Generex Oral-lyn™ (buccal insulin) for diabetes mellitus - National ...

National Horizon Scanning Centre
Generex Oral-lyn (buccal insulin)
for diabetes mellitus
September 2007
This technology summary is based on information available at the time of research
and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or
effectiveness of the health technology covered and should not be used for commercial purposes.
The National Horizon Scanning Centre Research Programme is part of the
National Institute for Health Research

September 2007 National Horizon Scanning Centre
News on emerging technologies in healthcare
Generex Oral-lyn (buccal insulin) for diabetes mellitus
Target group
• Type 1 and 2 diabetes mellitus.
Technology description
Generex Oral-lyn (buccal insulin, Oralin) is a liquid formulation of short acting insulin
that is administered using Generex's metered dosage aerosol applicator (RapidMist).
Generex Oral-lyn is sprayed into the oral cavity, where the insulin is absorbed into the
bloodstream through the mucosal lining.
Generex Oral-lyn is likely to be used as both an add-on to current long-acting insulin
treatment and a substitute for injectable short acting insulin. If licensed, it may replace the
need for injectable insulin throughout the day, requiring injections only for overnight
insulin maintenance in patients with type 1 disease and for many with type 2 disease.
Dosage is equivalent to current short-acting insulin. The formulation can be stored for up
to 3 months at room temperature if more that 15 months are left before product expiry.
Generex Oral-lyn was launched in Ecuador in December 2005.
Innovation and/or advantages
Generex Oral-lyn is the first insulin agonist to be administered and absorbed through
the buccal mucosa. Early trials suggest that the formulation is more rapidly absorbed in
the mouth with a more rapid onset of action than subcutaneous injected insulin. Generex
Oral-lyn may reduce the number of required injections, improving compliance, quality
of life and reducing needlestick hazards.
Developer
Generex Biotechnology Corporation.
Place of use
Home care e.g. home dialysis
� Secondary care e.g. general,
non-specialist hospital
General public e.g. over the
counter
Community or residential care e.g.
district nurses, physio
�Tertiary care e.g. highly specialist
services or hospital
Other:
Availability, launch or marketing dates, and licensing plans:
Phase III trials.
NHS or Government priority area:
This topic is relevant to the National Service Framework for Diabetes.
� Primary care e.g. used by GPs or
practice nurses
Emergency care e.g. paramedic
services, trauma care
Relevant guidance
• NICE clinical guideline: Diagnosis and management of type 1 diabetes in children,
young people and adults. July 2004
2
1 .
• NICE clinical guideline: Management of type 2 diabetes – managing blood glucose
levels. September 2002 2 .
• NICE clinical guideline in development: type 2 diabetes (update). Expected date of
issue March 2008. This is an update of the following guidelines: type 2 diabetes –
retinopathy, renal disease, blood glucose, management of blood pressure and blood
lipids.

September 2007 National Horizon Scanning Centre
News on emerging technologies in healthcare
• Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical
practice. December 2005 3 .
• SIGN – management of diabetes. Published November 2001. Review report 2005 4 .
• NICE have published guidance on the use of inhaled insulin (2006) 5 ; glitazones
(2003) 6 ; insulin pump therapy (2003) 7 ; insulin glargine (2002) 8 .
Clinical need and burden of disease
In England and Wales there were an estimated 2,018,000 people with diabetes in 2006 9 ,
with type 2 diabetes accounting for more than 85% 10 . Type 1 diabetes is classically a
disease of the young and is generally of rapid onset, but it can occur at any age. Type 2
diabetes is characteristically a disease of the middle aged or elderly and usually begins
subtly. Patients with diabetes have an average reduction in life expectancy of 5-10
years 11 . Cardiovascular disease accounts for up to 60% of all deaths from diabetes and is
the most common complication in Europeans with type 2 diabetes 12 . The risk of
myocardial infarction and stroke is two to five times higher for individuals with type 2
diabetes than in the general population 11 . For people with type 1 diabetes, there is a two-
to threefold increase in risk of developing CHD and stroke in later life 3 . Further diabetic
complications include nephropathy, retinopathy, foot ulceration and erectile dysfunction.
Existing comparators and treatments
There are three main types of insulin preparation given by subcutaneous injection:
1. short-acting, which have a relatively rapid onset of action and are injected just
before meals e.g. soluble insulin, insulin lispro, insulin aspart;
2. intermediate acting, often given at bedtime e.g. isophane insulin, insulin zinc
suspension;
3. long-acting, which have a slower onset of action and act for long periods e.g.
insulin glargine, insulin detemir.
Short-acting insulin can also be given by continuous subcutaneous infusion using a
portable infusion pump and by inhalation. For adults who have special visual needs, a
confirmed and severe needle phobia or injection site problems, injection devices or
needle-free systems may be used (including inhaled insulin).
Efficacy and safety
A phase III global multi-centre trial is ongoing. The company are unable to provide any
information.
Trial Type 2 diabetes: placebo-controlled Type 1: Safety and efficacy
Sponsor Generex Biotechnology Corporation Generex Biotechnology Corporation
Status Conference abstract 13
Conference abstract 14
Location Israel Ecuador
Design Randomised, double-blind, placebocontrolled
Observational
Participants in trial n= 26. Type 2 poorly controlled on once n=29 (24 adolescents, 5 young adult).
daily insulin glargine and metformin. Type 1 diabetes. Stabilisation period of
• In addition to regular treatment, 10 standard therapy for 28 days.
minutes before meal:
Split doses of Generex Oral-lyn
o Group one: Generex Oral-lyn 3 replaced lunchtime injection of regular
times a day
o Group two: placebo 3 times a day
• If glucose values above 12mmol/L
before meal or before bedtime,
insulin for 6 months.
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September 2007 National Horizon Scanning Centre
News on emerging technologies in healthcare
Follow-up
additional puffs given.
12 weeks 6 months
Outcome Postprandial glucose, fasting glucose,
HbA1c, fructosamine
Safety and efficacy
Key results Interim results at 8 weeks:
21 subjects had good compliance. 8
• no change in fasting glucose
subjects had very poor compliance.
• 15.4% reduction in postprandial Good compliance score: 51.9 (standard
glucose in Generex Oral-lyn group deviation 14.97) vs. poor compliance
(211.2mg±53.7 to 178.5mg±39.1) vs. score 14 (standard deviation 10.87) (P<
3.5% elevation (202.7mg±60.1 to
210.1mg±5.2) in placebo
• Fructosamine 6.4% reduction in
Generex Oral-lyn group vs 3.6% in
placebo
• HbA1c 6.6% reduction vs 3.4% in
placebo
0.001).
Major adverse effects None stated
Trial Type 1: Controlled
Sponsor Generex Biotechnology Corporation
Status Conference abstract 15
Location Ecuador
Design Cohort, controlled
Participants in trial n=25. Type-1 diabetes. Stabilisation period of standard therapy.
Control Group (n=11) twice daily isophane insulin + three times daily regular
insulin
Treated Group (n=14) twice daily isophane insulin and three times daily prandial
split doses of Generex Oral-lyn.
Follow-up 99 days
Outcomes Fructosamine, HbA1c
Key results HbA1c: 7.3% to 6.8% in control group vs. 6.8 to 6.1% in Generex Oral-lyn group
(P≤ 0.035)
Fructosamine: 355.7 to 354.6 in control group vs. 313.2 to 319.2 in Generex Orallyn
group (not significant)
Major adverse effects None stated
Estimated cost and cost impact
The cost of Generex Oral-lyn is currently unconfirmed. Any potential increase in
treatment costs may be offset by savings from better health outcomes, potential reduced
healthcare service use due to improved compliance and improved glycemic control.
Potential or intended impact – speculative
Patients
� Reduced morbidity Reduced mortality or increased �Improved quality of life for
survival
patients and/or carers
Quicker, earlier or more accurate
diagnosis or identification of disease
Other: Non identified
Services
� Increased use: monitoring of
change from subcutaneous insulin
Decreased use
Service reorganisation required � Staff or training required
Other: Non identified
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September 2007 National Horizon Scanning Centre
Costs
� Increased unit cost compared to
alternative
New costs:
References
Increased costs: more patients
coming for treatment
� Savings: improved compliance
and control
News on emerging technologies in healthcare
Increased costs: capital
investment needed
Other:
1 National Institute for Clinical Excellence. Clinical Guideline. Diagnosis and management of type 1 diabetes in
children, young people and adults. July 2004
2 National Institute for Clinical Excellence. Inherited Clinical Guideline G. Management of type 2 diabetes:
Management of blood glucose. September 2002.
3 Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart. Volume
91 Supplement V, December 2005
4 Scottish Intercollegiate Guidelines Network. Management of Diabetes. 2001 (update 2005). Guideline number
55.
5 National Institute for Health and Clinical Excellence. Diabetes (type 1 and 2) – inhaled insulin. December
2006.
6 National Institute for Clinical Excellence. Guidance on the use of glitazones for the treatment of type 2
diabetes. London. August 2003.
7 National Institute for Clinical Excellence. Diabetes (type 1) - insulin pump therapy: The clinical effectiveness
and cost effectiveness of insulin pump therapy. February 2003.
8 National Institute for Clinical Excellence. Guidance on the use of long-acting insulin analogues for the
treatment of diabetes – insulin glargine. London. National Institute for Clinical Excellence. December 2002.
9 Diabetes UK. Reports and Statistics. Diabetes prevalence 2006. Hhttp://www.diabetes.org.uk/H. Accessed on
8 th August 2007.
10 National Institute For Health and Clinical Excellence. Final scope for type 2 diabetes guideline. June 2006.
11 Marshall SM, Flyvbjerg A. Prevention and early detection of vascular complications of diabetes. BMJ 2006;
333:475-480.
12 Diabetes Mellitus - an update for healthcare professionals. British Medical Association 2004.
13 Raz I, Dubinsky A, Kidron M et al. Addition of Oralin at meal-times in subjects with type-2 diabetes
maintained on glargine + metformin – a comparison with placebo. American Diabetes Association annual
meeting 2005 (abstract number 2063-PO)
14 Guevara-Aguirre J, Guevara-Aguirre M, Saavedra J et al. 6-Month Safety and Efficacy of Lunch-Time Oral
Insulin in Juvenile Type-1 DM Subjects Receiving Basal Glargine Insulin and Pre-Breakfast and Pre-Dinner
S.C. Regular Insulin. American Diabetes Association annual meeting. 2007 (abstract number 2760-PO)
15 Guevara-Aguirre J, Guevara-Aguirre M, Saavedra J. Comparison of Pre-prandial s.c. Regular Insulin vs
Prandial Oral Insulin in Adult Type-1 DM Subjects Receiving Basal s.c. Twice Daily Isophane Insulin (NPH).
American Diabetes Association annual meeting. 2007 (abstract number 0474-P)
The National Institute for Health Research National Horizon Scanning Centre Research
Programme is funded by the Department of Health.
The views expressed in this publication are those of the author and not necessarily those of the
NHS, the NIHR or the Department of Health
The National Horizon Scanning Centre,
Department of Public Health and Epidemiology
University of Birmingham, Edgbaston, Birmingham, B15 2TT, England
Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269
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