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The Institute of Clinical and Economic Review (ICER), is an independent organization that seeks to improve healthcare value by providing comprehensive clinical and cost-effectiveness analyses of treatments. In February they held an open input period for their planned review of inotersen and patisiran treatments for hereditary transthyretin-related amyloidosis (hATTR).This allows ICER to address the concerns of the community such as disease burden, patient preferences, importance of the treatments and current treatment landscape from patients, clinicians, policymakers, manufacturers and other healthcare decision makers and ensure that the report has the broadest possible relevancy.

ARC provided an extensive outline in response to ICER’s draft scoping document for the evaluation of patisiran and inotersen for hATTR and, as a result, changes to their draft were made in accordance with the feedback ARC provided.

The Revised Scoping Document for ICER’s upcoming evaluation of inotersen and patisiran treatments has now been published and can be reviewed here.

Below is a copy of the report ARC provided:

Proposed patient population for the review

The scoping document states that ‘the population of focus for the review is adults with hereditary (hATTR) amyloidosis, formerly known as familial amyloid polyneuropathy (FAP).’ This is not an accurate description of hATTR. hATTR is characterized by the deposition of amyloid derived from transthyretin in various organs and tissues, including peripheral nerves and the heart. hATTR-FAP and familial amyloid cardiomyopathy (hATTR-FAC) – also known as hATTR-PN and hATTR-CM – are two clinical presentations of hATTR, but they are not mutually exclusive; many hATTR patients will experience both polyneuropathy and cardiomyopathy.

For the avoidance of doubt, the background and population sections should clarify that this is a multi-systemic disease. While all patients in the studies for the drugs under review had familial amyloid polyneuropathy (hATTR-FAP or hATTR-PN), patients may have also had cardiac involvement; as such, exploratory cardiomyopathy endpoints were also included in the studies and may be relevant for this evaluation.

Current treatment of hATTR

ARC considers it important to clearly outline the current treatment paradigm for the hATTR patient population to set the right context for the evaluation of the new treatments. Currently there is no licensed or off-label disease-modifying treatment approach that constitutes standard of care in hATTR.

Tafamadis is not approved by the FDA for hATTR-FAP and clinical trials for use of tafamidis in hATTR-CM remain ongoing. Some patients continue to receive open-label treatment with patisiran or inotersen following their participation in controlled studies, or through each product’s expanded access program.

While liver transplantation is a potential treatment, it is only indicated for a very small minority of this patient population with very early stage polyneuropathy. Furthermore, due to personal preference, concern over transplant-related risks and shortage of organ availability, very few patients receive this treatment.

The scoping document refers to diflunisal as being ‘currently considered first line treatment’. Diflunisal is used off-label with a considerable number of hATTR patients. However, it is contraindicated for certain patients (for example, those who are on anticoagulants). It is also unlicensed for this patient population and there is only limited evidence of its effectiveness. Clinical experts tell us that while it is used in the absence of alternatives, there is no clear evidence of its effectiveness. As such we do not think it is an appropriate comparator for this evaluation.

Symptom management approaches are the basis of current standard of care alongside diflunisal. These approaches do not delay the course of the disease but can alleviate disabling symptoms and improve quality of life, for example, by reducing neuropathic pain (e.g. gabapentin) and improving autonomic function, particularly gastrointestinal symptoms (e.g. immodium, codeine, erythromycin and rarely colostomy), cardiac function (e.g. diuretics) and blood pressure control. To this end, ICER should consider the main symptom management approaches as being the mainstay of standard treatment.

Analytic framework – direct comparison

hATTR patients and their families are eagerly anticipating the availability of the two treatments covered by this evaluation (patisiran and inotersen) as well as future new licensed treatments that have the potential to modify and delay progression of their disease.

We note in the analytic framework that ICER intends to directly compare patisiran and inotersen should data allow. Despite some obvious similarities between the two drugs they should not, however, be considered as equivalent. Both drugs offer considerable potential benefits and a significant step change in the management of hATTR. ARC believes it is important that both options should be available for patients and their physicians to choose from, based on personal preference, feasibility and other factors.

From a patient perspective the different administration of these drugs is a critical consideration alongside the differences in their potential efficacy benefits and side-effects.  For many patients, regular infusions in hospital or in alternative setting (patisiran) will not be feasible or desirable, while for other patients such a regimen may be feasible and/or preferred over inotersen after consideration of all the factors associated with both treatments.

In addition, should patients need to discontinue one of the treatments for any reason (for lack of efficacy or undesired effects) they should have the option of trying an alternative. Assuming equivalence could limit choice for clinicians and patients and jeopardise their to effectively manage the disease.

Analytic framework – potential other benefits and contextual considerations

This patient population has very significant unmet need. The disease is extremely debilitating and life-limiting for which current standard of care is predominantly limited to symptom management.

The physical effects of the disease impact the ability of many patients to function day-to-day and to participate in family, work and social activities. As symptoms deteriorate, many patients are no longer able to be independent. They may lose the ability to walk, drive and work, leading to additional financial, emotional and caregiver burden.

The disease causes a tremendous emotional burden, and this often extends to caregivers and family members. The hereditary nature of the disease means many patients have been caregivers for loved ones before succumbing to the disease themselves and live with the knowledge that they may pass it onto their children. The disease has a substantial lifelong impact on entire families.

The disease places a significant burden on family members as they provide physical and emotional care to patients while experiencing a considerable emotional burden of their own in dealing with the realities of the disease. Family members often become full or part-time caregivers with consequences on their work, social and financial situations.

In offering an option that can stabilize and stop further deterioration these new treatments can make a considerable improvement to patients’ and families’ quality of life. Effective control of the disease could support patients and caregivers to remain at work, retain independence and participate in family and wider life. It could also significantly reduce patients’ reliance on and use of supportive care treatments.

The technologies themselves are also innovative in the way they offer a novel treatment approach for this disease. To date there are no alternatives that inhibit the production of transthyretin, thereby slowing the progression of the disease.

In providing an effective disease-modifying option, these treatments represent a significant step change in the potential management of hATTR and in meeting the unmet need of this patient population.

There are numerous health benefits that are not fully captured by the clinical data. hATTR is a heterogeneous disease and patients are affected by symptoms in different ways. Fatigue, peripheral neuropathy, gastrointestinal events, incontinence, erectile dysfunction, muscle weakness, pain, insomnia and vision problems are particularly cited by patients and family members in our research as having a significant impact on their quality of life. Not all of these are captured by the clinical data or quality of life tools, yet it is important to recognize that control of the disease could improve the specific symptoms that matter most to patients.