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FA Aspart > FA Aspart QandA > Flashcards

FA Aspart QandA Flashcards

1
Q

If a patient takes 200 U of faster-acting insulin aspart (a
hypothetically very high daily dose) the intake of the excipients would
be ________ fold less than the normal recommended dietary intake

A

30-100

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2
Q

True or false.
The changes between faster aspart and conventional insulin aspart in the first 30 minutes are of the same magnitude as those found between conventional insulin aspart and regular human insulin.

A

True

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3
Q

Compared with conventional insulin aspart, faster aspart has:

__________ higher insulin concentration in the blood within the first 30 minutes

A

Two fold

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4
Q

Compared with conventional insulin aspart, faster aspart has:

> ________% insulin action within the first 30 minutes

A

50

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5
Q

Compared with conventional insulin aspart, faster aspart has:

__________ overall exposure (AUCtotal)

A

Same

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6
Q

Why is faster-acting insulin aspart faster than conventional insulin aspart?

A

our hypothesis the ability of niacinamide to promote a more rapid dissociation of insulin aspart hexamers into monomers after subcutaneous injection, thereby facilitating a more rapid initial absorption.

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7
Q

Has a direct effect of niacinamide on local blood flow been established?

A

No, but we cannot rule out that such an effect also plays a role.

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8
Q

How long has aspart been approved by FDA?

A

Since 2000 (1999 with EMA)

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9
Q

In comparison to aspart and RHI, how does faster aspart compare to aspart with in the first 30 minutes?

A

Similar.

Based on GIR in the first 30 min after dosing (AUCGIR, 0–30 min), the difference in early glucose-lowering effect between faster-acting insulin aspart and insulin aspart (treatment ratio 1.48, 95% CI 1.13; 2.02; Figure 3A) in the present study is similar to that between insulin aspart and regular human insulin (ratio 1.38, 95% CI 0.78; 2.89; Figure 3B; data on file and adapted from Heinemann et al. [20]); both datasets were analyzed in the same manner.

Note the difference with aspart and RHI was not significant.

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10
Q

Compared with conventional insulin aspart, faster aspart has:
_________ as fast onset of appearance in the blood
__________ higher insulin concentration in the blood within the first 30 minutes
>________ % insulin action within the first 30 minutes
__________ overall exposure (AUCtotal)

A

Twice
Two fold
50
Same

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11
Q

Hepatic glucose production (HGP) accounts for close to _____% of PPG in T2DM (versus 20% in controls without diabetes) and is rapidly reduced in response to insulin delivery to the liver.

Current rapid-acting insulin analogues do not mimic endogenous prandial insulin secretion to the extent needed to rapidly suppress HGP in response to a meal

A

40%

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12
Q

In Onset 1, faster acting Aspart had a (significant or non significant) difference in the overall rate of severe or confirmed hypoglycaemia between groups.

A

….no significant difference in the overall rate of severe or confirmed hypoglycaemia between groups.

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13
Q

What is the pooled PK/PD analysis?

A

a post-hoc patient-level meta-analysis including 218 adults with T1D from 6 comparable phase 1 randomised,
double-blind crossover trials comparing the PK and PD properties of faster aspart and conventional insulin aspart.

PK was assessed in all 6 studies after subjects received a s.c. dose of 0.2 U/kg of insulin.

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14
Q

What 4 major points did is the pooled PK/PD analysis show?

A

 Twice as fast onset of appearance
 Two-fold higher insulin exposure within the first 30 minutes
 >50% greater insulin action within the first 30 minutes
 Same overall exposure (AUCtotal)

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15
Q

What doses were compared to aspart in PK/PD studies?

Are the PK/PD properties seen with faster aspart independent of dose?

A

0.1 U/kg, 0.2 U/kg and 0.4 U/kg

Yes. Across the dose range, the earlier onset of appearance (~5 min) and higher early exposure (AUCIAsp,0-30 min treatment ratios: 1.5-2.2 ) with faster aspart was consistently observed. The glucose-lowering action of faster aspart was also greater during the first 30 minutes across the
three doses investigated (treatment ratios: 1.5-2.1).

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16
Q

Are the differences seen in the PK/PD studies clinically relevant for 1 hour and 2 hour PPG and A1c?

A

As demonstrated in the large phase 3a onset® studies, the differences reported in PK/PD properties have translated into significant differences in:

  • HbA1c
  • 1 and 2 hour PPG for people with T1D,
  • 1 hour PPG for people with T2D,

which we consider a meaningful improvement for patients.

17
Q

Is within-subject variability improved with faster aspart compared with conventional insulin aspart?

A

No.

Within-subject variability of faster aspart was investigated in a double-blinded, glucose clamp trial where subjects with T1D received three single 0.2 U/kg injections of faster aspart or conventional insulin aspart. Faster aspart showed low day-to-day variability in early glucose-lowering effect with coefficients of variance not significantly different from conventional insulin aspart. This was also the case for total and maximum glucose-lowering effect.

17
Q

Does faster aspart appear faster with CSII compared with injection administration? Why or why not?

A

Yes.

The reason for this finding is still not completely understood and comparisons across trials should always be done with caution;

however, a hypothesis could be that the continuous supply of niacinamide in a CSII setting further augments the rate of dissociation of insulin monomers, thereby further increasing the early absorption

18
Q

How many trials were in the Phase 3a program?

A

4

18
Q

Are there plans to study glulisine and faster acting aspart?

A

No

19
Q

Was continuous glucose monitoring (CGM) performed in the onset trials? What were the findings?

A

Yes. Onset 1 and 2. No difference by CGMS.

CGM was performed in approximately 30 subjects from each treatment arm in the onset® 1
and 2 trials, not powered to demonstrate differences and hence did not confirm any differences between the treatment
groups.

20
Q

Will a cardiovascular (CV) outcomes study be performed for faster aspart?

A

No.

21
Q

Did you observe any adverse reactions or effects due to the added excipients?

A

No

24
Q

What is planned for phase 3b?

A

2 kids and three adults

 A basal-bolus trial in children with T1D (NN1218-4101, onset® 7).
 A pump trial in children with T1D (NN1218-4305, onset® 6).

 A pump trial in adults with T1D (NN1218-3854, onset® 5).
 A basal-bolus trial in adults with T1D with insulin degludec compared to conventional insulin aspart (NN1218-4131, onset® 8).
 A basal-bolus in adults with T2D with degludec compared to conventional insulin aspart (NN1218-4113, onset® 9).

26
Q

In Onset 1, there was (superior or non-inferior) PPG control?

A

This study demonstrated improved glycaemic control with superior PPG control at 2-hours with mealtime faster aspart compared
with conventional insulin aspart in patients with T1D on basal-bolus treatment

27
Q

Onset 1 (was or was not) a double blinded study

A

Double blinded

28
Q

Onset 1 was in type __ diabetes comparing faster acting Aspart to _____.

A

Type 1; Aspart

29
Q

Why does faster-acting insulin aspart lead to a better HbA1c than conventional insulin aspart in T1D in Onset 1?

A

In onset® 1, the reduced levels of PPG may have contributed to the lower end-of-trial (26 weeks) HbA1c achieved

31
Q

In Onset 1, the overall adverse event rate including hypoglycemia rate was ________ (higher/similar/lower)

A

Similar

32
Q

Onset 2 was in type __ diabetes comparing faster acting Aspart to _____.

A

Type 2; Aspart

33
Q

3a trials with faster aspart in T2? How are they different?

A

Onset 1:
The two faster aspart arms comparing pre (blinded) and post meal (unblinded) faster aspart with conventional insulin aspart. 300 patients in each arm. (first study bigger)

Onset 4:
Pump study looking at occlusion in adults using their own MiniMed Paradigm® pump. No difference found. 25 patients in faster acting aspart, 12 in aspart. (doesn’t take much to show difference)

34
Q

3a trials with faster aspart in T2? How are they different?

A

Onset 2:
Compared faster acting aspart to aspart adding on to patients on basal + metformin. >300 each group (first study bigger)

Onset 3:
Compared faster acting aspart to nothing adding on to patients on basal + metformin. Onset 3, lets see which is better, continuing basal or adding bonus. Just over 100 each group. (doesn’t take much to show difference)

35
Q

Onset 2

How complicated was the titration algorithm?

A

simple daily patient driven titration algorithm

36
Q

Onset 2

How were the results of HgA1c and 2 hour PPG different from Onset 1?

A

Statistically similar results for HgA1c and 2 hour PPG (as opposed to better in Onset 1 with faster aspart).

The 1 hour PPG in both Onset 1 and Onset 2 were similar.

37
Q

Why are the differences in glycaemic control demonstrated in onset® 1 not reported in onset® 2?

A

Endogenous insulin.

The onset® 2 trial included patients with T2D naïve to bolus insulin.

Patients with T2D are a more heterogeneous population than people with T1D, particularly with respect to endogenous insulin secretion in
response to meals and variation in the degree of insulin resistance. It is possible that the variability in people with T2D could mask any differences in glycaemic control that could arise from a faster mealtime insulin.

38
Q

How were hypoglycemia rates in onset 1 and 2?

A

Overall similar to aspart. However, c/w PK/PD more was seen within first 1-2 hours with faster acting aspart (1st hour for onset 1 and 2nd hour for onset 2)

39
Q

Purpose of onset 3? Results for HgA1c, hypoglycemia, and weight gain?

A

To demonstrate its better to add faster acting aspart than just continuing basal insulin when A1c is >7.5%

Results for HgA1c, hypoglycemia, and weight gain were as expected with all statistically different.

40
Q

Purpose of onset 4? Results?

A

To see if there was any difference in occlusions with faster acting aspart vs aspart in T1 adults on Medtronic pumps.

No difference number of microscopically confirmed episodes of infusion set occlusions

FA Aspart (1 decks)

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