Source:    Askthedoctor mailinglist
Date:        April 12, 2002

Are Drug Companies Evil?
by Dr. Abe Lieberman

In an E-mail dated 4/9/02 Will Johnnston APDA Chapter President from
Salisbury MD questioned my ethics and those of the Drug Companies. Among
other statements he made in a letter to a Dr. Jorge Romero he said:
It should be mentioned that Pharmacia (the makers of pramipexole) also
produce cabergoline which is marketed as a PD drug in Europe as Cabaser
and has been considered to be about equal to Mirapex, Requip, or Permax.
Cabergoline is a favorite in Europe because it is a "one pill a day"
medicine rather than a "three pill a day" like Mirapex. It is also less
expensive than Mirapex and similar drugs. It is available in the US from
Pharmacia as Dostinex It is approved by the FDA for the treatment of
hyperprolactinemia (excess milk production in post-partum women) and is
priced extremely high, eight 0.5 mg tablets a month supply for $235. At
this price the cost for its use in this country for PD, 0.5 mg to 6 mg a
day would be at least $1000 per month

Dr. Romero replied:

You are absolutely right about cabergoline. It is a better drug. However
it would not be wise of Pharmacia to market it for PD in the US to compete
with their own drug, pramipexole. They probably want to milk pramipexole
for all it’s worth before trying to bring in cabergoline The current
excuse is that cabergoline is not approved by the FDA. The question is
whether Pharamica is seeking approval for PD. All indications are that
they are not. It’s wonderful to have well informed people like you.

I believe I’m better informed about cabergoline and pramipexole (Mirapex)
than either Dr. Romero or Mr. Will Johnnston. My colleagues and I
performed the first multi-center double blind trial of cabergoline in the
world! See the summary below. I was a founding member of the subsequent
Cabergoline Study Group. I’ve probably had as much or more experience
studying and using cabergoline than anyone.

I was the lead author for the first large multi-center trial of
pramipexole (Mirapex). See the summary below. I’ve probably had as much or
more experience studying and using pramipexole than anyone.

As there are no double-blind randomized trials comparing cabergoline and
pramipexole definitive statements, such as Dr. Romero’s, as to which is
the better drug cannot be made. I have had patients who were on
cabergoline and subsequently were on pramipexole. And I have had patients
who were on pramipexole and were subsequently on cabergoline. In my
opinion, I consider pramipexole a better drug. It is as effective as
cabergoline in reducing "wearing off" but in addition it has a better
effect on tremor. And in many patients it has an anti-depressant effect.
Cabergoline has a longer half-life in the blood but this does not
necessarily translate into a longer effect in the brain. Many PD patients
need at least 2 doses a day. In addition when side effects such as
hallucinations, confusion, paranoia and agitation occur they take longer,
much longer to clear on cabergoline than pramipexole.

Pharmacia developed cabergoline. Upjohn and Boehringer (another drug
company) developed pramipexole. When Pharmacia merged with Upjohn,
Pharmacia had a choice as to which drug, cabergoline or pramipexole, it
should continue to study and bring to market. Pharmacia Upjohn consulted
with several PD specialists including myself. They asked which was the
better drug. The answer, almost uniformly was pramipexole. In addition
Upjohn had information, from animal studies, that pramipexole might slow
the progression of PD. No such information was available for cabergoline.
This was the basis for choosing pramipexole and not cabergoline.

Regarding economics. It costs, in the US, approximately $200,000,000 to
$500,000,000 to bring a drug from development in the laboratory to FDA
approval. The cost is smaller in "niche" or "orphan" markets such as
hyper-prolactinemia. If the cost were not smaller there would be no drugs
for such conditions. PD is not a "niche" or "orphan" market. It is too
large to be an "orphan" and too small to be a "blockbuster." If you were a
CEO of a drug company and you had an opportunity to develop a drug for PD
with a total market, for all PD drugs, world-wide, of $750,000,000 or a
drug for arthritis, with a market of $10,000,000,000, a 13 times greater
market for the same drug development cost, which would you develop? The
next time you wonder why there aren’t more drugs for PD, think about
markets. For Pharmacia to bring cabergoline to market as a PD drug, as Dr.
Romero suggests, would cost about $200,000,000. The market for PD will not
support two drugs, fairly similar, by the same company. Better to invest
the money in research. To it’s credit Pharmacia is investing in PD
research. Pharmacia choose pramipexole because it was at least as good as
cabergoline. Plus there was evidence to think it might also slow
progression.

When Pharmacia merged with Upjohn and decided to market pramipexole it had
to share the profits with Boehringer, pramipexole’s co-developer. If it
choose to market cabergoline it would NOT have had to share the profits
with anyone. The economics favor marketing cabergoline. Nonetheless, Dr.
Romero says,

They (Pharmacia) probably want to milk pramipexole for all it’s worth
before trying to bring in cabergoline.

Dr Romero does not mention that when pramipexole’s patent expires and
cheaper generic versions are available, cabergoline’s patent will also
have expired and cheaper generics will be available. In effect there will
be no one to "milk."

PD is a chronic, progressive, debilitating disease and I wish we had a
cure. In lieu of a cure we have drugs that effectively treat many of PD’s
disabling symptoms. We would like a benevolent government to develop drugs
and distribute them free of charge. The last benevolent government that
promised to do so was the late Soviet Union. We would like drugs to be
cheaper. But we demand drugs be absolutely safe. And, if they’re not we
sue. Law suits, and the threat of law suits, drive up insurance costs, and
drive up the price of each drug we take.

I practiced PD before there were effective drugs: and it was BAD.
Patients, in a short period of time became rigid, bed bound and died Then,
patients would have given their life’s savings for the drugs we now take
for granted. I took the time and made the effort to write this because I
am on the side of PD patients. And I needed to remind you and especially
Mr. Johnnston and Dr. Romero that so are the drug companies.


The following article appeared in Neurology volume 49, 1997. It was
shortened by Dr. Lieberman the author of the article.

Clinical evaluation of pramipexole in advanced Parkinson's disease:
Results of a double-blind, placebo-controlled, parallel-group study
A Lieberman, A Ranhosky and D Korts

Abstract
We compared the efficacy, safety, a tolerability of pramipexole, and a
dopamine agonist with novel properties, with those of placebo in advanced
PD patients with motor fluctuations under levodopa treatment. Pramipexole
improved motor function of patients during "on" and "off" periods,
decreased the time spent in "off" periods, reduced the severity of "off"
periods, decreased disability and PD severity during "on" and "off"
periods, as assessed by the Unified Parkinson Disease Rating Scale, and
permitted a reduction in levodopa dosage.

Adverse effects related to the central nervous system were similar to
those reported with other dopamine agonists, and the gastrointestinal and
cardiovascular tolerability of the compound was satisfactory.

Discussion
Pramipexole is a dopamine agonist with novel properties. It acts as a full
agonist on the D2 receptor family with preferential affinity to the D3
family. These properties suggest its utility in Parkinson’s disease (PD).

We studied pramipexole pharmacokinetics, efficacy, safety and tolerability
for 9 weeks in 55 patients with early PD who were not previously treated
with levodopa. Pharmacokinetic data are reported separately.

In the earlier study, the 28 de novo PD patients receiving pramipexole
experienced a significant 140% improvement from baseline on the Unified
Parkinson Disease Rating Scale (UPDRS) Activities of Daily Living (ADL)
Scale and a non significant improvement on the UPDRS Motor Examination
over the 27 patients receiving placebo.

The present study demonstrates that pramipexole, when administered
concurrently with levodopa, improves patients with advanced PD and
levodopa-induced motor fluctuations. Compared with placebo, pramipexole,
administered at a maximal daily dosage of 4.5 mg, improved activities of
daily living of patients with advanced PD, as determined by Part II of the
UPDRS assessed in the "off" and "on" periods.

Compared with placebo, pramipexole patients were improved as determined by
the UPDRS Motor Evaluation assessed in the "on" period. Pramipexole
decreased the time patients spent in the "of" period and the severity of
the "off" period; it decreased disability as determined by the
Schwab-England Scale in the "off" and "on" periods; and it decreased PD
severity as determined by the Hoehn and Yahr Scale in the "off" and "on"
periods. Individual motor signs that improved most were resting tremor,
rigidity and limb bradykinesia. The addition of pramipexole resulted in a
27% reduction in the dosage of levodopa.

The magnitude of improvement in ADL (21%), motor evaluation (25%), and
time in the "off" period (31%) compared favorably with that of other
dopamine agonists such as bromocriptine, pergolide, and cabergoline in
patients with advanced PD. CNS adverse events were similar to those
previously reported with bromocriptine, pergolide, and cabergoline,
whereas gastrointestinal and cardiovascular adverse events were less
frequent.

This study included more patients and centers and used more efficacy
measures than previous studies that evaluated dopamine agonists. In
addition, this study, more than others, attempted to correct for
differences among centers and observers.

Based on the results of this study and the previous study in de novo
patients, pramipexole is an effective and safe treatment for all stages of
PD from early to advanced, can be used alone or in combination with
levodopa and appears to be as effective as bromocriptine, pergolide, and
cabergoline.

The major difference between pramipexole and other dopamine agonists may
reside in pramipexole’s ability to bind with and activate D3 receptors in
the striatum and limbic region. A mood disorder, distinct from depression
and characterized by anxiety, decreased attention span, apathy and/or
anhedonia, affects many PD patients. Unlike PD patients with true clinical
depression, patients with this mood disorder may not complain of guilt,
remorse or sadness and they may not respond to antidepressant. In this
study, many of the investigators commented on the decreased anxiety,
enhanced attention span, and decreased apathy among patients treated with
pramipexole. These observations may reflect investigators’ optimism.
However, these observations will have to be validated by further studies.
The possibility that pramipexole may offer a window into the mood
disorders of PD is provocative.


The following article appeared in "Neurology" volume 43 1993. It was
shortened by Dr. Lieberman the author of the article.

Multicenter study of cabergoline, a long-acting dopamine receptor agonist,
in Parkinson's disease patients with fluctuating responses to
levodopa/carbidopa

A Lieberman, S Imke, M Muenter, K Wheeler, JE Ahlskog, JY Matsumoto, DM
Maraganore, KF Wright and J Schoenfelder

Abstract
We administered cabergoline, a potent, once-a-day dopamine against, to 61
Patients with advanced Parkinson's disease (PD) and response
fluctuations--"wearing-off"--"On-off" phenomena. The patients were on stable
doses of levodopa/carbidopa. During the first 5 weeks, patients were
randomized to allow equal numbers to end titration at each of five daily
doses of cabergoline from 0.5 to 2.5 mg. We evaluated the patients using the
Unified Parkinson's Disease Rating Scale (UPDRS) and diaries of motor
performance. This part of the study was double-blinded.

After 5 weeks, the mean Activities of Daily Living (ADL) score on the
UPDRS significantly decreased by 22% the mean Motor Score in the "off"
period significantly decreased by 14% (p< 0.0001), and the mean Motor Score
in the "on" period significantly decreased by 22%. The mean percent "off"
time decreased by 9.0%.

Twenty-three patients (38%) achieved at least a 25% improvement in the
combined ADL and motor examination of the UPDRS. 4 patients dropped out
because of adverse effects. We treated 37 patients, including some
patients who had experienced a transient 25% improvement, for an
additional 8 weeks in an open manner until they achieved a 25% improvement
or reached a maximum of 5 mg/d. The other patients were continued in a
double-blind manner on the dose of cabergoline they had achieved at the
end of week 5. At the end of 13 weeks, the group of 37 patients achieved
additional significant improvements in mean ADL and mean motor scores in
the "on" and "off" periods. The percent time "off" decreased by 31%. This
change was significant. Cabergoline is an effective dopamine agonist,
which, because it is easy to administer, is especially useful for patients
with PD and response fluctuations.

Discussion
Cabergoline, like bromocriptine, lisuride, and pergolide, is an ergoline
derivative and dopamine agonist relatively specific for the D2-receptor.
Cabergoline is longer acting than bromocroptine, lisuride, or pergolide.
Plasma activity peaks between 0.5 and 4 hours with an elimination
half-life of about 65 hours. By comparison, bromocriptine peaks at 1.2
hours and has an elimination half-life of 3.0 hours.

Initially, the antiparkinson activity of cabergoline was demonstrated in
an open, dose-ranging study in Italy. 22 patients with PD took cabergoline
once a day starting at 0.75 mg with escalation at weekly intervals to a
maximum of 2.0 mg/day. Improvement, defined as a 25% reduction in score on
the PD rating scale, occurred in 19 patients. Three patients withdrew from
the study because of lack of efficacy and two because of adverse effects
(a toxic psychosis in one and orthostatic hypotension in the other).

Our objective in this study was to assess the efficacy of increasing doses
of cabergoline and to confirm the previous open study.

Cabergoline is a safe and effective dopamine agonist. During the 5-week
double-blind treatment period, the 61 patients achieved a 22% improvement
in ADL scores, a 14% improvement in "off" period motor scores, and a 22%
improvement in "on" period motor scores. All of the changes were
significant. 23 of 61 patients (39%) achieved a 25% improvement by the end
of the 5-week double phase, and they continued on stable doses of
cabergoline in a blind manner during the next 8 weeks. 32 patients were
treated with increasing doses of cabergoline during the next 8 weeks. Five
patients dropped out of the study.

After 13 weeks, the 61 patients achieved a 35% improvement in ADL, a 17%
improvement in "off" score, a 24% improvement in "on" score and a 31%
decrease in hours "off." All of the changes were significant. The dose of
levodopa was reduced by 12%.

Four patients dropped out because of adverse effects, and in only two of
them could the adverse effects be definitively attributed to cabergoline.
These results are comparable with those of similar to studies of
bromocriptine, lisuride and pergolide except that cabergoline is easier to
administer and better tolerated with fewer patients dropping out because
of adverse effects.

Our results are less than those of an open study of 36 patients on a
higher dose of cabergoline (mean, 12.4 + 4.3 mg) are. In that study, the
severity of the "off" periods was reduced by 53%, the severity of the "on"
periods was reduced by 43% and the duration of the "off" periods was
reduced by 82%. The dose of levodopa was reduced by 38%. The duration of
the study was 14.2 months (range 7 to 35 months).

Our results are comparable with those of Hutton and colleagues who studied
25 patients. They began cabergoline, double blind, at 0.5 mg/d and
escalated the dose weekly to 2.5 mg/d. Patients improved significantly in
ADL and in "on" and "off" motor scores of the UPDRS. There were no serious
adverse effects.

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