SirolimusA classic case of drug repurposing in the treatment of CHI

A parent’s perspective

A parent’s perspective

What is hyperinsulinism (CHI)

Scarlett’s journey living with the disease

and her treatment using sirolimus

The HI Fund, the Children’s Hyperinsulinism

Charity, their link with Findacure and the

future

What is hyperinsulinism (CHI)

The body has a unique system of controlling

blood glucose levels

In CHI the pancreas is blind to the blood sugar

levels and therefore continues to produce

insulin which results in hypoglycaemia

Difficulties / delays in diagnosis and treatment

means children can suffer permanent brain

injuries, cerebral palsy, or even death

CHI Video

CHI video

Histology / presentation

2 main types – Diffuse and Focal

Diffuse – throughout the whole of the

pancreas

Focal – localised – chance of cure –

sometimes misleading as can be

widespread in reality

CHI treatment flowchart

Scarlett’s journey living with

the disease and her treatment

using sirolimus

Day of Scarlett’s birth

Scarlett was born on 21/07/2012 at 6pm

7 weeks early weighed 5lb 4oz

Emergency c – section due to suspected vasia praevia

Put in Special Care Baby Unit as precaution

On CPAP for first few hours of life

Blood glucose level low so given IV dextrose

Scarlett at SCBU Warwick

Warwick Hospital – 18 days

Blood glucose level remained persistently low

Utilised umbilical cord to use higher strengths of dextrose

Initially under management of UHCW then under BCH. BCH couriered over some diazoxide - unresponsive

Scarlett being transferred

from Warwick to Birmingham

Birmingham Children’s Hospital

Transferred from Warwick to BCH on Tuesday afternoon

Continued on diazoxide

Canula put on head because of serious trouble with IV access – Kelly distraught!

Lowest blood sugar 1.2

On emergency theatre list for central line

Central line inserted on Friday lunch

Registrar stated need for transfer to GOSH

Saturday am – transferred to GOSH

Scarlett central line insertion

Arrival at GOSH Arrive at Rainforest ward

Met HI team on Monday morning

Discuss plan for Scarlett

Treatment begins on diazoxide again!

Genetic tests for me and Kelly

GOSH – early stages

Scarlett remains unresponsive to diazoxide

Scarlett begins treatment on octreotide

Several attempts made to wean Scarlett off

medication

Scarlett always showed positive signs until last

moment then reverted back to start again!

Decision to send her for a PET scan

Family photo at GOSH

GOSH – 18F Dopa PET scan Gold standard in diagnosis of CHI

Genetics test results come back

inconclusive

Scarlett went for PET scan and was first

NHS patient to have PET CT scan at UCLH

Scarlett confirmed as having diffuse

disease

PET Scan

PET scan image

Post PET scan Further attempts with Diazoxide and

Octreotide.

Mid – late October Scarlett reacting well to treatment and Prof. Hussain suggested may be able to go home – never say Scarlett is doing well!

Within 24 hours on continuous feed and 50% dextrose! – Kelly devastated!

Surgery

Start November Dr Hussain and HI team

felt surgery was the only option left

Met with Professor Pierro – surgeon and

date was set for November 17th

Scarlett begins process of increasing

weight for surgery

Sirolimus – a lifeline

Dr Hussain and HI team suggested Scarlett start sirolimus on the basis that there is no harm trying at this stage. Scarlett fed well and in general good health.

Me and Kelly have no real idea of what it is but request the team promise that surgery is not cancelled as we just want to get home by now.

Within a week significant improvement. In 2 weeks off IV dextrose and allowed home.

Scarlett’s first trip outside and home!

What is sirolimus

Oral solution known as Rapamune

Used primarily as a immuno - suppressant

drug to stop rejection of organs in kidney

transplants.

Studies shown to have common side

effect of increasing blood sugar levels -

hyperglycaemia

Sirolimus oral solution

How it is believed to work

Sirolimus is known as a m - TOR inhibitor. m

- TOR – (mammalian – target of

rapamycin)

m – TOR is a key signalling kinase

(enzyme) that affects broad aspects of

cellular functions, including metabolism,

growth, aging and memory.

Use of sirolimus leads to hyperglycaemia

resulting in normogylcaemia in diffuse HI

patients.

M – TOR signalling pathways

Other uses of sirolimus

Genetic epileptic condition

Lung disease LAM

EHE cancer

Cystic hygroma

Tuberous Scelorosis Complex TSC

Von Hippel Lindau syndrome VHL

Familial Multiple Discoid Fibromas FMDF

Gleoneuronal brain tumours

Use to date on CHI patients

First used at Great Ormond Street Hospital in

November 2012 on Scarlett.

Used with success on other patients at

GOSH subsequently.

Now being used at the other UK specialist

designated centre in Manchester and

around the world – Canada, Australia and

North America

Journal published

A paper was published in the New England Journal of Medicine recognising the work carried out by the research team in London on June 19th 2014.

Paper named: Sirolimus in Severe Hyperinsulinemic Hypoglycemia.

Paper showed that 4 patients with diffuse disease achieve normoglycemia after 12 months

Scarlett’s sirolimus journey First patient to successfully remain stable long

term – over 3 and a half years to date. Avoiding major surgery to remove entire pancreas.

Number of upper respiratory tract (lung) infections - seasonal

Takes preventative antibiotic daily to counteract risk of respiratory infection

Has octreotide injections 4 times daily – slowly being weaned off

Gastrostomy inserted in November 2013 due to poor eating

Scarlett Today Scarlett is below lowest percentile for her height

In 18 – 24 months clothes at 3 and half years of age

Scarlett’s weight is approximately 15.35kg

Big improvement in growth since gastrostomy (weight and height)

Feeding still remains a big issue – nowhere near enough eaten to keep stable

Use gastrostomy to provide sufficient calories to keep stable – 80% of RDA – 20% orally

Family photo today

Scarlett next

At nursery school. Working on EHC plan for primary school

Produce care plan in case of emergency in conjunction with HI team

Improve her eating working with dieticians at GOSH

Getting her off the octreotide injections

Scarlett not suffered any development delay due to early treatment / diagnosis

Scarlett bones have a low density – possible mild brittle bone disease – awaiting further investigation

The HI Fund, Children’s

Hyperinsulinism Charity, link

with Findacure and the future

The HI Fund

Founded in 2003

Funds used to pay for research

Raised over £350,000 to date

Restricts who can be approached / use of

funds

The Children’s Hyperinsulinism

Charity

Charitable status granted this month

Allows the charity to approach private

organisations

Use funds to provide family conferences,

raise awareness and back into HI Fund

Approached Professor Hussain in 2015 about Crowdfunding campaign – begins in March 2016

Working to establish cost of CHI to the NHS –drug repurposing

Carrying out interviews with rare disease publications to raise awareness of CHI

Crowdfunding campaign

photos

Crowdfunding campaign

Scarlett

No major surgery

Pre-feed testing

Non diabetic

Eating issues

High infection risk

Grow out of condition

Jessica

Major surgery

CGM – hourly

Type 1 diabetic

Enzyme treatment

Normal infection risk

Life long treatment

The costs of CHI to the NHS

and families

Visible

GPs

Local hospital

Specialist centres

Surgical costs

Prescriptions

Hidden

Psychological

Time

Financial

Missing out

Form filling!

Loneliness

Planning everything

The future……

Lobbying MPs and raising awareness

Working with Findacure and Eurordis

Xoma 358 – correcting faulty cells

Sirolimus without immuno-suppressant qualities

Betacure project – imaging during surgery

New drug trial at GOSH – unknown at present

Thank you for listening and

please ask any questions