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Safety in Lactation: Drugs for movement disorders

10 November 2018Additional information relating to breastfeeding To be used in conjunction with individual drug entries for specific information and guidance.  Drugs for dystonias and other involuntary…
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Lactation Safety Information

-
For transthyretin amyloidosis
No published evidence of safety
Low levels anticipated in milk due to very high protein binding although very long half-life increases risk of accumulation in breastfed infants
Monitor infant for adverse effects associated with adult use
8 November 2018

New Medicines

Vyndaqel (EU), Vyndamax (US) Transthyretin cardiomyopathy (TTR-CM), wild-type or hereditary - free acid formulation of tafamidis (61mg)

Information

Vyndaqel (EU), Vyndamax (US)
New formulation
Pfizer
Pfizer

Development and Regulatory status

Licensed but not launched
Approved (Licensed)
Launched
Yes
Mar 21NICE appeal hearing takes place [15].
Jan 21Due to the COVID-19 pandemic and increasing pressures on the NHS at the moment, health service representatives are busy on the NHS front-line and unable to sit on an appeal panel at the present time. Therefore the appeal hearing on 18 & 19 January has been postponed and will be rescheduled for a later date. This will delay plans for UK launch [14].
Feb 20Approved in EU [13].
Dec 19Tafamidis 61mg capsules are available in the UK via the Early Access to Medicines Scheme [12].
Dec 19The European line extension application was based on the PIII ATTR-ACT study, plus findings from an evaluation of the free acid form of tafamidis 61mg. The tafamidis 61mg capsule corresponds to an 80mg tafamidis meglumine dose (4x 20mg capsules) and was developed for patient convenience to enable a single capsule for daily administration. VYNDAQEL 61 mg and VYNDAQEL 20 mg are not substitutable on a per milligram basis [10].
Dec 19Pfizer announced today that the CHMP of the EMA has adopted a positive opinion recommending approval of tafamidis 61mg capsules (Vyndaqel) for treatment of wild-type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy [10].
Sep 19Pfizer launches 61mg capsules of tafamidis meglumine in the US for the treatment of ATTR-CM in adults to reduce cardiovascular mortality and cardiovascular-related hospitalisation [11].
May 19Pfizer estimates Vyndamax 61mg capsules will be commercially available beginning in latter half of 2019, as the product is currently being manufactured. They aim to transition all patients from Vyndaqel to Vyndamax once sufficient supply is available, given its convenient, single capsule daily dosing. The products are not substitutable on a per milligram basis [9].
May 19Pfizer have announced a list price of $225,000 per year [8].
May 19Approved in US [7].
Jan 19The submission for the tafamidis free acid formulation (61mg, capsule) was based on results from the pivotal PIII ATTR-ACT study which used the meglumine salt [5].
Jan 19Pfizer have filed NDAs for two forms of tafamidis (meglumine salt and free acid) with US FDA. Tafamidis meglumine form (20 mg capsule) has been granted Priority Review with a target PDUFA action date of July 2019. Tafamidis free acid form (61 mg capsule) will be under Standard Review. This form is bioequivalent to the 80 mg tafamidis meglumine dose, which was administered as four 20 mg capsules in ATTR-ACT trial; it was developed for patient convenience to enable a single capsule for daily administration. Target PDUFA action date for this is November 2019 [4].
Dec 12Orphan designation (EU/3/12/1066) granted in the EU for the treatment of senile systemic amyloidosis. Already has orphan drug status in the US for symptomatic transthyretin amyloid cardiomyopathy [1].

Category

Amyloid fibrillogenesis inhibitor; first-in-class pharmacological chaperone and disease modifying agent. Free acid formulation.
Transthyretin (TTR)-related familial amyloidotic cardiomyopathy is a hereditary TTR-related systemic amyloidosis (ATTR) with predominant cardiac involvement resulting from myocardial infiltration of abnormal amyloid protein. Prevalence is unknown. In patients with cardiac-related symptoms, 5-year survival is less than 50%. Major events include progressive heart failure and sudden death due to arrhythmia [6].
Transthyretin cardiomyopathy (TTR-CM), wild-type or hereditary - free acid formulation of tafamidis (61mg)
Oral

Further information

Yes
To be confirmed

Trial or other data

Mar 18Pfizer announce primary endpoint met in PIII ATTR-ACT study, demonstrating a statistically significant reduction in combination of all-cause mortality and frequency of cardiovascular-related hospitalizations compared to placebo at 30 months. Preliminary safety data show that tafamidis is generally well tolerated in this population [3].
Nov 13NCT01994889 is a PIII an international, double-blind, randomized study of tafamidis meglumine 20mg or 80mg daily vs placebo in 400 subjects diagnosed with transthyretin cardiomyopathy (TTR-CM). The primary outcome is all-cause mortality and frequency of cardiovascular-related hospitalization over 30 months. Inclusion criteria include: medical history of heart failure, evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness > 12 mm and presence of amyloid deposits in biopsy tissue and presence of a variant TTR genotype and/or TTR precursor protein identification by mass spectrometry. The study starts Dec 13 and is due to complete Oct 17 [2].

Evidence based evaluations

VyndaqelTransthyretin cardiomyopathy (TTR-CM) - meglumine salt of tafamidis (20mg)

Information

Vyndaqel
Licence extension / variation
Pfizer
Pfizer

Development and Regulatory status

Not recommended for approval (Negative opinion)
Not recommended for approval (Negative opinion)
Launched
Yes
Yes
Dec 19 It is not clear at this time whether Pfizer applied for a licence extension for the 20mg capsule formulation of Vyndaqel, as no official negative opinion has been issued (rather the licence for the 20mg formulation has been confirmed as not including ATTR-CM) [15].
Dec 19The EAMS for Vyndaqel applies to the 61mg free acid formulation, not the 20mg meglumine formulation [13].
Dec 19EU CHMP has not approved Vyndaqel 20mg capsules (tafamidis meglumine) for ATTR-CM. This formulation is indicated only for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment [15].
Dec 19Recommended for EU approval under exceptional circumstances by CHMP - as a new presentation, tafadimis free acid 61 mg soft capsules; the indication for the new presentation is ”for the treatment of wild‑type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM)"[15].
May 19Is currently pre-registration in the EU [14].
May 19MHRA gives Early Access to Medicines Scheme (EAMS) opinion to Pfizer for Vyndaquel for "treatment of transthyretin amyloidosis in adult patients with wild type or hereditary cardiomyopathy to reduce all-cause mortality and cardiovascular-related hospitalisation". EAMS opinions allow companies to market medicines in the UK before full licensing where there is considered to be a high unmet clinical need and a full risk-management scheme is in place [13].
May 19Pfizer have announced a list price of $225,000 per year [12]
May 19Approved in US [11]
Jan 19Pfizer have filed NDAs for two forms of tafamidis (meglumine salt and free acid) with US FDA. Tafamidis meglumine form (20 mg capsule) has been granted Priority Review with a target PDUFA action date of July 2019. Tafamidis free acid form (61 mg capsule) will be under Standard Review. This form is bioequivalent to the 80 mg tafamidis meglumine dose, which was administered as four 20 mg capsules in ATTR-ACT trial; it was developed for patient convenience to enable a single capsule for daily administration. Target PDUFA action date for this is November 2019 [10].
May 18FDA grants breakthrough therapy designation based on topline results from the ATTR-ACT study. [9]
Oct 15PIII development continues. Tafamidis has orphan status in EU & US for familial amyloid cardiomyopathy due to a genetic variation of the TTR gene (TTR-FAC) [4].

Category

Amyloid fibrillogenesis inhibitor; pharmacological chaperone and disease modifying agent. Meglumine salt.
Transthyretin (TTR)-related familial amyloidotic cardiomyopathy is a hereditary TTR-related systemic amyloidosis (ATTR) with predominant cardiac involvement resulting from myocardial infiltration of abnormal amyloid protein. Prevalence is unknown. In patients with cardiac-related symptoms, 5-year survival is less than 50%. Major events include progressive heart failure and sudden death due to arrhythmia [3].
Transthyretin cardiomyopathy (TTR-CM) - meglumine salt of tafamidis (20mg)
Oral

Trial or other data

May 19Currently, there are no approved pharmacological treatments specifically indicated for transthyretin cardiomyopathy and the average life expectancy for people with this is 3 to 5 years from diagnosis [9]
Mar 18Pfizer announce primary endpoint met in PIII ATTR-ACT study, demonstrating a statistically significant reduction in combination of all-cause mortality and frequency of cardiovascular-related hospitalizations compared to placebo at 30 months. Preliminary safety data show that tafamidis is generally well tolerated in this population [8].
Aug 17Phase III development for Cardiomyopathy is ongoing in the EU and USA (NCT01994889) [7]
Jun 16Pfizer initiates a PIII extension trial (NCT02791230) for Cardiomyopathy in US [6] .
Nov 15The PIII ATTR-ACT study (NCT01994889) is ongoing, but not recruiting participants [5].
Mar 15PIII ATTR-ACT study (NCT01994889) continues to recruit pts. Now due to complete Aug 18 [2].
Nov 13NCT01994889 is a PIII an international, double-blind, randomized study of tafamidis meglumine 20mg or 80mg daily vs placebo in 400 subjects diagnosed with transthyretin cardiomyopathy (TTR-CM). The primary outcome is all-cause mortality and frequency of cardiovascular-related hospitalization over 30 months. Inclusion criteria include: medical history of heart failure, evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness > 12 mm and presence of amyloid deposits in biopsy tissue and presence of a variant TTR genotype and/or TTR precursor protein identification by mass spectrometry. The study starts Dec 13 and is due to complete Oct 17 [1].

Evidence based evaluations