FDA approves long awaited Tresiba & Ryzodeg for diabetes mellitus.

September 25, 2015

The U.S. Food and Drug Administration approved Tresiba (insulin degludec injection) and Ryzodeg 70/30 (insulin degludec/insulin aspart injection) to improve blood sugar (glucose) control in adults with diabetes mellitus, after review of the class II resubmissions of the New Drug Applications (NDAs).

Earlier in 2013, FDA had rejected approval of these two drugs because of concerns over cardiovascular outcomes. On 26 March 2015, Novo Nordisk announced the decision to submit the class II resubmissions of the NDAs following the completion of the interim analysis of the cardiovascular outcomes trial for insulin degludec, DEVOTE.

INSULIN DEGLUDEC

The insulin degludec drug product is a solution for subcutaneous injection. The drug is intended to cover basal insulin requirements in patients with T1DM and T2DM.

The drug substance in insulin degludec is an analogue of human insulin produced using yeast recombinant DNA technology and chemical modification. Insulin degludec differs from human insulin by omission of a threonine residue at the amino terminal B-chain (B30) and by attachment of a 16 carbon fatty acid to the epsilon-amino group of the lysine residue at position 29 of the B-chain through a gamma-glutamic acid spacer.

degludec

Two formulation strengths are proposed in the degludec application:

  1. one containing 100 units of analogue insulin per milliliter (600 nmol/mL)
  2. a twice concentrated formulation containing 200 units of analogue insulin per milliliter (1200 nmol/mL).

The product formulation was optimized using standard excipients to delay systemic absorption of the drug substance from the subcutaneous depot in order to prolong the time action profile of the insulin. The fatty acid moiety of degludec insulin binds to albumin and further contributes to the protracted time action profile.

Tresiba is a long-acting insulin analog indicated to improve glycemic control in adults with type 1 and 2 diabetes mellitus. Dosing of Tresiba should be individualized based on the patient’s needs. Tresiba is administered subcutaneously once daily at any time of day.

INSULIN DEGLUDEC/ASPART (Ryzodeg)

The insulin degludec/aspart (Ryzodeg 70/30)  fixed ratio drug product is a solution for subcutaneous injection. The drug is intended to cover basal insulin requirements and prandial insulin requirements for one meal of the day in patients with T1DM and T2DM.

The drug substances in insulin degludec/aspart are two insulin analogues: degludec insulin and the approved analogue, aspart insulin. The drug product formulation strength is 100 units per milliliter (600 nmol/mL) and contains 70% degludec weight (i.e., 420 nmol of degludec insulin in 1 mL) and 30% aspart weight by volume (i.e., 180 nmol of aspart insulin in 1 mL).

Degludec Insulin In-Vitro Pharmacology

Insulin degludec was found to be selective for the insulin receptor (IR) and the structurally similar insulin like growth factor receptor (IGF-1R) in assays of standard receptors and transporters. Insulin degludec was shown to bind the two insulin receptor isoforms (IR-A and IR-B) with similar affinity.

Degludec insulin binds human insulin receptors with less affinity than regular human insulin (relative affinity of degludec was 13 and 15% that of regular insulin for IR-A and IR-B isoforms respectively). Presence of albumin in experimental conditions lowered the binding affinity of degludec for the human insulin receptor further (comparative affinity to regular insulin: 4.3% for the IR-A and 3.2% for the IR-B isoforms).

This finding is not unexpected as degludec insulin binds to proteins (i.e., a property of its fatty acid moiety) and in the presence of protein, less free degludec insulin is available to bind receptors.

Common protein-bound drugs like ibuprofen, warfarin, acetylsalicylate, salicylate and frequently used antidiabetic agents glimepiride, metformin, sitagliptin and liraglutide as well as palmitate, oleate and linoleate did not affect insulin degludec binding to human serum albumin at therapeutically/physiologically relevant drug concentrations.

No or only minor effect on individual cytochrome P-450 (CYP) expression.

Clinical Pharmacology

Steady state serum concentrations of degludec insulin are reached after 2–3 days of once daily subcutaneous dosing. Total exposure, at steady state after subcutaneous administration, is dose proportional within the therapeutic dose range in subjects with T1DM and T2DM.

Degludec insulin was detectable in serum for at least 120 hours (5 days) after the last steady state subcutaneous dose of degludec was administered. The ½ life in this setting was approximately 25 hours.

The duration of action of degludec insulin was demonstrated to last beyond 42 hours. Because of this prolonged half-life, the applicant also investigated flexible dosing regimens of degludec in its clinical development program.

Advance age (i.e., ≥ 65 years of age), sex (i.e., male, female), race and ethnicity did not impact total exposure at steady state. Renal function and hepatic function did not impact the pharmacokinetic properties after a single dose.

Efficacy and Safety

The efficacy and safety of Tresiba used in combination with mealtime insulin for the treatment of patients with type-1 diabetes were evaluated in two 26-week and one 52-week active-controlled clinical trials involving 1,102 participants exposed to Tresiba.

The efficacy and safety of Tresiba used in combination with mealtime insulin or used as add-on to common background oral antidiabetic drugs for the treatment of patients with T2DM were evaluated in four 26-week and two 52-week active-controlled clinical trials involving 2,702 participants exposed to Tresiba. In participants with type 1 and 2 diabetes who had inadequate blood sugar control at trial entry, treatment with Tresiba provided reductions in HbA1c (hemoglobin A1c or glycosylated hemoglobin, a measure of blood sugar control) in line with reductions achieved with other, previously approved long-acting insulin.

The efficacy and safety of Ryzodeg 70/30 used in combination with mealtime insulin for the treatment of patients with type 1 diabetes were evaluated in one 26-week active controlled clinical trial involving 362 participants exposed to Ryzodeg 70/30.

The efficacy and safety of Ryzodeg 70/30 administered once or twice daily for the treatment of patients with type 2 diabetes were evaluated in four active controlled 26-week clinical trials involving 998 participants exposed to Ryzodeg 70/30. In participants with type 1 and 2 diabetes who had inadequate blood sugar control at trial entry, treatment with Ryzodeg 70/30 provided reductions in HbA1c equivalent to reductions achieved with other, previously approved long-acting or pre-mixed insulin.

Warnings & Precautions

  1. Diabetic ketoacidosis: Tresiba and Ryzodeg should not be used in those who have increased ketones in their blood or urine . Patients or caregivers should monitor blood glucose in all patients treated with insulin. Insulin regimens should be modified cautiously and only under medical supervision.

2. Hypoglycemia Tresiba and Ryzodeg may cause low blood sugar (hypoglycemia), which can be life-threatening. Patients should be monitored more closely with changes to insulin dosage, co-administration of other glucose-lowering medications, meal pattern, physical activity, and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness.

3.Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin.

ADRs

The most common adverse reactions associated with Tresiba and Ryzodeg in clinical trials were hypoglycemia, allergic reactions, injection site reactions, pitting at the injection site (lipodystrophy), itching, rash, edema, and weight gain.

Tresiba and Ryzodeg are manufactured by Novo Nordisk in Plainsboro, New Jersey.

Meanwhile, Novo Nordisk is developing a faster-acting insulin aspart for the treatment of type I and type II diabetes. The company intends to file for its approval in the U.S. and the EU by 2015-end or early 2016.

Source:

USFDA News.

FDA Briefing document.

http://www.fda.gov.