With over 7000 medicines in development, new treatments will continue to change patients’ lives; slowing disease progression, avoiding illness and reducing overall costs for healthcare systems. But developing a new medicines is a long, complex and risky process with no guarantees of success. Over the coming weeks we look at number of new medicines and role pharmaceutical incentives or IP has played in their development.

Transthyretin (TTR) Familial Amyloid Polyneuropathy (TTR-FAP) is a rare, progressive and fatal neurodegenerative disease that affects approximately 10,000 patients worldwide, although the prevalence is anticipated to be much higher.[1] [2] [3] It has been reported in 36 countries, including Portugal, Brazil, Japan, Sweden, the United States, Taiwan, France, Italy, Spain, and Germany. 

Mutations of the TTR gene can result in the production of unstable TTR proteins which can accumulate as amyloid fibrils. Amyloid fibrils can deposit in a variety of organs including the nerves, heart and kidneys, interfering with normal function.[4] [5]

Patients with TTR-FAP experience significantly diminished quality of life due to symptoms including polyneuropathy characterized by sensory loss, pain and weakness in the lower limbs; as well as severe impairment of the autonomic nervous system commonly manifesting as erectile dysfunction, alternating diarrhea and constipation, unintentional weight loss, orthostatic hypotension, urinary incontinence, urinary retention and delayed gastric emptying.[6] [7] [8] [9] Typically within 5 to 6 years of the onset of symptoms, patients lose the ability to walk, needing wheelchair assistance, and eventually become bedridden and unable to care for themselves.[10] [11] [12] TTR-FAP typically occurs during active adult years with onset as early as the 30s, followed by disease progression that reaches the terminal stage in approximately 10 years on average.[13] [14] [15]

TTR-FAP affects men and women equally. A person has a 50% chance of inheriting TTR-FAP, if a biological parent has it. 61% of caregivers of patients with TTR-FAP have reported symptoms of the disease.[16] On average, it takes four years for a patient to receive an accurate diagnosis. Living with TTR-FAP is a strain on personal resources, including finances and time, for both patients and their caregivers, who are often family members. As TTR-FAP progresses, many patients are unable to remain employed and struggle with participating in daily activities, such as household chores. When employed, both patients and their caregivers experience a significant disruption in work productivity.[17]

How Vyndaqel Works

Vyndaqel (tafamidis) is used to delay nerve damage caused by TTR-FAP in adult patients with stage 1 symptomatic polyneuropathy. The active substance in Vyndaqel, tafamidis, is a TTR stabilizer. It attaches to TTR, which prevents the protein from breaking up, thereby stopping the formation of amyloid and slowing down the progression of the nerve disease.

Before the approval of Vyndaqel there were no approved medications to treat TTR-FAP and the only available treatment of this rare disease was liver transplantation.[18] Vyndaqel represents a major advancement for patients with this rare, progressive and fatal disease.

Challenges in Developing the Medicine

The discovery and development programme for Tafamadis was conducted over the past 20 years, with clinical trials starting in 2005. In total, there have been 13 clinical trials and two non-interventional, observational studies of tafamidis, with experience in 127 patients.

The active pharmaceutical ingredient, specifically tafamidis meglumine salt, and the softgel capsule formulation posed several technical challenges to overcome. These included stability challenges that negatively impacted the shelf-life and commercial supply chain for the product. Pfizer’s pharmaceutical sciences and global supply teams (more than 20 colleagues) worked in partnership also with external scientists over a period of 6 years to enhance the robustness of the product by refining its components, applying appropriate manufacturing controls and identifying more protective packaging to improve its long term stability.

The Pharmaceutical Incentives and Rewards for innovation

In November 2011 the European Commission approved Vyndaqel for the treatment of TTR amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment. The medicine had previously been granted orphan designation by the European Commission, which was maintained when it was authorised for marketing.

As an orphan medicine, Vyndaqel benefits from ten years of orphan market exclusivity from the date when it was authorised for marketing in the European Union. During this period Vyndaqel is protected from market competition with similar medicines approved for the same orphan designated indications.

Given the rarity of TTR-FAP and the challenges inherent in developing the product, the orphan incentive was an important factor in bringing Vyndaqel through the R&D process and making it available to patients.

[1] Dattilo PB. Familial (ATTR) amyloidosis misdiagnosed as primary (AL) variant: a case report. Cases J. 2009;2:9295-9298.

[2] Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic polyneuropathy. Arch Neurol. 2005;62:1057-1062.

[3] Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007;36:411-423.

[4] See footnote 3 (Benson).

[5] Hou X, Aguilar M-I, Small DH. Transthyretin and familial amyloidotic polyneuropathy: recent progress in understanding the molecular mechanism of neurodegeneration. FEBS J. 2007;274:1637-1650.

[6] See footnote 3 (Benson).

[7] See footnote 5 (Hou).

[8] Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.

[9] Sekijima Y, Yoshida K, Tokuda T, Ikeda S. Familial transthyretin amyloidosis. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews [Internet]. Seattle WA: University of Washington, Seattle; 1993-2009. http://www.ncbi.nlm.nih.gov/books/NBK1194/. Accessed January 31, 2011.

[10] Jonsèn E, Athlin E, Suhr O. Familial amyloidotic patients’ experience of the disease and of liver transplantation. J Adv Nurs. 1998;27:52-58..

[11] Coutinho P, da Silva AM, Lima JL, Barbosa AR. Forty years of experience with type 1 amyloid neuropathy: review of 483 cases. In: Glenner GG, e Costa PP, de Freitas AF, eds. Amyloid and Amyloidosis. Amsterdam: Excerpta Medica; 1980:88-98.

[12] Suhr OB, Svendsen IH, Andersson R, et al. Hereditary transthyretin amyloidosis from a Scandinavian perspective. J Intern Med. 2003;254:225-235.

[13] See footnote 5 (Hou).

[14] See footnote 10 (Jonsèn).

[15] Plante´-Bordeneuve V, Ferreira A, Lalu T, et al. Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP). Neurology. 2007;69:693–698.

[16] Stewart M, Loftus J, Lenderking WR, et al. Characterizing disease burden in an ultrarare disease in the U.S. Poster presented at: ISPOR 16th Annual European Congress, November 4-6; 2013, Dublin, Ireland.

[17] See footnote 17 (Stewart).

[18] http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2009/11/human_orphan_000690.jsp&mid=WC0b01ac058001d12b