLT3 mutation, the composite CR was 44% (4% with CR, 0% with incomplete platelet recovery, and 40% with incomplete hematologic recovery). The median duration of response was 11.3 weeks and median overall survival was 23.1 weeks.

For the 38 patients without the mutation, the composite CR was 34% (3% with CR, 3% with incomplete platelet recovery, and 29% with incomplete hematologic recovery). The median duration of response was 5.0 weeks and median overall survival 25.6 weeks.

Of the 137 patients 18 to 60 years of age, 47 (34%) underwent HSCT after responding to quizartinib. Some of these patients have survived more than 2 years without any disease recurrence, Dr. Levis said.

Adverse events included nausea (reported by 38% of patients), anemia (29%), QT prolongation (26%), vomiting (26%), febrile neutropenia (25%), diarrhea (20%), and fatigue (20%). Adverse events led to discontinuation of treatment in 10% of patients.

Quizartinib was “extremely well tolerated,” Dr. Levis noted. The main adverse events are the QT prolongation and myelosuppression, but these are “manageable,” he said.
“We are still playing around with the dose,” he explained. A future trial will look at using lower doses of the drug, and a randomized trial of 30 mg vs 60 mg is planned.

The findings from this phase 2 trial of quizartinib in patients with relapsed and refractory AML are “especially encouraging,” said Jorge Cortes, MD, deputy chair in the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston, in a statement. “In the patients with the FLT3-ITD mutation, quizartinib represents the most active single agent we have observed with any class of investigational drugs in this challenging patient population,” he added.

The study was funded by Astellas/Ambit, the developers of quizartinib. Dr. Levis reports consultancy for Ambit Biosciences. Several of his coauthors are company employees. Dr. Keating reports serving on the data safety monitoring board for Clavis, Novartis, and Pfizer.

American Society of Hematology (ASH) 54th Annual Meeting: Abstract 673. Presented December 10, 2012.

The new anti-diabetes drug GLP-1 receptor agonists

March 31, 2012 Diabetes, Drug Informatics, Pharmacology 1 comment , , ,

A GLP-1R agonist Exenatide approved by FDA.

This article comes from references available on internet. It is about a new drug called Glucagon-like Peptide-1 [GLP-1] Receptor Agonists.

So GLP-1R Agonists is analog of human glucagon-like peptide-1, and it acts as GLP-1 receptor agonist to increase insulin secretion in the presence of elevated blood glucose. Also it delays gastric emptying to decrease postprandial glucose and decreases glucagon secretion.

So what is Glucagon-like Peptide-1 [GLP-1]?

GLP-1 is one kind of native human hormones called Incretins, which is produced by the proglucagon gene in L-cells of the small intestine. GLP-1 decreases and control blood glucose by various mechanism including: [1].Liver: reduces hepatic glucose output by inhibiting glucagon release. [2]. Alpha cell: inhibits glucagon secretion. [3].CNS: promotes satiety. [4].Stomach: slows gastric emptying. [5].Beta cell: stimulates glucose-dependent insulin secretion and beta-cell differentiation and proliferation.

Thus, modulating GLP-1 levels and GLP-1 activity through administration of the native hormone, analogs, and mimetics or by inhibiting its degradation has become a major focus of investigation for treating type 2 diabetes over the past decade.

Another important thing, where can we find the receptor of GLP-1?

The receptor is found on pancreatic periductal cells and β-cells and in the kidney, heart, stomach, and brain. GLP-1 receptor (GLP-1R) knockout mice have fasting hyperglycemia and abnormal glucose tolerance but are not obese.


[1].Medscape: Guideline Discusses Oral Pharmacotherapy for Type 2 Diabetes. Full reference:
[2].Glucagon-Like Peptide 1-Based Therapies for Type 2 Diabetes: A Focus on Exenatide. Full reference:
[3].Glucagon-Like Peptide-1 Receptor Agonists Promote Weight Loss. Full reference:

Guideline discusses oral pharmacotherapy for Type 2 diabetes

March 29, 2012 Diabetes, Pharmacology, Therapeutics No comments , ,

In this article the author disscuss several oral anti-diabetes drugs, including:

  • Metformin
  • Sulfonylureas
  • Meglitinides
  • Thiazolidinediones
  • Dipeptidyl Peptidase-4 [DPP-4] inhibitors
  • Glucagon-like Peptide-1 [GLP-1] Receptor Antagonists Note: According relative references I think Medscape have made a mistake. It should be Agonists instead of Antagonists.

I reviewed my pharmacology textbooks (a very old version) and found there were only four types of oral anti-diabetes drugs. They are Biguanides, Sulfonylureas, and α-glucosidase inhibitor. I searched on Medscape for the other types of oral anti-diabetes drug and what I found nothing. So I tried to serach on WebMD and Medscape for “Meglitinides” “Thiazolidinediones” “Dipeptidyl Peptidase-4 [DPP-4] inhibitors” “Glucagon-like Peptide-1 [GLP-1] Receptor Antagonists“. Note: It should be Agonists here

Oral anti-diabetes drugs.

Here is what I found on WebMD and Medscape:

Meglitinides includes Nateglinide and Repaglinide. Meglitinides works via increasing the amount of insulin produced by the pancreas. It’s similar to the way sulfonylureas works.

Thiazolidinediones includes Pioglitazone and Rosiglitazone. How dose Thiazolidinediones work is not well understood so far. But we do know that it works via improving the way cells in the body respond to insulin (or lowering insulin resistance). By the way Pioglitazone may help in the treatment of high cholesterol by reducing triglycerides and increasing high-density lipoproteins (HDL) in the blood. Rosiglitazone increases high-density lipoproteins (HDL) and slightly increases low-density lipoproteins (LDL).

Dipeptidyl Peptidase-4 [DPP-4] inhibitors includes Saxagliptin and Sitagliptin. They work via helping your body make more insulin after a meal. They also reduce blood sugar your body makes. They can make these effects by increasing and prolonging incretin hormone activity which are inactivated by DPP-4 enzyme.

PS: Incretins increase insulin release and synthesis from pancreatic beta cells and reduce glucagon secretion pancreatic alpha cells.

About Glucagon-like Peptide-1 [GLP-1] Receptor Antagonists, Note: It should be Agonists here there are some different opinions on internet. So I do not post the information about GLP-1 Receptor Antagonists. Maybe one key word was typed mistakenly. I have sent tweets to my friend for confirming. (more…)