2 The condition

2.1

Hereditary transthyretin (hATTR) amyloidosis is an ultra-rare condition caused by inherited mutations in the transthyretin (TTR) gene. This causes the liver to produce abnormal TTR protein, which accumulates as deposits in body tissues (amyloidosis). These deposits can disrupt the structure and damage the function of affected tissues.

2.2

Because hATTR amyloidosis can affect tissues throughout the body, people may have a range of symptoms relating to 1 or more systems. These can include the autonomic nervous system, peripheral nerves, heart, gastrointestinal system, eyes and central nervous system. The effects and complications of the condition can lead to death within 3 to 15 years of symptoms developing. At the time of the evidence submission, there were thought to be around 150 people with hATTR amyloidosis in the UK.

2.3

Scoring systems for evaluating hATTR amyloidosis include scores based on disability due to peripheral neuropathy, for example, the polyneuropathy disability (PND) score and the familial amyloidotic polyneuropathy (FAP) stage (Coutinho et al. 1980). A description of each and the relationship between PND scores and FAP stages is reported in table 1.

**Table 1 Description and relationship between PND scores and FAP stages**
Polyneuropathy disability score	Score description	Familial amyloidotic polyneuropathy stage	Stage description
0	No impairment	0	No symptoms
I	Sensory disturbances, preserved walking capability	1	Unimpaired ambulation; mostly mild sensory and motor neuropathy in the lower limbs
II	Impaired walking capability but ability to walk without a stick or crutches	2	Assistance with ambulation needed; mostly moderate impairment progression to the lower limbs, upper limbs and trunk
IIIA	Walking only with the help of 1 stick or crutch	2	Assistance with ambulation needed; mostly moderate impairment progression to the lower limbs, upper limbs and trunk
IIIB	Walking with the help of 2 sticks or crutches	2	Assistance with ambulation needed; mostly moderate impairment progression to the lower limbs, upper limbs and trunk
IV	Confined to a wheelchair or bedridden	3	Wheelchair-bound or bedridden; severe sensory and motor neuropathy of all limbs

2.4

While some people with hATTR may mainly have either polyneuropathy or cardiomyopathy symptoms, most patients seen in the NHS will have both over the course of the condition. In the UK, the most common genetic mutations associated with combined polyneuropathy and cardiac involvement are Val122Ile (39%), Thr60Ala (25%) and Val30Met (17%). The Val30Met mutation is associated with higher survival rates. Val122Ile is primarily associated with cardiomyopathy.

2.5

At the time of the evaluation, treatment options for people with hATTR amyloidosis were limited. They mainly focused on symptom relief and supportive care (including pain management, and nutritional and mobility support), and lessening the effects of the condition on other organs (for example, pacemakers, arrhythmia management). During the evaluation of patisiran, NICE published its highly specialised technology guidance on inotersen, recommending it, within its marketing authorisation, as an option for treating stage 1 and stage 2 polyneuropathy in adults with hATTR amyloidosis. Other pharmacological treatments may be used, including diflunisal, which is sometimes used outside of its marketing authorisation to treat hATTR amyloidosis. It is contraindicated in people with cardiac impairment and those taking anticoagulants.

2.6

Liver transplant, which prevents the formation of additional amyloid deposits, might be an option for some people. However, a transplant can only be done early in the course of the condition, and outcomes are poor in people with cardiac involvement, so it is rarely done in England.

2.7

The National Amyloidosis Centre in London provides the only highly specialised service for people with amyloidosis and related disorders in the UK. People with hATTR amyloidosis are assessed (for overall clinical status, neuropathy progression and cardiac involvement) and followed up every 6 months at the Centre, and treatment is started there. The company proposes that people would start treatment with patisiran at the Centre and then, if appropriate, choose whether to continue to have treatment there or at home. At the second meeting, the company explained that some people already have patisiran at home after having 3 infusions in the Centre, and that this is expected to become the routine place for patisiran administration in clinical practice.