AMRN
Está un poco asquerosito de formato, pero os servirá. Son mis apuntes directos del informe de la FDA.
" el experto aprobaría la dosis de 4g de Vascepa en enfermos con triglicéridos muy altos > 500 mg/dl especialemnte en aras de la prevención de la pancratitis y los problemas cardíacos
The applicant also submitted a
study report for the ANCHOR tr
ial; the dataset for this
trial was not submitted as part of the
NDA. The applicant had been told by the Agency
that since the ANCHOR trial was conducted in
a population different
from that sought in
the indication, ANCHOR would not suppor
t the indication for very high TG >
500 mg/dL.
The MARINE trial is the focus of the effica
cy review in Section 6, whereas the safety
review focuses on both the pooled data from
the MARINE and the ANCHOR trials (the
Hypertriglyceridemic Placebo-Controlled Dataset)
No safety signals were noted in the market
ing application which wo
uld require specific
post-marketing safety evaluation other than outlined un
der 21 CFR 314.80
Dice que algunos estudiso habían hecho saltar las alertas sobre los posibles efectos secundarios de los aceites estos, pero que han quedado disipados con el metaanálisis Cochrane. Además, el estudios Jelis japonés sobre Lovaza tampoco arroja preocupaciones especiales. La FDA concluye que los efectos secundarios no tienen importancia o son asumibles.
Los estudios Marine y Anchor demuestran el efecto farmacocinético del aceite en la disminución de los triglicéridos.
El proceso de absorción es similar que el de las grasas de la dieta alimenticia
This study was conducted with a total daily dose of 2g of Vascepa in
both Groups A and B. Therefore the maximum dose of 4g Vascepa was not studied.
There are studies in the literature which i
ndicate that exposure to omega-3 FA need to be
in the range of several weeks and up to 52 weeks for change in bleeding times to be
observed. Furthermore, a study with patients on background aspirin and clopidogrel
therapy would have been useful to further evaluate a bleeding risk.
El único problema tonto que veo hasta el momento es que no se han presentado estudios con los 4g
This application also contained a study r
eport, but not the dataset, for the ANCHOR
trial. This trial was not considered pivotal
to the efficacy claims
of Vascepa for this NDA.
The ANCHOR trial investigated patients
with TG between 200 mg/dL and 499 mg/dL
despite statin therapy. The applicant was told
prior to this NDA submission that data
from the ANCHOR trial woul
d not be mentioned in the Vascepa labeling until, at a
minimum, 50% enrollment of a cardio
vascular outcomes trial was reached.
Important Safety Issues With
Consideration to Related Drugs
With regard to the only other FDA approved omega-3 fatty acid product (Lovaza), there have been four areas of potential safety concern: increases in LDL-C, liver enzymes, blood glucose, and a possible increase in bleeding risk.
The increase in LDL-C is thought to be due to the increased activity of LPL activity.4 This increased activity enhances the conversion of very low density lipoprotein (VLDL) and intermediate –density lipoproteins (IDL) to LDL-C. The current Lovaza label states that patients with hepatic impairment should have ALT and AST monitored periodically during therapy . This stems from a greater number of patients with upward shifts in ALT levels, without a concurrent increase in AST shifts in the Integrated Summary of Safety (ISS) of Lovaza monotherapy trials.
Historically, some studies have raised concern that omega-3 ethyl ester consumption could increase fasting plasma glucose (FPG) without corresponding increase in Clinical Review Iffat Nasrin Chowdhury, MD NDA 202057 Vascepa/Icosapent Ethyl 14 HbA1C.5 However, a recent Cochrane meta-analysis suggested that neither the FPG nor the HbA1c increased with omega-3 ethyl ester therapy.
6
Pooled data from the Lovaza NDA datasets (post-hoc) showed a slight increase in median FPG in the Lovaza
treatment group (median change +6.5mg/dL) as compared to the placebo group (+2 mg/dL).
Metabolism of omega-3 fatty acids, specifically EPA, produces eicosanoids of the thromboxane A3 and leukotriene 5 series, which are associated with reduced platelet aggregation, increased vasodilation, and
inhibited leukocyte chemotaxis.
7
Omega-3 acid ethyl esters have been shown in vitro to significantly reduce platelet aggregation by
reducing production of thromboxane A2 and increasing production of thromboxane A3.
The relationship of these in vitro findings to bleeding risk is much less clear. Currently the labeling for Lovaza includes cautionary statements with regard to bleeding risk. In addition to safety issues related to Lov
aza,, ethyl EPA has been investigated in a large study in Japan. In The Effects of eicosapentaenoic
acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-la
bel, blinded endpoint analysis, 18,645 Japanese patients were randomly assigned to either 1800 mg of EPA
plus a statin or statin alone.
Safety concerns in this study included changes in creatine phosphokinase (CPK) and liver enzymes. Adverse effects (AEs) that were more common in the treatment group than in the control group included gastrointestinal
disturbances, skin abnormality, and haemorrhage (cerebral, fundus, epitaxis, subcutaneous). No further information on bleeding events is available from the published JELIS report.
The Agency issued a review of the safety of EPA and DHA administered or consumed together in the Federal Register of June 5, 1997 (US FDA Substances Affirmed as Generally Recognized as Safe,
With respect to effects on bleeding ti
me, the FDA concluded that although EPA and DHA appeared to cause small, dose-related increases in bleeding time of unclear clinical relevance, bleeding time increases associated with the use of 3g/day or less of
EPA plus DHA either do not occur or are of no adverse significance.
With respect to the effects on glycemic control in type 2 diabetics, the FDA concluded that a dose-related effect is likely, and may be clinically relevant at high daily intake levels, but a daily intake if 3g/day or less of EPA and DHA causes no clinically significant effects on glycemic control.
With respect to effects of EPA and DHA on LDL-C, the FDA concluded that there appeared to be a trend toward increased LDL-C with increased fish oil consumption in all population subgroups, with a magnitude of the increase appearing greater in populations with abnormal blood lipid levels, hypertension, diabetes, and cardiovascular disease
A preIND meeting was held on 14 July 2008. During the discussion, it was agreed that a
single study could potentially suffice for the indication “as an adjunct to diet to reduce triglycerides in adult patients with very high > 500 mg/dL triglyceride levels” provided that the results are robust. The agency defined robust re sults as: results that are statistically significant; results from a study with a low drop out rate; study results that are consistent across treatment centers; and results from a study with a large sample size.
On 26 April 2010, the applicant requested to change ANCHOR due to low enrollment. Agreement was reached to change the HbA1C exclusion criteria from 9.0% to 9.5%; to nicrease the LDL-C entry criteria upper limit by 15% to >40 to <155 mg/dL; and to increase the TG entry criteria to >170 mg/dL.
The applicant is relying on non-clinical literature references for the marketed Japanese product Epadel to support this application
According to the pharmacology/toxicology reviewer, there's a reasonable evidence to conclude that Vascepa is highly similar to the marketed ethyl-EPA product Epadel for the following points:
- source of ethyl-Epa before purification is fish.
- Specification for purity of ethyl-epa are identical (>96%)
- The impurities for each product are similar, but not identical; however, the concentration limits for this are generally low intemediates in x metabolism are part of the complex mixture of x
Non clinical repeat dose toxicolody study results fueron similares pero no completamente idénticos entre ambos productos en ratas (probaablemente debido a la variabilidad experimientan entre estudios, que es aceptable). Este las similitudes se encuentran, por ejemplo, alteraciones de la piel/pelo con secreción de grasa, alteraciones del recuento de glóbulos blancos, de los factores de coagulación y aumento de las enzimas hepáticas.
A partir de los datos científicos y perfiles toxicológicos, es razonable concluir que Epadel y Vascepa son productos similares.
Sin embargo, desde una perspectiva reglamentaria, Amarin no ha demostrado de manera direta la comparatibilidad ente Epadel y Vascepa. Hay ausencia de un esdudio directo o de farmacocinética realizado por AMarin que demuestre la comparabilidad entre ambos. ES por tanto que se envió la carta de 74.días a AMRN:
“As there is no adequate bridging information to Epadel, conduct an appropriate non-clinical study (e.g. 28-Day repeat dose toxicology study in the rat) to demonstrate at a minimum, PK comparability between Epadel and Vascepa (AMR101), so that you may rely on published Epadel literature for your 505(b)(2) application.
Como respuesta, el solicitante accedió a realiza un estudio no clínico que ligara la información entre Epadel y Vascepa que presentó el 17 de mayo de 2012 " A 4 Week Study of AMR101 and Epadel by Oral Gavage
Administration in Rats". E lequipo de farmacología/toxicologío concluyó que este estudio demostraba el vínculo entre ambos.
Omega-3 fatty acids (omega-3 FA), fats commonly found in marine and plant oils, are considered “essential” fatty acids, meaning that they cannot be synthesized by the human body but are vital for normal metabolism.
8
The three most commonly known omega-3 FA are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and
alpha-linolenic acid (ALA)
he drug product from Amarin contains a purified icosapent ethyl.
Icosapent ethyl (ethyl
eicosapentaenoic acid or ethyl-EPA) is the et
hyl ester of EPA. Icosapent ethyl acts as a
prodrug for EPA, as it is hydrol
yzed enzymatically by esterases, particularly pancreatic
lipase, to liberate the free acid EPA.
Mechanism of Action
A single mechanism of acti
on to explain the effects of omega-3 FA has not been
identified. Instead, multiple ph
armacologic effects are involv
ed. Results from preclinical
and clinical studies suggest that EPA
1) reduces hepatic very low-density lipopr
otein triglyceride (VLDL-TG) synthesis or
secretion and
2) enhances TG clearance from
circulating VLDL particles
Extensive study has shown that EPA reduces
TG synthesis or secretion by decreasing
lipogenesis, increasing
β
-oxidation of fatty acids, and increasing degr
adation of apoB-
100.
9
EPA also accelerates TG clearance by increasing lipoprotein lipase (LPL) activity
which promotes remova
l of TG from VLDL.
The treatment groups were well balanced with respect to demographics and baseline
characteristics in the ANCHOR study
n total, 2309 patients were screened, of
which 702 patients were assigned randomly to
double-blind treatment and 1607
patients discontinued prior
to randomization (see
figure below). The most common reason fo
r pre-randomization
discontinuation was
failure to satisfy inclusion/exclusion criter
ia for the study.
Y el quid del meollo
Objetivo principal: triglicéridos
La modificación porcentual media de triglicéridos desde el inicio al punto final (semana 12) fue del -18% para el grupo de 4 g de Vascespa, -6% para el grupo de 2 g de Vacespa y +6% para el grupo de placebo. La media de diferencia entre el grupo de 4 g y el placebo es del -22% (p>0,0001) y entre el grupo de 2 g y el pacebo -10% (p=0,005).
Objetivo secundario: colesterol de las LDL
Media de la diferencia entre el grupo de 4 g y el placebo = -6,2% (p=0,0067)
Media de la diferencia entre el grupo de 2 g y el placebo = -3,6% (p=0,0867)
Para los grupos de 4 g y 2g de Vacespa, el límit superior del intervalo de confianza al 97,5% (97,5% CI) fue de <6% (-1,7 y 0,5 respectivamente), lo que indica que las dosis no fueron infeiores al placebo. Además, el grupo de 4 g de Vascepa para el colessteorl LDL demostró ser superior al grupo con placebo.
Colesterol no HDL
Media de la diferencia en el colesterol no HDL con 4 g Vacespa = -5,0% (desde inicio a punto final en la semana 12)
Media de la diferencia en el colesterol no HDL con 2g Vacespa = +2,4% (p=0,0867) (desde inicio a punto final en la semana 12)
Media de la diferencia en el colesterol no HDL con placebo = +9,8%
Media de la diferencia entre el grupo de 4 g y el placebo para colesterol no HDL = -13,6% (p ajustado=0,0001)
Media de la diferencia entre el grupo de 2 g y el placebo para colesterol no HDL = -5,5% (p ajustado=0,0140)
Colesterol VLDL
Media de la diferencia en el colesterol VLDL con 4 g Vacespa = -12,1% (desde inicio a punto final en la semana 12)
Media de la diferencia en el colesterol VLDL con 2g Vacespa = +1,6% (desde inicio a punto final en la semana 12)
Media de la diferencia en el colesterol VLDL con placebo = +15% (desde inicio a punto final en la semana 12)
Media de la diferencia entre el grupo de 4 g y el placebo para colesterol VLDL = -24,4% (p ajustado=0,0001)
Media de la diferencia entre el grupo de 2 g y el placebo para colesterol VLDL = -10,5% (p ajustado=0,0170)
Colesterol HDL
Media de la diferencia en el colesterol HDL con 4 g Vacespa = -1,0% (desde inicio a punto final en la semana 12)
Media de la diferencia en el colesterol HDL con 2 g Vacespa = +0,0% (desde inicio a punto final en la semana 12)
Media de la diferencia en el colesterol HDL con placebo = +4,8%
Media de la diferencia entre el grupo de 4 g y el placebo para colesterol HDL = -4,5% (p ajustado=0,0013)
Media de la diferencia entre el grupo de 2 g y el placebo para colesterol HDL = -2,2% (p ajustado=0,1265)
The indication for Vascepa is for
treatment of very high TG, >
500 mg/dL. Patients with
very high TG have a strong genetic component
to their disease and have an increased
risk for acute pancreatitis. Therefore, the pr
imary goal for therapy is to lower TG to
prevent this complication. Therapy is consid
ered to be successful if TG is lowered to
<500 mg/dL; often it is not possible
to normalize TG in these patients.
11
Methods recommended by the NCEP ATPIII to
reduce the risk of acute pancreatitis
include discontinuation of drugs
that raise TG, very low-fat
diets, and TG-lowering drugs
such as fibrates or nicotinic acid. The NCEP guidelines also state that omega-3 fatty
acids are alternatives to fibrates or
nicotinic acid for the treatment of
hypertriglyceridemia, particularly chyomicronemia.
Numerous studies have shown that both
the major omega-3 FA, EPA and DHA, lower
serum TG levels, but a study comparing the effects of EPA monotherapy to DHA
monotherapy showed that DHA consistently
had a more pronounced TG-lowering effect
than EPA across all baseline concentrations of TG. This study also showed that DHA
may be responsible for an increase in HDL-C whereas EPA may produce a small
decrease in TC.
12
Thus EPA and DHA have differ
ential effects on lipoprotein
metabolism.
All individual SAEs occurred infrequently. The complete study
report for the MARINE and ANCHOR trials were searched for additional cases of
coronary artery disease, non-cardiac chest pain and subarachnoid hemorrhage and none
were found. In addition to the two SAEs of subarachnoid hemorrhage, a search of the
literature elicited no reports of subarachnoi
d hemorrhage in patients taking fish oil
products.
In a systematic review by Desai et al,
the potential interactions between dietary
supplements and anti-platelet drugs were
evaluated. Effects on bleeding time were
evaluated with the combinati
on of omega-3 FA and acetylsa
licylic acid. Compared to
baseline, significant increase (p<0.05) in
bleeding time of
13-42% and 55-82% were
observed with omega-3 FA alone or in co
mbination with acetylsalicylic acid,
respectively. In three trials the additiona
l 19-44% increases in bleeding time with
combination therapy over acetylsalicylic ac
id were significant (p<0.05). The studies
evaluated in the review were conducted wi
th treatment durati
ons of omega-3 FA and
acetylsalicylic acid between 2 and 25 weeks.
20
Harris (2007) summarized clinical trials
with omega-3 FA and findings related to
bleeding complications (see tabl
e below). According to that
author, the risk for clinically
significant bleeding is “v
irtually nonexistent”.
Bleeding-Related AEs Identifi
ed in the Safety Dataset
The following table presents the incidence of pat
ients with TEAEs that may be related to
bleeding or bruising (as identified by the
sponsor) in the CNS, Hypertriglyceridemia
Placebo-controlled integrated
datasets, and in the Overall AMR101 Integrated Dataset.
The CNS and hypertriglyceridemia dataset
includes TEAEs that occurred during double-
blind treatment, and the Overall AMR101 in
tegrated dataset includes TEAEs that
occurred during both double-bl
ind and open-label treatment
during these studies.
Bleeding-Related AEs Identifi
ed in the Safety Dataset
The following table presents the incidence of pat
ients with TEAEs that may be related to
bleeding or bruising (as identified by the
sponsor) in the CNS, Hypertriglyceridemia
Placebo-controlled integrated
datasets, and in the Overall AMR101 Integrated Dataset.
The CNS and hypertriglyceridemia dataset
includes TEAEs that occurred during double-
blind treatment, and the Overall AMR101 in
tegrated dataset includes TEAEs that
occurred during both double-bl
ind and open-label treatment
during these studies.
Bleeding-Related AEs Identifi
ed in the Safety Dataset
The following table presents the incidence of pat
ients with TEAEs that may be related to
bleeding or bruising (as identified by the
sponsor) in the CNS, Hypertriglyceridemia
Placebo-controlled integrated
datasets, and in the Overall AMR101 Integrated Dataset.
The CNS and hypertriglyceridemia dataset
includes TEAEs that occurred during double-
blind treatment, and the Overall AMR101 in
tegrated dataset includes TEAEs that
occurred during both double-bl
ind and open-label treatment
during these studies.
Clinical Review
Iffat Nasrin Chowdhury, MD
NDA 202057
Vascepa/Icosapent Ethyl
109
Source: ISS, Table 7-14, pg. 85.
In the Hypertriglyceridemia, Placebo-Controlled dataset, there were 3.4% bleeding-
related TEAEs in patients on Vascepa compar
ed to 1.9% of patients on Placebo. The
percentage of bleeding-related TEAEs was si
milar for patients on Vascepa (2.5%) as
compared to Placebo (2.5%) in the CNS
Placebo-Controlled Integrated Dataset.
This reviewer reviewed the narratives of
the six cases of subdur
al hematoma, subdural
hemorrhage, and subarachnoid hemo
rrhage reported in the NDA.
There is no definitive answer as to whether omega-3 FA increases
the risk for bleeding. Regulatory recommendations with Vascepa and concomitant
anticoagulants should convey caution.
Liver enzymes
There were numerically more patients on Vasc
epa with mild elevations of ALT (up to
2XULN) than Placebo, 12.8% vs. 10.3%, re
spectively. The elevations seemed to be
dose-related with more patients on Vascepa 4g (14.4%) with elevated ALT than
Vascepa 2g (11.3%
The applicant conducted analyses of TEAEs by
patients receiving concomitant statins
compared to those not receiving concomit
ant statins for the
Hypertriglyceridemia
Placebo-Controlled Integrat
ed Dataset. A total of 481 patients received concomitant
statin treatment with Vasc
epa treatment in this populati
on, and 141 patients did not
receive concomitant statin treatment. T
he incidence of patients reporting TEAEs was
greater in patients receiving
concomitant statins (47.6%) co
mpared to those not taking
concomitant statins (39.7%).
The overall AE profile was
generally similar for these
groups
CArcinogenicidad
Reviewer Comment: Although female rats in the high dose group (exposure margin 7X
the 4g/day clinical dose) had increased incidence of combined hemangiomas/
hemangiosarcomas at the mesenteric lymph node, the incidence of these vascular
tumors at all anatomical sites combined was not statistically significant. Additionally,
male rats did not exhibit an imbalance in vascular tumors at any anatomical site. These
findings combined with the lack of imbalance in vascular tumors in mice suggest that the
finding of increased hemangiomas/ hemangiosarcomas is of limited clinical significance.
Previous studies have demonstrated that t
he generation of reacti
ve oxygen species and
an excessive inflammatory reaction are in
volved in the progression of neural damage
following brain ischemia. In this study,
we focused on the anti-inflammatory and
antioxidant properties of eicosapentaenoic
acid (EPA). EPA treatment significantly inhibited DNA
oxidative damage (P < .05) and accumulation
of Iba1-positive cells in the CA1 area at
12 and 72 hours after the induction of isc
hemia, and also decreased apoptotic neurons
and neuronal death (P < .001) at 72 hour
s after ischemia. EPA treatment also
significantly improved memo
ry function (P < .05). T
hese findings suggest that EPA
inhibits the inflammatory reaction and oxi
dative damage occurring after ischemic brain
injury, and also may contribute to t
he prevention of neural damage and memory
impairment following such injury.
Advisory Committee Meeting
An Advisory Committee meeting was not cons
idered necessary given that there were
no major safety issues identified with Vascepa.
Assessment
From a clinical standpoint, the NDA is fil
eable, but pharmacology-toxicology team has a
Refuse-to-File Issue. Specifically, ph
arm-tox does not have adequate bridging
information (for reproductive t
oxicology) to Epadel to support
the 505(b)(2) application.
Pues ya lo tengo bastante claro. Les "aceptan" los datos de Lovaza, pero tienen que justificar que puede aplicarse la equivalencia entre japos y estadounidenses.
Sea o no fácil de demostrar, para mí esto tiene la implicación negativa de que no han seguido las órdenes de la FDA. Y, aunque todo esté bien, aquí lo importante es la presentación correcta del papeleo. Y en el informe se insisten en varios lugares en que se les ha avisado y comenta también explícitamente que la hipercolesterolemia es hereditaria, que ya existen fármacos para tratarla y que lo más preocupante es la pancreatitis relacionada. Y además, tienen al equipo de toxicidad en contra.
