From Alzheimer’s to Zebrafish: Eclectic Science and Regulatory Stories 36
of biologically active proteins, is extremely toxic.13 There is no antivenin preparation for
bites from a Gila monster. Exendin-4 is a 39 amino acid peptide produced in the salivary
gland of H. suspectum.14 It induces insulin release through activation of the glucagon-like
peptide-1(GLP-1).
New Drugs
Ziconotide
The initial research involved in discovering ziconotide began in the early 1970s, when
Baldomero Olivera returned to the Philippines to set up a laboratory. During his postdoc-
toral work, Olivera had helped to isolate and purify DNA ligase, an enzyme that joins
pieces of DNA. Because he was a shell collector, he wondered whether poisonous cone
snails might contain molecules that could block nerve channels. His research led to a
growing recognition of the diversity of cone snails and their toxins. It has been estimated
that at least 50,000 peptides are produced by 500 species.15 Dr. Olivera’s work was of inter-
est to George Miljanich, then a biochemist at the University of Southern California. Dr.
Miljanich had done research on the function of different molecular pathways that send
chemical signals to nervous system receptors. The impetus for his work was a grant from
the National Institutes of Health for developing cone snail toxins as probes to determine
the roles of various calcium channel types in this chemical signaling process. After joining
the small biotech company, Neurex, Dr. Miljanich persuaded colleagues to undertake the
synthesis of omega-conopeptides, toxins that block calcium channels.
As mentioned earlier, ziconotide is the first selective N-type voltage sensitive cal-
cium channel (VSCCs) blocking agent used in medicine.16 (Calcium ion influx into nerve
terminals through voltage-sensitive calcium channels is the trigger that initiates neu-
rotransmitter release.) Ziconotide is indicated for the management of severe chronic pain
in patients for whom intrathecal (IT) therapy is warranted, and who are intolerant of
or refractory to such other treatment as systemic analgesics, adjunctive therapies or IT
morphine. The drug must be administered intrathecally to maximize antinociception (lack
of perception to traumatic stimuli or pain) and minimize sympatholysis. (Sympatholysis
is inhibition of adrenergic nerve activity that, among other things, is needed to maintain
blood pressure.) There is no evidence of tolerance to ziconotide or of addictive behavior in
animals treated with it.17 Ziconotide is a 25 amino acid, polybasic peptide containing three
disulfide bridges with a molecular weight of 2639 daltons.
In experimental studies of absorption, distribution, metabolism and elimination,
intravenous ziconotide appeared and diminished rapidly in plasma and resulted in rela-
tively little plasma protein binding. Intravenous ziconotide was degraded in animal brain
tissue in two to 24 hours, producing no detectable intermediates. Intrathecal ziconotide
was cleared less quickly from the cerebrospinal fluid with a clearance similar to that of
bulk CSF. This clearance rate likely means that the drug’s distribution through the CSF
is rapid and that the drug is cleared, not by metabolism, but by bulk flow of CSF into the
circulation, where it is rapidly degraded.
Ziconotide is administered through appropriate programmable microinfusion pumps
that can be either implanted or external, releasing the drug into the fluid surrounding the
spinal cord. Dosage is initiated at no more than 2.4 mcg/day (0.1 mcg/hour) and titrated
to the patient’s response. Doses may be titrated upward by up to 2.4 mcg/day (0.1 mcg/
hr) at intervals of no more than two to three times a week.
FDA approval was based upon the treatment of more than 1,200 patients and three
Phase 3, pivotal clinical trials, which evaluated the efficacy and safety in patients with severe
chronic pain that was not adequately managed by a regimen of systemic and IT analgesics or
other drugs. These trials involved a variety of patient populations, including patients with
pain related to cancer, AIDS, failed back surgery and other non-malignant causes.18,19
of biologically active proteins, is extremely toxic.13 There is no antivenin preparation for
bites from a Gila monster. Exendin-4 is a 39 amino acid peptide produced in the salivary
gland of H. suspectum.14 It induces insulin release through activation of the glucagon-like
peptide-1(GLP-1).
New Drugs
Ziconotide
The initial research involved in discovering ziconotide began in the early 1970s, when
Baldomero Olivera returned to the Philippines to set up a laboratory. During his postdoc-
toral work, Olivera had helped to isolate and purify DNA ligase, an enzyme that joins
pieces of DNA. Because he was a shell collector, he wondered whether poisonous cone
snails might contain molecules that could block nerve channels. His research led to a
growing recognition of the diversity of cone snails and their toxins. It has been estimated
that at least 50,000 peptides are produced by 500 species.15 Dr. Olivera’s work was of inter-
est to George Miljanich, then a biochemist at the University of Southern California. Dr.
Miljanich had done research on the function of different molecular pathways that send
chemical signals to nervous system receptors. The impetus for his work was a grant from
the National Institutes of Health for developing cone snail toxins as probes to determine
the roles of various calcium channel types in this chemical signaling process. After joining
the small biotech company, Neurex, Dr. Miljanich persuaded colleagues to undertake the
synthesis of omega-conopeptides, toxins that block calcium channels.
As mentioned earlier, ziconotide is the first selective N-type voltage sensitive cal-
cium channel (VSCCs) blocking agent used in medicine.16 (Calcium ion influx into nerve
terminals through voltage-sensitive calcium channels is the trigger that initiates neu-
rotransmitter release.) Ziconotide is indicated for the management of severe chronic pain
in patients for whom intrathecal (IT) therapy is warranted, and who are intolerant of
or refractory to such other treatment as systemic analgesics, adjunctive therapies or IT
morphine. The drug must be administered intrathecally to maximize antinociception (lack
of perception to traumatic stimuli or pain) and minimize sympatholysis. (Sympatholysis
is inhibition of adrenergic nerve activity that, among other things, is needed to maintain
blood pressure.) There is no evidence of tolerance to ziconotide or of addictive behavior in
animals treated with it.17 Ziconotide is a 25 amino acid, polybasic peptide containing three
disulfide bridges with a molecular weight of 2639 daltons.
In experimental studies of absorption, distribution, metabolism and elimination,
intravenous ziconotide appeared and diminished rapidly in plasma and resulted in rela-
tively little plasma protein binding. Intravenous ziconotide was degraded in animal brain
tissue in two to 24 hours, producing no detectable intermediates. Intrathecal ziconotide
was cleared less quickly from the cerebrospinal fluid with a clearance similar to that of
bulk CSF. This clearance rate likely means that the drug’s distribution through the CSF
is rapid and that the drug is cleared, not by metabolism, but by bulk flow of CSF into the
circulation, where it is rapidly degraded.
Ziconotide is administered through appropriate programmable microinfusion pumps
that can be either implanted or external, releasing the drug into the fluid surrounding the
spinal cord. Dosage is initiated at no more than 2.4 mcg/day (0.1 mcg/hour) and titrated
to the patient’s response. Doses may be titrated upward by up to 2.4 mcg/day (0.1 mcg/
hr) at intervals of no more than two to three times a week.
FDA approval was based upon the treatment of more than 1,200 patients and three
Phase 3, pivotal clinical trials, which evaluated the efficacy and safety in patients with severe
chronic pain that was not adequately managed by a regimen of systemic and IT analgesics or
other drugs. These trials involved a variety of patient populations, including patients with
pain related to cancer, AIDS, failed back surgery and other non-malignant causes.18,19