Mipomersen
Encyclopedia
Mipomersen is a cholesterol-reducing drug
candidate. It is an antisense therapeutic
that targets the messenger RNA
for apolipoprotein B
. It is administered as a weekly injection.
linkages rather than the phosphodiester linkages of RNA and DNA, and the sugar parts are deoxyribose
in the middle part of the molecule and 2'-O-methoxyethyl-modified ribose at the two ends. These exotic sugars make the drug resistant to degradation by nucleases, allowing it to be administered weekly. The drug accumulates in the liver
, which is convenient since apolipoprotein B predominantly acts there.
Mipomersen completed two separate phase-3 trials with two more Phase 3 trials to be presented in mid-2010.
The two completed Phase 3 trials were in patients with familial hypercholesterolemia
(FH), both homozygous (ho) and heterozygous (he). FH is a genetic disorder that causes exceptionally high levels of low-density lipoprotein cholesterol
. Both trials showed exceptional performance with the highest efficacy seen so far in those two patient populations, and with relatively low drop-out rates compared to other injectable drugs. Both of these trials also demonstrated the continued manageable safety and tolerability profile of mipomersen.
The remaining Phase 3 studies are due to be presented shortly (mid-2010) and include patients at high risk (HR) or who are severe hypercholesterolemic (SH). While the expectation is that the severe SH population is closer to the hoFH popualtion, the HR population perceives itself to be at lower risk and could benefit from the drug subsequently, under less stringent rules than a planned clinical trial. The efficacy for both of these trials is expected to be comparable to what has been seen so far in other trials. Also, no new severe adverse events (SAEs) have been observed in the un-blinded Phase 3 trials and none are expected in the rest of the Phase 3 program.
August 2010: Third and forth phase 3 trials were stated to have met primary and secondary endpoints.
Genzyme plans to file for the first indication in the first half of 2011 in both the US and EU for hoFH & SH. Subsequently Genzyme plans on filing in the EU only for heFH as the FDA is requesting an outcome study be performed for any indication beyons the first.
Mipomersen is a synthetic molecule and launch quantities will be manufactured by Isis at their Carlsbad manufacturing facilities, and fill & finish will be performed at a third party facility.
In addition to the Phase 3 program, mipomersen is being tested in statin
-intolerant patients in a Phase 2 study and alternative dosing regimens of mipomersen are being tested in Phase 1 studies. The alternative dosing regimen studies are to address long term patient and physician convenience for administering the drug. The drug, when approved, will be provided in a small size needle syringe and can be self-injected by patients. The needle is only one gauge larger than that of insulin making it possibly acceptable and tolerable from the patient's perspective by decreasing the pain of injection. The inconvenience factor of injecting the medication, as opposed to swallowing a pill will likely factor in potentially treating high and moderate risk populations.
Hypolipidemic agent
Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. They are called lipid-lowering drugs or agents.- Classes of hypolipidemic drugs :...
candidate. It is an antisense therapeutic
Antisense therapy
Antisense therapy is a form of treatment for genetic disorders or infections.When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nuc acid that will bind to the messenger RNA produced by that gene and inactivate...
that targets the messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
for apolipoprotein B
Apolipoprotein B
Apolipoprotein B is the primary apolipoprotein of low-density lipoproteins , which is responsible for carrying cholesterol to tissues. While it is unclear exactly what functional role APOB plays in LDL, it is the primary apolipoprotein component and is absolutely required for its formation...
. It is administered as a weekly injection.
Structure
The compound is a 'second-generation' antisense oligonucleotide; the nucleotides are linked with phosphorothioateThiophosphate
A thiophosphate is a family of compounds and anions with the general chemical formula PS4-xOx3- . The state of protonation is usually not specified. They could be bound to as many as three protons for the neutral H3PS4-xOx species. Two protons correspond to the related monoanions, and one...
linkages rather than the phosphodiester linkages of RNA and DNA, and the sugar parts are deoxyribose
Deoxyribose
Deoxyribose, more, precisely 2-deoxyribose, is a monosaccharide with idealized formula H---3-H. Its name indicates that it is a deoxy sugar, meaning that it is derived from the sugar ribose by loss of an oxygen atom...
in the middle part of the molecule and 2'-O-methoxyethyl-modified ribose at the two ends. These exotic sugars make the drug resistant to degradation by nucleases, allowing it to be administered weekly. The drug accumulates in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, which is convenient since apolipoprotein B predominantly acts there.
Clinical development
The drug was discovered and developed to Phase 2 POC by ISIS Pharmaceuticals and subsequently licensed to Genzyme Corporation in an auction-style licensing bid. Isis earned an upfront payment of $325 million, with payments of a further $825 million if certain mileestones are met. The licensing deal closed in June 2008.Mipomersen completed two separate phase-3 trials with two more Phase 3 trials to be presented in mid-2010.
The two completed Phase 3 trials were in patients with familial hypercholesterolemia
Familial hypercholesterolemia
Familial hypercholesterolemia is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein , in the blood and early cardiovascular disease...
(FH), both homozygous (ho) and heterozygous (he). FH is a genetic disorder that causes exceptionally high levels of low-density lipoprotein cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
. Both trials showed exceptional performance with the highest efficacy seen so far in those two patient populations, and with relatively low drop-out rates compared to other injectable drugs. Both of these trials also demonstrated the continued manageable safety and tolerability profile of mipomersen.
The remaining Phase 3 studies are due to be presented shortly (mid-2010) and include patients at high risk (HR) or who are severe hypercholesterolemic (SH). While the expectation is that the severe SH population is closer to the hoFH popualtion, the HR population perceives itself to be at lower risk and could benefit from the drug subsequently, under less stringent rules than a planned clinical trial. The efficacy for both of these trials is expected to be comparable to what has been seen so far in other trials. Also, no new severe adverse events (SAEs) have been observed in the un-blinded Phase 3 trials and none are expected in the rest of the Phase 3 program.
August 2010: Third and forth phase 3 trials were stated to have met primary and secondary endpoints.
Genzyme plans to file for the first indication in the first half of 2011 in both the US and EU for hoFH & SH. Subsequently Genzyme plans on filing in the EU only for heFH as the FDA is requesting an outcome study be performed for any indication beyons the first.
Mipomersen is a synthetic molecule and launch quantities will be manufactured by Isis at their Carlsbad manufacturing facilities, and fill & finish will be performed at a third party facility.
In addition to the Phase 3 program, mipomersen is being tested in statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
-intolerant patients in a Phase 2 study and alternative dosing regimens of mipomersen are being tested in Phase 1 studies. The alternative dosing regimen studies are to address long term patient and physician convenience for administering the drug. The drug, when approved, will be provided in a small size needle syringe and can be self-injected by patients. The needle is only one gauge larger than that of insulin making it possibly acceptable and tolerable from the patient's perspective by decreasing the pain of injection. The inconvenience factor of injecting the medication, as opposed to swallowing a pill will likely factor in potentially treating high and moderate risk populations.